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Longevity Library · Lab reference

Written by Daniel Tagge, MD
Updated October 10, 2026
Reviewed October 12, 2026
32 sources · Measured in µg/dL

System: Chronobiology

Morning cortisolSerum cortisol, 8 AM · Hydrocortisone (endogenous)

A morning serum cortisol is a screening test for adrenal insufficiency and little else: guidelines read a value below about 3 µg/dL as indicative of insufficiency, about 5 as suggestive when ACTH is measured with it, and above about 15 as likely excluding it (about 14 on newer specific assays), with everything in between settled by a stimulation test. It does not measure stress, it does not diagnose or exclude cortisol excess, and no outcome study ties a morning value inside the laboratory range to health; the cohorts that found risk measured the shape of the day (flatter slopes and higher evening values), urinary cortisol, or hair cortisol.

Cortisol is the adrenal glucocorticoid, released in pulses on a circadian rhythm that peaks around waking and bottoms out near midnight. Laboratories print about 6 to 23 µg/dL for a morning draw, lower on newer assays. The low end is well mapped by two Endocrine Society guidelines; the upper end and the middle are where the number is most over-read. The evidence that matters for long-term health is about the rhythm, not the morning point.

01 · The scale

Where the laboratory range and the evidence sit.

Risk did not sit at any morning value inside the range. In the Whitehall II cohort a flatter fall in cortisol across the day, not the morning level, predicted cardiovascular death; the highest tertile of 24-hour urinary cortisol carried five times the cardiovascular mortality in older Italians; high hair cortisol went with a history of cardiovascular disease and diabetes in older Dutch adults; and across 80 studies a flatter daily slope went with poorer health. At the low end, guideline thresholds for adrenal insufficiency are the only firm numbers.

051015202530

  1. Common laboratory morning range (assay-dependent; lower on newer assays)

    6 to 23 µg/dL · Typical US laboratories; Javorsky 2021

  2. Below about 3: adrenal insufficiency indicated; urgent with symptoms

    0 to 3 µg/dL · Fleseriu 2016

  3. Below about 5 with ACTH: insufficiency suggested; stimulation test

    3 to 5 µg/dL · Bornstein 2016

  4. Indeterminate for insufficiency: a stimulation test decides

    5 to 15 µg/dL · Fleseriu 2016; Gasco 2026

  5. Above about 15 (about 14 on newer assays): insufficiency likely excluded

    15 to 23 µg/dL · Fleseriu 2016; Javorsky 2021

  6. Above the range: not a diagnosis of excess; oral estrogen, acute stress and illness raise it

    23 and above µg/dL · Nieman 2008; Bornstein 2016

  • Laboratory range
  • Evidence supports
  • Guideline goal or unstudied
  • Higher risk in studies
Scale in µg/dL. Some laboratories report nmol/L; multiply µg/dL by about 27.6 for nmol/L. Bands show where studies found something, not a recommendation for any one person.

02 · What it is

What Morning cortisol measures.

Cortisol is made by the adrenal cortex under ACTH from the pituitary, which in turn answers to corticotropin-releasing hormone from the hypothalamus; the three together are the HPA axis, and the end product feeds back to restrain the axis. Secretion is not steady: glucocorticoids are released in pulses about every 60 to 90 minutes, riding on a 24-hour rhythm with a peak around the habitual sleep-wake transition and minimal levels in the evening and early night. A morning draw catches the hormone near its daily high, which is why the morning is the standard time to test for deficiency.1,2Grade A

The first 30 to 45 minutes after waking carry an extra rise on top of the circadian curve, the cortisol awakening response. In three studies totaling 152 children, adults and older people, salivary free cortisol rose by 50 to 75 percent within 30 minutes of waking; a later review put the rise at 50 to 160 percent, about 9 nmol/L in saliva on average, and found no agreed norms for the absolute values either at waking or 30 minutes later. An expert consensus from the International Society of Psychoneuroendocrinology treats the response as a research measure that depends on sampling at the moment of waking, not as a clinical test. The practical point for a blood draw: a cortisol taken 20 minutes after waking and one taken two hours after waking are different numbers from the same person.3,4,5Grade B

More than 90 percent of circulating cortisol is bound to protein, chiefly corticosteroid-binding globulin (CBG), and a serum cortisol measures the total, bound plus free. Anything that moves CBG moves the total without moving the free hormone the tissues see, which is the single most important reason a morning cortisol misleads: oral estrogen raises it, and the low albumin of critical illness lowers it. Saliva, urine and hair measure the free or cumulative fraction and are the tools the guidelines reach for when the question is excess rather than deficiency.6,7Grade A

03 · Origins

Where it came from, and where it sits in the network.

