Cortisone (S5) - Bedtime

Your body is supposed to dial down its main stress hormone before sleep. When that nightly drop fails to happen, the consequences show up across your health: worse sleep, higher blood pressure, more belly fat, blunted mood, and a quietly elevated risk of heart disease and diabetes. A bedtime saliva sample can show whether that nightly wind-down is actually occurring.

This test measures cortisone, the inactive twin of cortisol, in saliva taken right before bed. Salivary cortisone tracks free, biologically active cortisol very closely (correlation around 0.95 across hundreds of paired samples) and is unaffected by changes in cortisol-binding proteins that distort blood tests. In other words, it gives you a cleaner read on your true late-night stress hormone exposure than most blood draws can.

What This Test Actually Measures

Cortisol and cortisone are glucocorticoid steroids made by your adrenal glands under direction from the brain (the hypothalamic-pituitary-adrenal axis, or HPA axis, your body's central stress-response circuit). Inside the salivary gland, an enzyme converts cortisol into cortisone, which is why saliva contains relatively more cortisone than blood does. That makes salivary cortisone a sensitive way to read free cortisol activity.

In a healthy daily rhythm, levels rise sharply before you wake up, peak shortly after waking, then fall steadily through the day to a low point around bedtime. The bedtime sample (sometimes labeled S5 in a 5-point saliva profile) captures that low point. A flattened daily decline, or a level that stays high at night, signals a stress hormone system that is not switching off properly.

Heart Disease and Mortality Risk

The strongest outcome data come from the Whitehall II study of 4,047 British civil servants followed for about six years. People with higher bedtime cortisol had nearly twice the risk of dying from cardiovascular disease for each one-standard-deviation increase. A flatter daily decline raised cardiovascular death risk by roughly 87% and all-cause death risk by about 30%, even after accounting for age, sex, employment grade, and sampling time.

In a separate study of 229 people with systolic heart failure followed for 18 months, those in the top quartile of evening salivary cortisol had about 2.5 times the risk of dying compared with the rest, independent of age, heart failure severity, and NT-proBNP (a standard heart failure blood marker). Morning cortisol did not predict mortality. The signal lives in the evening.

These studies measured cortisol rather than cortisone specifically, but because salivary cortisone closely mirrors free cortisol, the implications travel: a high bedtime number in either form is a warning sign that the HPA axis is staying activated when it should be resting.

Type 2 Diabetes Risk

In more than 3,200 adults from the Whitehall II cohort followed for roughly a decade, higher bedtime cortisol and a flatter daily slope predicted future development of type 2 diabetes and impaired fasting glucose. People with persistent evening cortisol elevation tend to drift toward insulin resistance, central weight gain, and metabolic syndrome long before fasting glucose moves on a standard panel.

Sleep, Mood, and Cognition

Elevated bedtime cortisol shows up in people with bipolar disorder who have a history of suicide attempts, marking HPA hyperactivity in this high-risk subgroup. In stroke survivors, high bedtime salivary cortisol predicted brain atrophy and cognitive decline up to two years later, after adjusting for age, education, smoking, stroke severity, ApoE4 (a genetic risk variant for Alzheimer's), and BMI (body mass index).

In midlife women, higher long-term cortisol and cortisone levels were linked to worse subjective sleep, longer time to fall asleep, lower sleep efficiency, and more sleep disturbances. Chronic hypercortisolism (a sustained excess of cortisol, the hallmark of Cushing's syndrome) is associated with depression, sleep problems, and cognitive impairment that often improve once cortisol normalizes.

Cushing's Syndrome and Autonomous Cortisol Secretion

The classic clinical use of bedtime salivary cortisol or cortisone is to detect Cushing's syndrome, a condition where the body produces too much cortisol. Late-night salivary cortisol above roughly 550 ng/dL identified 93% of Cushing's patients while excluding all controls in one study. In children with obesity and clinical features suggesting Cushing's, a bedtime salivary cortisol cutoff of 8 nmol/L showed 100% sensitivity and 100% specificity in that cohort.

Salivary cortisone is particularly useful for catching milder forms of cortisol excess. In adrenal incidentalomas (small adrenal tumors found by chance on imaging), nearly all patients with autonomous cortisol secretion had elevated late-night salivary cortisone, but fewer than half had elevated late-night salivary cortisol. After a dexamethasone suppression test (a standard endocrine challenge), salivary cortisone identified non-suppressors with 85% sensitivity and 92% specificity.

Adrenal Insufficiency

The flip side is detecting too little cortisol. Waking salivary cortisone has been studied as a screening tool for adrenal insufficiency, identifying people who fail an ACTH stimulation test with an area under the curve of 0.95 (where 1.0 is perfect). Bedtime values are most useful in combination with morning samples to map the full daily curve. A pattern of low morning levels with a flat daily slope is the signal that matters.

Reference Ranges

Salivary cortisone ranges depend heavily on the lab and the assay used. The values below come from research using sensitive lab methods in adults and are illustrative orientation, not universal targets. Your lab will likely use slightly different cutpoints, and a bedtime sample is interpreted in the context of your full daily curve, not in isolation.

Compare your results within the same lab over time for the most meaningful trend. Different labs use different cutpoints and units (typically ng/mL or nmol/L), and absolute numbers are not directly comparable across methods.

Why One Reading Is Not Enough

Salivary cortisone has substantial day-to-day biological variability. Within a single person, the coefficient of variation ranges from 19% to 49% depending on time of day. A change in a single reading needs to be roughly 55% to 194% to exceed random variation. That means one bedtime sample can mislead you in either direction.

The right approach is serial: get a baseline, ideally as part of a multi-point daily profile (morning, midday, evening, bedtime), then retest in 3 to 6 months if you are making meaningful changes (managing stress, improving sleep, treating a condition), and at least annually thereafter. Trend matters more than any single number.

When Results Can Be Misleading

• Acute stress or illness in the days before testing: a fight with your partner, a deadline, a cold, or recent surgery can transiently raise evening cortisol and cortisone. Wait until you are back to baseline.
• Sample contamination: blood in the mouth from brushing, recent food or drink, or smoking within 30 minutes of collection can distort results. Avoid eating, drinking, brushing, or smoking for at least half an hour before the bedtime sample.
• Late-night light, screen exposure, or shift work: these shift the circadian rhythm itself, so a high bedtime value may reflect a disrupted clock rather than disease.
• Inconsistent sleep timing: bedtime samples should be taken at a consistent time relative to your usual sleep onset, ideally just before lying down.

What to Do With an Abnormal Result

A single elevated bedtime cortisone is not a diagnosis. The most useful next step is to confirm with a repeat sample, ideally as part of a full daily profile. If the elevation is consistent, the standard workup includes morning cortisol and ACTH (the pituitary hormone that drives cortisol release), a 24-hour urinary free cortisol, and a 1 mg overnight dexamethasone suppression test. DHEA-S (an adrenal androgen) can help characterize adrenal output. If the pattern is consistent with hypercortisolism, an endocrinologist should be involved.

If the issue looks more like chronic HPA activation rather than disease (mildly elevated bedtime values with a flattened slope but normal morning numbers), the workup focuses on contributors: sleep disruption, untreated obstructive sleep apnea, chronic psychological stress, alcohol intake, and metabolic markers like fasting insulin, HbA1c (a three-month average of blood sugar), and a lipid panel.