The receptor is older than the hormone. Cortisol and aldosterone both act through members of the steroid receptor family, and the 2006 resurrection of the ancestral corticoid receptor, the gene from which the glucocorticoid and mineralocorticoid receptors later split, showed that long before aldosterone existed the ancestral receptor already bound it, as a structural by-product of its partnership with chemically similar, more ancient ligands; two amino acid changes in the ancestral sequence were enough to recapitulate the modern glucocorticoid receptor's specificity. The authors named the pattern molecular exploitation: an older molecule, constrained for one role, recruited into a new functional pair. The same logic explains why cortisol still binds the mineralocorticoid receptor with the same in vitro affinity as aldosterone, and why the kidney needs an enzyme, 11β-hydroxysteroid dehydrogenase type 2, to inactivate cortisol locally so that aldosterone can do its job.8,9Grade C

The axis above the hormone is at least as old as vertebrates. The proteins, gene structures and signaling pathways of the hypothalamic-pituitary-adrenal axis were present in the earliest vertebrates and have been kept by natural selection; in every vertebrate studied the axis is activated by stressors and is controlled by peptides of the corticotropin-releasing factor family, of which four related members have been identified, and glucocorticoids are the downstream effectors with essential roles in development, energy balance and behavior. The peptides also time life-history transitions, metamorphosis in amphibians and birth in mammals, which places the stress hormone in a lineage of molecules that tell an animal when conditions have changed. The circadian layer sits on top: a master clock in the suprachiasmatic nucleus, entrained by light, drives the adrenal rhythm, secondary clocks in most peripheral tissues including the adrenal itself run on the same molecular machinery, and the robust daily rhythm of glucocorticoids is recognized as a major internal synchronizer of the whole system. The pre-waking peak is anticipation built into the clock: the hormone that mobilizes fuel arrives before the demand.2,1Grade C

In the network, cortisol is an energy and defense signal. Acute elevations promote glucose production from the liver, release of free fatty acids from fat stores and protein breakdown, and cortisol inhibits insulin release from the pancreas; in laboratory sleep restriction the evening rise in cortisol has been proposed as one mechanism of the fall in insulin sensitivity. Its actions on immunity and inflammation, cardiovascular function, metabolism and reproduction are not one action but several, which a 2000 review sorted into permissive, suppressive, stimulatory and preparative, depending on the endpoint. That is why the shelf reads Morning cortisol beside Fasting glucose, Fasting insulin and hs-CRP, beside TSH, and beside Total testosterone (men) and SHBG, and why a single morning value is a proxy for none of them: it is one point on a pulsatile, 24-hour signal whose shape, not its morning height, is what the outcome studies measured.1,10Grade C

04 · The laboratory range

What a laboratory calls normal.

About 6 to 23 µg/dL for a morning draw, assay-dependent, and lower on newer specific assays.

The printed range depends on the assay more than most tests. Older polyclonal immunoassays read higher than newer monoclonal assays and mass spectrometry; when 110 patients' ACTH stimulation tests were run in parallel, the historical cutoff of 18 µg/dL flagged 14.5 percent of them as insufficient on the older Elecsys I assay but 29 percent on Elecsys II, 22.4 percent on Access and 32 percent by LC-MS/MS, and the authors recalculated the equivalent cutoffs at 14.6, 14.8 and 14.5 µg/dL. A morning cortisol from a 2010 report and one from a 2025 report may not be the same scale.11Grade B

The Endocrine Society's 2016 hypopituitarism guideline gives the thresholds most clinicians use: a morning cortisol below 3 µg/dL is indicative of adrenal insufficiency, above 15 µg/dL likely excludes it, and values between 3 and 15 call for a stimulation test, with a peak below 18.1 µg/dL (500 nmol/L) at 30 or 60 minutes indicating insufficiency. The 2016 primary adrenal insufficiency guideline uses a lower screening line, a morning cortisol below 140 nmol/L (5 µg/dL) together with ACTH, and notes that the threshold is controversial, with studies arguing for levels above 285 nmol/L (10.3 µg/dL); it calls the stimulated cutoff assay dependent and reports that the low reference limit 30 minutes after corticotropin ranges from 418 to 574 nmol/L across methods.12,13Grade A

On a second-generation assay the lines move down. In 435 adults with pituitary disorders tested with low-dose ACTH, a morning cortisol at or below about 8.1 µg/dL predicted central adrenal insufficiency with 95.2 percent specificity, and a value above about 14.4 µg/dL excluded it with 95.2 percent sensitivity, against the guideline's stimulated peak; against the lower peak used with the newer assay, the lines were about 6.1 and 14.1 µg/dL. These are pituitary-clinic patients, not the general population, and the exclusion line left most people in the indeterminate zone.14Grade C

The laboratory range is a morning range. Cortisol secreted in the evening and early night is minimal in health, and the age-related rise of that nadir, not the morning peak, is the part of the curve that drifts with age. A reference interval printed for 8 AM says nothing about a sample drawn at 4 PM, and a laboratory that applies the morning range to an afternoon draw will call a normal afternoon value low.1Grade B

05 · The evidence

What the studies support.

The best general-population test of the morning value is negative. In the Whitehall II cohort, 4,047 British civil servants aged 61 on average gave six saliva samples across a weekday (at waking, 30 minutes, 2.5, 8 and 12 hours, and bedtime) and were followed for a mean of 6.1 years, with 139 deaths, 32 of them cardiovascular. A flatter decline in cortisol across the day carried a hazard of 1.30 for all-cause death per standard deviation of flattening and 1.87 for cardiovascular death, independent of a wide range of covariates. There was no association between morning cortisol, or the awakening response, and any mortality outcome. The shape of the day predicted death; the morning height did not.15Grade B

Pooling 179 associations from 80 studies published to January 2015, flatter diurnal cortisol slopes went with poorer health across all studies (average effect size r equals 0.147), in 10 of 12 subtypes of emotional and physical outcome, and most strongly for immune and inflammatory outcomes (r equals 0.288). The authors discuss the flat slope as either a marker or a mechanism of stress-related disease and cannot tell which; most of the studies were cross-sectional.16Grade B

Cumulative measures carry the clearest signal. In the InCHIANTI cohort, 861 Italians aged 65 and older had 24-hour urinary cortisol measured and were followed for a mean of 5.7 years, with 183 deaths, 41 cardiovascular; the highest tertile of urinary cortisol carried a hazard of 5.00 (95 percent confidence interval 2.02 to 12.37) for cardiovascular death, consistent in people with and without cardiovascular disease at baseline, and no excess of noncardiovascular death. The confidence interval is wide, the cardiovascular deaths were few, and a 24-hour urine is a different measurement from a morning blood draw.17Grade B

In the Longitudinal Aging Study Amsterdam, serum cortisol was measured in 1,181 older adults and salivary cortisol in 998, with six to seven and a half years of follow-up. Men in the highest tertile of salivary morning cortisol had a hazard of 1.63 for death versus the lowest, and women in the highest tertile of salivary evening cortisol a hazard of 1.82; in men a high serum cortisol went with higher odds of hypertension (1.38) and diabetes (1.38) and lower odds of chronic lung disease (0.72). The mortality findings differ by sex and by sample, which is a reason to hold them loosely.18Grade C

Hair integrates about a month of cortisol per centimeter. Among 283 community-dwelling Dutch adults (median age 75) chosen at random from the same cohort, cortisol in the proximal 3 cm of scalp hair, roughly three months of exposure, was lower in women than men (21.0 versus 26.3 pg/mg), and high hair cortisol carried an odds ratio of 2.7 for a history of cardiovascular disease and 3.2 for type 2 diabetes, with no association to noncardiovascular disease. This is a cross-sectional association with self-reported disease, and the authors note that single-time-point serum and saliva studies had been inconclusive.19Grade C

A meta-analysis of hair cortisol across 124 samples from 66 studies (10,289 people) found 22 percent higher hair cortisol in stress-exposed groups overall, 43 percent higher when the stress was still ongoing, and no difference when it was past; it also found 17 percent lower hair cortisol in anxiety disorders including PTSD, no consistent association with self-reported stress or depressiveness, and positive associations with body mass index, waist-to-hip ratio and systolic blood pressure. Hair cortisol tracks sustained exposure, and it does not track how stressed a person says they feel.20Grade B

The framework behind all of this is allostatic load: physiological systems fluctuate to meet demands rather than holding constant (allostasis), and the cost of chronic exposure to heightened or fluctuating neuroendocrine responses, accumulated over time, predisposes to disease. It is a framework, stated by its authors as a formulation to be tested, and it predicts that the burden shows up in cumulative and rhythm measures, not in one morning number.21,22Grade C

At the top of the scale, a high morning serum cortisol is not a diagnosis of Cushing's syndrome and a normal one does not exclude it. The Endocrine Society's 2008 guideline lists random serum cortisol among the tests it recommends against, with accuracy too low to recommend, and recommends instead a 24-hour urinary free cortisol, a late-night salivary cortisol (92 to 100 percent sensitivity and 93 to 100 percent specificity across studies), or a dexamethasone suppression test, followed by a second test if the first is abnormal. European population studies put the incidence at two to three cases per million people per year.7Grade A

At the bottom, the stimulation test the guidelines rely on is itself imperfect: pooling 30 studies with 1,209 adults, both the high-dose and low-dose ACTH tests had low sensitivity and high specificity for secondary adrenal insufficiency, adequate to rule the diagnosis in but not to rule it out. A borderline morning cortisol and a borderline stimulation test together are a clinical judgment, not a verdict.23Grade B

06 · What moves it

The levers with evidence behind them.

What is listed here has been tested. The size of each effect, and the size of the study, are in the sentence, so a small effect reads as a small effect.

  • Time since waking

    raises it by half or more in the first 30 minutes, then it falls through the day

    Free cortisol rose by 50 to 75 percent within 30 minutes of waking in 152 people across three studies, and the awakening response as a whole is regulated separately from the rest of the circadian curve. A morning draw is only comparable with a prior one if both were taken at about the same interval after waking, and the time on the requisition is the clock time, not the waking time.3,4Grade B

  • Sleep loss and shift work

    raises evening cortisol and flattens the curve; the rhythm does not shift quickly

    When 11 young men were restricted to 4 hours in bed for six nights, evening cortisol was raised and glucose tolerance fell compared with a week of 12 hours in bed. The 24-hour cortisol profile does not adapt rapidly to shifts in the light-dark, activity or feeding cycle, as in jet lag and rotating shifts, though its amplitude may fall, and urinary cortisol in night-shift workers has been reported to rise by 16 percent during daytime sleep. A morning draw after a night shift is a sample from a displaced rhythm.24,1Grade B

  • Oral estrogen

    raises total cortisol through binding globulin, and raises free cortisol somewhat too

    Estrogen raises corticosteroid-binding globulin, and because serum assays measure total cortisol the number climbs with it; the Cushing guideline reports false-positive overnight dexamethasone tests in 50 percent of women on the oral contraceptive pill and advises withdrawing estrogen for six weeks before testing where possible. In 23 women taking a 30 µg ethinyl estradiol pill compared with 15 cycling controls, total cortisol and CBG were raised and so, less expectedly, were free cortisol (32.3 versus 18.0 nmol/L) and salivary cortisol (18.8 versus 9.2 nmol/L); a pharmacokinetic study found women on the pill cleared cortisol more slowly with a longer half-life. A morning cortisol on oral estrogen reads high and is not a sign of excess.7,25,26Grade B

  • Exercise

    moderate and hard exercise raise it acutely; easy exercise does not

    In 12 moderately trained men exercising 30 minutes at 40, 60 and 80 percent of maximal oxygen uptake, cortisol changed by plus 5.7, plus 39.9 and plus 83.1 percent from before to after, against minus 6.6 percent on a resting day; the 60 and 80 percent sessions were significantly higher, partly from plasma volume loss, and once that was corrected the easy session lowered cortisol. The acute rise is the hormone doing its job of fueling effort, not a harm, and a blood draw after a hard morning workout will read high.27Grade C

  • Caffeine

    raises it after a dose; daily use blunts but does not abolish the response

    In a double-blind crossover of 48 men and 48 women, caffeine after five days of abstinence produced a robust rise in salivary cortisol across the test day; five days of 300 or 600 mg a day abolished the response to the 9 AM dose, although cortisol rose again after the 1 PM dose. A coffee before a morning draw matters more in someone who does not usually drink it.28Grade C

  • Alcohol

    heavy regular drinking raises it and flattens the daily slope

    In 2,693 men and 977 women of Whitehall II, salivary cortisol rose by about 3 percent per unit of alcohol consumed per week in men, the slope of decline across the day was flatter in heavy drinkers, and in women the awakening response was larger in heavy than moderate drinkers (14.15 versus 8.69 nmol/L). The authors attribute this to chronic change in the axis, not to drinking on the day of sampling. This is cross-sectional.29Grade C

  • Mindfulness and stress-reduction programs

    lower stress biomarkers a little in trials

    Across 32 randomized trials with 2,880 participants, mindfulness-based interventions changed biomarkers of inflammation and stress, cortisol among them, by a small amount relative to controls (Hedges g equals minus 0.11), with no difference by type of sample, biomarker or duration, and with low study quality and evidence of publication bias noted by the authors. The effect may be real; it is small.30Grade B

  • Licorice

    raises cortisol's action at the kidney without raising the morning number

    Licorice inhibits 11β-hydroxysteroid dehydrogenase type 2, the enzyme that inactivates cortisol in the kidney and other sodium-handling tissues, so cortisol, which binds the mineralocorticoid receptor as readily as aldosterone in vitro, acts there unopposed, producing an acquired mineralocorticoid excess. Pooling 18 studies of 337 people consuming at least 100 mg of glycyrrhizic acid a day, systolic blood pressure rose by 5.45 mmHg and diastolic by 3.19, potassium fell by 0.33 mmol/L, and renin and aldosterone fell, in proportion to dose. The serum cortisol can look unremarkable while the blood pressure tells the story.9,31Grade B

  • Glucocorticoid medication

    suppresses the body's own cortisol and can cross-react with the assay

    Any glucocorticoid taken by mouth, by injection, inhaled or applied to skin can suppress the HPA axis, and the hypopituitarism guideline warns that prednisolone cross-reacts in many cortisol assays while dexamethasone does not; the primary adrenal insufficiency guideline, for its part, asks that anyone with indicative symptoms be tested for insufficiency, with a low threshold in acutely ill people. A morning cortisol in someone on, or recently off, a steroid medication is a question for the prescriber, never a number to read alone.12,13Grade A

07 · Reading it well

Caveats, and what belongs with a physician.

In serious illness total cortisol stops meaning what it usually means. Among 66 critically ill patients and 33 healthy volunteers, baseline free cortisol was similar in patients with low albumin (2.5 g/dL or less) and near-normal albumin (5.1 and 5.2 µg/dL) and several times higher than in controls (0.6 µg/dL), yet the stimulated total cortisol was subnormal (18.5 µg/dL or less) in 14 patients, all with low protein; nearly 40 percent of the hypoproteinemic patients had a subnormal total cortisol with normal adrenal function. A total cortisol drawn during an acute illness, in hospital or shortly after, should not be read against outpatient thresholds.6Grade B

The same number means different things on different assays. Specific monoclonal immunoassays and mass spectrometry read lower than the older polyclonal assays on which the 18 µg/dL stimulated cutoff and the 3-to-15 morning window were built, which is why cutoffs of 14 to 15 µg/dL have been proposed for the newer methods and why the primary adrenal insufficiency guideline calls the exclusion cutoff assay dependent. Compare a cortisol only with a prior cortisol from the same laboratory on the same platform, and ask which platform it is.11,13Grade B

The claim that chronic stress exhausts the adrenal glands into a low-cortisol state called "adrenal fatigue" has been examined systematically. Of 3,470 articles screened, 58 studies met criteria, 33 in healthy people and 25 in symptomatic patients, most using direct awakening cortisol, the awakening response or the salivary rhythm; the results conflicted almost systematically regardless of the test used, the methods were often ones endocrinologists do not endorse, and the authors concluded there is no substantiation that the condition exists. No endocrine society recognizes it. Fatigue with a normal morning cortisol has other explanations worth finding; a genuinely low morning cortisol is adrenal insufficiency, a real and treatable disease, and is handled as one.32Grade A

A morning cortisol does not read stress. The outcome studies that found risk used six saliva samples across a day, a 24-hour urine or three months of hair; the one large cohort that also looked at morning cortisol found it unrelated to death; and hair cortisol, the best cumulative measure, does not track self-reported stress at all. The hormone's own pulsatility, the awakening response, caffeine, exercise and the walk to the laboratory all move a single sample, and a review of the field notes that the awakening response itself is best thought of as a partly predictable mild stressor.15,20,1Grade B

The awakening response and the daily slope are research measurements with their own rules. The expert consensus for the awakening response requires objective verification of waking time and sampling within minutes of it, because the measure is invalid when the first sample is late; there are no agreed norms for absolute salivary values at waking; and home saliva kits sold for "cortisol curves" rarely meet those standards. A four-point saliva curve is more informative than a morning serum value only when it is collected the way the studies collected it.5,4Grade A

Pregnancy raises CBG and total cortisol so far that the primary adrenal insufficiency guideline cites stimulated cutoffs of 700, 800 and 900 nmol/L (25, 29 and 32 µg/dL) by trimester, and the Cushing guideline notes that estrogen-containing drugs and pregnancy alter every serum measure. Nothing on this page applies to a pregnant reader without a physician who knows the trimester-specific thresholds.13,7Grade A

See a physician

  • A morning cortisol below about 3 to 5 µg/dL, especially with fatigue, weight loss, dizziness on standing, nausea, salt craving, low blood pressure or darkening skin. Untreated adrenal insufficiency can become a crisis; this is urgent, the same day.
  • Anyone on a steroid medication by any route (tablets, injections, inhalers, creams), or who has stopped one in the past year, with a low or borderline morning cortisol or with symptoms of insufficiency. Never stop or change the medication over a number.
  • Weight gain concentrated in the trunk and face together with easy bruising, purple stretch marks, muscle weakness in the thighs or shoulders, new diabetes or hypertension, or thinning skin, whatever the morning cortisol reads: the tests for excess are a 24-hour urine, a late-night saliva sample or a dexamethasone test, not a morning draw.
  • A morning cortisol well above the laboratory range on a repeat draw in someone not taking oral estrogen and not acutely ill or stressed at the time of the draw.
  • A morning cortisol in the indeterminate zone (about 3 to 15 µg/dL) in anyone with a pituitary condition, a history of head injury or brain radiation, or symptoms of insufficiency, where a stimulation test is the next step.
  • Any cortisol result during pregnancy, or in a hospital or acute illness, which must be read against different thresholds.

This page is education, not individual medical advice, and reading it creates no physician-patient relationship.

08 · Open questions

What the literature does not settle.

  • No study has defined an optimal morning cortisol inside the laboratory range. The outcome literature measured the daily slope, the evening level, a 24-hour urine or three months of hair, and the one large cohort that tested the morning value found it unrelated to death.
  • The clinical meaning of the cortisol awakening response is unsettled: consensus guidelines standardize how to measure it, but whether a larger or a smaller response is the healthier one is not agreed, and its physiological function is still described as not clarified.
  • Whether hair cortisol becomes a clinical measure of cumulative exposure is open. It tracks ongoing stress, body mass and blood pressure in meta-analysis, and prevalent cardiovascular disease in one small sample, but there are no prospective outcome studies of adequate size and no agreed reference values.
  • The morning-cortisol thresholds for adrenal insufficiency were set on older assays. New cutoffs of about 14 to 15 µg/dL for the newer specific assays rest on one 110-patient parallel study and one 435-patient pituitary-clinic series; neither guideline has yet been revised, and laboratories do not print which generation of assay they ran.
  • Whether a flat daily slope causes disease, marks it, or results from it is unresolved; the meta-analytic evidence is largely cross-sectional and no trial has tried to steepen the slope and measure outcomes.

10

Questions

11 · Sources

32 sources, read in full.

Numbered in the order they appear. Each line says what this page relies on from the paper; the link opens the record at PubMed or the publisher.

  1. 1.

    Oster H, Challet E, Ott V, et al.. The Functional and Clinical Significance of the 24-Hour Rhythm of Circulating Glucocorticoids. Endocrine Reviews. 2017. PMID 27749086. DOI 10.1210/er.2015-1080.

    Review · Glucocorticoids follow a circadian rhythm peaking around the habitual sleep-wake transition with evening and early-night minima, released in 60- to 90-minute pulses under the suprachiasmatic master clock; the rhythm is a major internal synchronizer; cortisol promotes liver gluconeogenesis and inhibits insulin release; the profile does not adapt rapidly to shift work; night-shift urinary cortisol rises 16 percent during daytime sleep; the nadir rises with age.

  2. 2.

    Denver RJ. Structural and functional evolution of vertebrate neuroendocrine stress systems. Annals of the New York Academy of Sciences. 2009. PMID 19456324. DOI 10.1111/j.1749-6632.2009.04433.x.

    Review · The HPA axis's proteins, gene structures and signaling pathways were present in the earliest vertebrates; it is activated by stressors in all vertebrates studied and controlled by four paralogous CRF-family peptides, which also time metamorphosis and birth; glucocorticoids are the downstream effectors.

  3. 3.

    Pruessner JC, Wolf OT, Hellhammer DH, et al.. Free cortisol levels after awakening: a reliable biological marker for the assessment of adrenocortical activity. Life Sciences. 1997. PMID 9416776. DOI 10.1016/s0024-3205(97)01008-4.

    Cross-sectional study · In three studies totaling 152 people, salivary free cortisol rose 50 to 75 percent within 30 minutes of waking; day-to-day stability of the response was r 0.39 to 0.67; single fixed-time assessments were less reliable than repeated waking-referenced ones.

  4. 4.

    Clow A, Thorn L, Evans P, Hucklebridge F. The awakening cortisol response: methodological issues and significance. Stress. 2004. PMID 15204030. DOI 10.1080/10253890410001667205.

    Review · Salivary cortisol rises 50 to 160 percent in the 30 minutes after waking (about 9 nmol/L on average, range 4 to 15); there are no agreed norms for absolute values at waking (4.7 to 18.5 nmol/L) or 30 minutes later; the response is under a distinct regulatory influence and whether larger or smaller is healthier remains unclear.

  5. 5.

    Stalder T, Kirschbaum C, Kudielka BM, et al.. Assessment of the cortisol awakening response: Expert consensus guidelines. Psychoneuroendocrinology. 2016. PMID 26563991. DOI 10.1016/j.psyneuen.2015.10.010.

    Consensus statement · The International Society of Psychoneuroendocrinology consensus: the awakening response is the rise over the first 30 to 45 minutes after waking, its validity depends on sampling timed from the moment of awakening with objective adherence control, and it is a research measure requiring standardized protocols.

  6. 6.

    Hamrahian AH, Oseni TS, Arafah BM. Measurements of serum free cortisol in critically ill patients. New England Journal of Medicine. 2004. PMID 15084695. DOI 10.1056/NEJMoa020266.

    Cross-sectional study · More than 90 percent of cortisol is protein-bound; in 66 critically ill patients and 33 controls, free cortisol was 5.1 and 5.2 µg/dL in low- and near-normal-albumin patients versus 0.6 in controls, while stimulated total cortisol was subnormal (18.5 µg/dL or less) in 14 patients, all hypoproteinemic; nearly 40 percent of hypoproteinemic patients had subnormal total cortisol with normal adrenal function.

  7. 7.

    Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. Journal of Clinical Endocrinology and Metabolism. 2008. PMID 18334580. DOI 10.1210/jc.2008-0125.

    Guideline · Random serum cortisol is among the tests recommended against; initial tests are urinary free cortisol, late-night salivary cortisol (92 to 100 percent sensitivity, 93 to 100 percent specificity) or dexamethasone suppression; estrogens raise CBG, with false-positive overnight suppression tests in 50 percent of women on the pill; incidence two to three per million per year.

  8. 8.

    Bridgham JT, Carroll SM, Thornton JW. Evolution of hormone-receptor complexity by molecular exploitation. Science. 2006. PMID 16601189. DOI 10.1126/science.1123348.

    Laboratory method study · Ancestral gene resurrection showed the corticoid receptor's affinity for aldosterone existed long before the hormone, as a by-product of binding older ligands; two amino acid changes recapitulate modern glucocorticoid receptor specificity; the pattern is named molecular exploitation.

  9. 9.

    Ferrari P. The role of 11β-hydroxysteroid dehydrogenase type 2 in human hypertension. Biochimica et Biophysica Acta. 2010. PMID 19909806. DOI 10.1016/j.bbadis.2009.10.017.

    Review · Cortisol and aldosterone have the same in vitro affinity for the mineralocorticoid receptor; 11β-HSD2 inactivates cortisol in sodium-transporting tissues to protect the receptor; inhibition by licorice produces an acquired mineralocorticoid excess.

  10. 10.

    Sapolsky RM, Romero LM, Munck AU. How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocrine Reviews. 2000. PMID 10696570. DOI 10.1210/edrv.21.1.0389.

    Review · Glucocorticoid actions on cardiovascular function, fluid balance, immunity and inflammation, metabolism, the brain and reproduction fall into permissive, suppressive, stimulatory and preparative categories depending on the endpoint.

  11. 11.

    Javorsky BR, Raff H, Carroll TB, Algeciras-Schimnich A, Singh RJ, Colón-Franco JM, Findling JW. New Cutoffs for the Biochemical Diagnosis of Adrenal Insufficiency after ACTH Stimulation using Specific Cortisol Assays. Journal of the Endocrine Society. 2021. PMID 33768189. DOI 10.1210/jendso/bvab022.

    Laboratory method study · In 110 patients tested in parallel, the 18 µg/dL cutoff labeled 14.5, 29, 22.4 and 32 percent insufficient on Elecsys I, Elecsys II, Access and LC-MS/MS; recalculated 30-minute cutoffs 14.6, 14.8 and 14.5 µg/dL; recommends 14 to 15 µg/dL for the newer assays.

  12. 12.

    Fleseriu M, Hashim IA, Karavitaki N, Melmed S, Murad MH, Salvatori R, Samuels MH. Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline. Journal of Clinical Endocrinology and Metabolism. 2016. PMID 27736313. DOI 10.1210/jc.2016-2118.

    Guideline · Morning cortisol below 3 µg/dL is indicative of adrenal insufficiency, above 15 µg/dL likely excludes it, 3 to 15 calls for stimulation testing; stimulated peak below 18.1 µg/dL (500 nmol/L) indicates insufficiency; prednisolone cross-reacts in many cortisol assays; oral estrogen raises total cortisol through CBG.

  13. 13.

    Bornstein SR, Allolio B, Arlt W, et al.. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. Journal of Clinical Endocrinology and Metabolism. 2016. PMID 26760044. DOI 10.1210/jc.2015-1710.

    Guideline · Short corticotropin test is the gold standard; morning cortisol below 140 nmol/L (5 µg/dL) with ACTH as the preliminary screen, a controversial threshold; stimulated peak below 500 nmol/L (18 µg/dL) indicates insufficiency, assay dependent, with 30-minute low reference limits of 418 to 574 nmol/L across methods; estrogen and pregnancy raise CBG and total cortisol; pregnancy cutoffs 700, 800 and 900 nmol/L by trimester.

  14. 14.

    Gasco V, Bioletto F, Lucisano D, et al.. Morning cortisol and central adrenal insufficiency: new thresholds from low-dose ACTH test and second-generation assay. Journal of Endocrinological Investigation. 2026. PMID 41619159. DOI 10.1007/s40618-026-02807-5.

    Cross-sectional study · In 435 adults with pituitary disorders on a second-generation assay, a morning cortisol of 80.8 µg/L (about 8.1 µg/dL) or less predicted central adrenal insufficiency with 95.2 percent specificity and above 144.0 µg/L (about 14.4 µg/dL) excluded it with 95.2 percent sensitivity; with the lower assay-specific peak, the lines were 60.9 and 141 µg/L.

  15. 15.

    Kumari M, Shipley M, Stafford M, Kivimaki M. Association of diurnal patterns in salivary cortisol with all-cause and cardiovascular mortality: findings from the Whitehall II study. Journal of Clinical Endocrinology and Metabolism. 2011. PMID 21346074. DOI 10.1210/jc.2010-2137.

    Prospective cohort · In 4,047 adults (mean age 61) with six saliva samples across a day and 6.1 years of follow-up (139 deaths, 32 cardiovascular), a flatter diurnal slope carried hazard 1.30 for all-cause and 1.87 for cardiovascular death per SD; morning cortisol and the awakening response were unrelated to mortality.

  16. 16.

    Adam EK, Quinn ME, Tavernier R, McQuillan MT, Dahlke KA, Gilbert KE. Diurnal cortisol slopes and mental and physical health outcomes: A systematic review and meta-analysis. Psychoneuroendocrinology. 2017. PMID 28578301. DOI 10.1016/j.psyneuen.2017.05.018.

    Systematic review and meta-analysis · Across 179 associations from 80 studies, flatter diurnal slopes went with poorer health (r 0.147), in 10 of 12 outcome subtypes, largest for immune and inflammatory outcomes (r 0.288); marker versus mechanism unresolved.

  17. 17.

    Vogelzangs N, Beekman AT, Milaneschi Y, Bandinelli S, Ferrucci L, Penninx BW. Urinary cortisol and six-year risk of all-cause and cardiovascular mortality. Journal of Clinical Endocrinology and Metabolism. 2010. PMID 20739384. DOI 10.1210/jc.2010-0192.

    Prospective cohort · In 861 Italians aged 65 and over followed 5.7 years (183 deaths, 41 cardiovascular), the highest tertile of 24-hour urinary cortisol carried hazard 5.00 (2.02 to 12.37) for cardiovascular death, with no excess noncardiovascular death.

  18. 18.

    Schoorlemmer RM, Peeters GM, van Schoor NM, Lips P. Relationships between cortisol level, mortality and chronic diseases in older persons. Clinical Endocrinology. 2009. PMID 19226268. DOI 10.1111/j.1365-2265.2009.03552.x.

    Prospective cohort · In the Longitudinal Aging Study Amsterdam (serum cortisol in 1,181, salivary in 998), high salivary morning cortisol in men (hazard 1.63) and high salivary evening cortisol in women (1.82) predicted mortality; high serum cortisol in men went with hypertension (odds 1.38), diabetes (1.38) and less chronic lung disease (0.72).

  19. 19.

    Manenschijn L, Schaap L, van Schoor NM, et al.. High long-term cortisol levels, measured in scalp hair, are associated with a history of cardiovascular disease. Journal of Clinical Endocrinology and Metabolism. 2013. PMID 23596141. DOI 10.1210/jc.2012-3663.

    Cross-sectional study · In 283 older Dutch adults (median age 75), hair cortisol in the proximal 3 cm was 21.0 pg/mg in women and 26.3 in men; high hair cortisol carried odds 2.7 for cardiovascular disease and 3.2 for type 2 diabetes, with no association to noncardiovascular disease.

  20. 20.

    Stalder T, Steudte-Schmiedgen S, Alexander N, et al.. Stress-related and basic determinants of hair cortisol in humans: A meta-analysis. Psychoneuroendocrinology. 2017. PMID 28135674. DOI 10.1016/j.psyneuen.2016.12.017.

    Systematic review and meta-analysis · Across 124 samples from 66 studies (10,289 people), hair cortisol was 22 percent higher in stress-exposed groups and 43 percent higher with ongoing stress, 17 percent lower in anxiety disorders, unrelated to self-reported stress, and positively associated with body mass index, waist-to-hip ratio and systolic blood pressure; oral contraceptive use is a covariate.

  21. 21.

    McEwen BS, Stellar E. Stress and the individual. Mechanisms leading to disease. Archives of Internal Medicine. 1993. PMID 8379800.

    Review · Defines allostasis (physiological systems fluctuating to meet demand) and allostatic load (the cost of chronic exposure to fluctuating or heightened neural or neuroendocrine response), presented as a formulation to be tested.

  22. 22.

    McEwen BS. Protective and damaging effects of stress mediators. New England Journal of Medicine. 1998. PMID 9428819. DOI 10.1056/NEJM199801153380307.

    Review · The widely cited statement of the allostatic load framework for clinicians; cited here as the framework, with no numbers drawn from it.

  23. 23.

    Ospina NS, Al Nofal A, Bancos I, et al.. ACTH Stimulation Tests for the Diagnosis of Adrenal Insufficiency: Systematic Review and Meta-Analysis. Journal of Clinical Endocrinology and Metabolism. 2016. PMID 26649617. DOI 10.1210/jc.2015-1700.

    Systematic review and meta-analysis · Across 30 studies with 1,209 adults, high- and low-dose ACTH tests had low sensitivity and high specificity for secondary adrenal insufficiency (positive likelihood ratios 9.1 and 5.9, negative 0.39 and 0.19), adequate to rule in but not rule out; confidence low to moderate.

  24. 24.

    Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet. 1999. PMID 10543671. DOI 10.1016/S0140-6736(99)01376-8.

    Randomized trial · In 11 young men restricted to 4 hours in bed for six nights versus 12 hours, evening cortisol was raised, glucose tolerance was lower, thyrotropin was lower and sympathetic activity was higher.

  25. 25.

    Meulenberg PM, Ross HA, Swinkels LM, Benraad TJ. The effect of oral contraceptives on plasma-free and salivary cortisol and cortisone. Clinica Chimica Acta. 1987. PMID 3652459. DOI 10.1016/0009-8981(87)90183-5.

    Cross-sectional study · In 23 women on 30 µg ethinyl estradiol plus 150 µg desogestrel versus 15 controls, CBG and total cortisol were raised, and free cortisol (32.3 versus 18.0 nmol/L) and salivary cortisol (18.8 versus 9.2 nmol/L) were higher too.

  26. 26.

    Perogamvros I, Aarons L, Miller AG, Trainer PJ, Ray DW. Corticosteroid-binding globulin regulates cortisol pharmacokinetics. Clinical Endocrinology. 2011. PMID 21054475. DOI 10.1111/j.1365-2265.2010.03897.x.

    Laboratory method study · After intravenous hydrocortisone, women on the oral contraceptive pill had higher total-cortisol exposure and a longer half-life with lower clearance than controls, and higher free-cortisol exposure as well; CBG-null patients showed the reverse for total cortisol.

  27. 27.

    Hill EE, Zack E, Battaglini C, Viru M, Viru A, Hackney AC. Exercise and circulating cortisol levels: the intensity threshold effect. Journal of Endocrinological Investigation. 2008. PMID 18787373. DOI 10.1007/BF03345606.

    Laboratory method study · In 12 trained men, 30 minutes at 40, 60 and 80 percent of VO2max changed cortisol by plus 5.7, plus 39.9 and plus 83.1 percent versus minus 6.6 percent at rest; moderate to high intensity raises cortisol through hemoconcentration and ACTH; low intensity, corrected for plasma volume, lowers it.

  28. 28.

    Lovallo WR, Whitsett TL, al'Absi M, Sung BH, Vincent AS, Wilson MF. Caffeine stimulation of cortisol secretion across the waking hours in relation to caffeine intake levels. Psychosomatic Medicine. 2005. PMID 16204431. DOI 10.1097/01.psy.0000181270.20036.06.

    Randomized trial · In a double-blind crossover of 48 men and 48 women, caffeine after five days of abstinence robustly raised salivary cortisol across the day; 300 or 600 mg a day for five days abolished the response to the 9 AM dose but not to the 1 PM dose.

  29. 29.

    Badrick E, Bobak M, Britton A, Kirschbaum C, Marmot M, Kumari M. The relationship between alcohol consumption and cortisol secretion in an aging cohort. Journal of Clinical Endocrinology and Metabolism. 2008. PMID 18073316. DOI 10.1210/jc.2007-0737.

    Cross-sectional study · In 2,693 men and 977 women of Whitehall II, cortisol rose 3 percent per weekly unit of alcohol in men, the diurnal slope was flatter in heavy drinkers, and the awakening response was larger in heavy-drinking women (14.15 versus 8.69 nmol/L); attributed to chronic HPA change rather than same-day drinking.

  30. 30.

    Grasmann J, Almenräder F, Voracek M, Tran US. Only Small Effects of Mindfulness-Based Interventions on Biomarker Levels of Inflammation and Stress: A Preregistered Systematic Review and Two Three-Level Meta-Analyses. International Journal of Molecular Sciences. 2023. PMID 36901875. DOI 10.3390/ijms24054445.

    Systematic review and meta-analysis · Across 32 randomized trials (2,880 participants), mindfulness-based interventions changed inflammation and stress biomarkers by Hedges g minus 0.11 versus controls (pre-post minus 0.15 in 40 studies), with no moderation by biomarker or duration, low study quality and publication bias.

  31. 31.

    Penninkilampi R, Eslick EM, Eslick GD. The association between consistent licorice ingestion, hypertension and hypokalaemia: a systematic review and meta-analysis. Journal of Human Hypertension. 2017. PMID 28660884. DOI 10.1038/jhh.2017.45.

    Systematic review and meta-analysis · Across 18 studies (337 people) ingesting at least 100 mg glycyrrhizic acid daily, systolic pressure rose 5.45 mmHg and diastolic 3.19, potassium fell 0.33 mmol/L, and renin and aldosterone fell, with a dose-response for blood pressure.

  32. 32.

    Cadegiani FA, Kater CE. Adrenal fatigue does not exist: a systematic review. BMC Endocrine Disorders. 2016. PMID 27557747. DOI 10.1186/s12902-016-0128-4.

    Systematic review and meta-analysis · Of 3,470 articles, 58 studies (33 in healthy people, 25 in symptomatic patients) met criteria; results conflicted almost systematically regardless of test; no substantiation that adrenal fatigue is a medical condition; not recognized by any endocrinology society.

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