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Lessons Learned. Cortisol. Why Measure Cortisol?. Hyper- cortisolism or hypo- cortisolism associated with several disease conditions Cushing’s Disease Addison’s Disease Congenital Adrenal Hyperplasia Depression Thyroid Disease Cortisol is an objective marker of the stress response.

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Lessons learned

Lessons Learned


Why measure cortisol
Why Measure Cortisol?

  • Hyper-cortisolism or hypo-cortisolism associated with several disease conditions

    • Cushing’s Disease

    • Addison’s Disease

    • Congenital Adrenal Hyperplasia

    • Depression

    • Thyroid Disease

  • Cortisol is an objective marker of the stress response

What medium to use
What Medium to Use?

  • Urine

  • Blood (serum or plasma)

  • Saliva

  • Hair

    • Pros and Cons for each

Urine cortisol normal range 10 100 mcg 24hours
Urine Cortisol (Normal range 10-100 mcg/24hours)

  • Pros:

    • Non-invasive

    • 24-hr urine cortisol/creatinine ratio excellent diagnostic for disease states. Not influenced by diurnal rhythm.

  • Cons

    • Need a timed urine sample, so difficult to collect diurnal samples

    • Labor intensive for patients; can’t be used in patients with renal failure or dialysis

    • High rate of cross-reactivity (numerous excreted steroid metabolites in urine)

      • Most urine assays pick up cortisol metabolites (95%); only 2-3 % free cortisol

Blood cortisol
Blood Cortisol

  • Pros

    • Can collect diurnal data or after stress exposure

    • Best measure for diagnosing certain hyper-cortisol states (e.g., Cushing’s via dex suppression test)

  • Cons

    • Blood draw expectation may increase cortisol release

    • Provide measurement of cortisol at a single point in time

    • Major fraction bound to corticosteroid binding globulin (CBG) and albumin (only 2-3% free).

      • CBG influenced by pregnancy, oral contraceptives, hyperthyroidism – so levels measured may be high, but not reflective of bioactive cortisol

    • Methods for assaying serum free cortisol are time consuming, expensive and require advanced techniques (ultrafiltration, gel filtration, gold standard: equilibrium dialysis)

  • Salivary cortisol
    Salivary Cortisol

    • Pros

      • Non-invasive – can collect from infants, children, patients with poor veins

      • Avoids stress-induced rise in secretion (like with a blood draw)

      • Can collect at home or in the wild: Do not need to freeze or keep refrigerated

      • Can collect one time or diurnal data

      • Provides measure of free cortisol – best indicator of active hormone

      • Correlates well with serum levels across a 24-hour period

        • r=.67 in healthy people; r= .73 in patients with Addison’s disease; and r= .61 in patients with Cushing’s)

    • Cons

      • Provides measurement of cortisol concentration at a single point in time

      • Periodontal disease, eating, tooth brushing can affect levels

      • Sample quantity may be low (e.g., dry mouth, impatient)

      • Messy

    Hair cortisol
    Hair Cortisol

    • Pros

      • Biomarker of chronic stress

      • Relatively non-invasive

      • Only free cortisol represented

      • Easily transported and stored - put in an envelope or vial & store at room temp for months to years

      • Reflects cortisol levels over past months (Hair grows predictably about 1 cm/month) –

        • 1 cm closest to skull reflects last month; 2nd cm out reflects preceding month

          • So may not need to take multiple samples to evaluate chronic stress and perhaps compare months with and without a stressor

      • Not affected by hair color – but maybe by dying of hair

      • Significantly correlated with self-reports of stress (Kalra, 2007; Van Uum, 2008)

    • Cons

      • No clinically relevant reference range established to date

      • Exposure to exogenous steroids in lotions or creams may cause sample contamination

      • Mechanism of incorporation of cortisol into hair not known– is it from blood? Exocrine or sebaceous sources?

    Cortisol assays
    Cortisol Assays

    • Radioimmunoassay

    • Immunoassay - most common but may be at risk of cross reactivity with steroids other than cortisol (problematic in critically ill patients and in urine samples)

    • High pressure liquid chromatography (HPLC)/mass spectrometry

    Measurement and analysis
    Measurement and Analysis

    • A single sample

      • unreliable unless:

        • Collected accurately at a specific time of day for all subjects


        • Collected accurately at a specific time of day related to known time of awakening

    • Diurnal Rhythm

      • Unreliable unless collected accurately at correct times of day

    Measurement and analysis1
    Measurement and Analysis

    • Diurnal Rhythm

      • Usually collect between 3-6 samples over the course of 1-3 days to evaluate:

        • Awakening level – considered a measure of allostatic load

        • Awakening response (15-45 mins after awakening) – considered a measure of acute stress response.

        • Then one or more collections across the day

          • High in morning, then falls over the day, lowest late in the evening (Kudielka& Kirschbaum, 2003)

        • If an individual or group deviate from that rhythm, indicates dysregulation

    Awakening response
    Awakening Response

    • Awakening Response (Pruessner, 1997)

      [30 min post awakening] – [awakening]


    Area under the curve
    Area Under the Curve

    • Mathematically transforms multivariate data into a summary of the information (Fekedulegn et al., 2007).

    • Reflects the total cortisol released during the day

    • Provides information on the magnitude of the response

    Measurement and analysis2
    Measurement and Analysis

    • Must validate correct collection times

      • Self-report

      • Phone calls

      • MEMs Caps (electronic monitoring)

    Special populations
    Special Populations

    • Pregnant women

      • Levels very high but maintain a diurnal rhythm

      • Blood levels very high unless measure only free because CBG increases significantly

        blood = bound + free

    • Infants and toddlers

    Thank you
    Thank you!

    • Questions?


    • Fekedulegn, D.B., Andrew, M.E., Burchfiel, C.M, et al. (2007). Area under the curve and other summary indicators of repeated waking cortisol measurements. Psychosomatic Medicine, 69, 651-659.

    • Kalra, S., Einarson, A., Karaskov, T., Van Uums, S., & Koren, G., (2007). The relationship between stress and hair cortisol in healthy pregnant women. Clinical and Investigative Medicine, 30, E103-107.

    • Kudielka, B.M., Kirschbaum, C. (2003). Awakening cortisol response are influenced by health status and awakening time but not by menstrual cycle phase. Psychoneuroendocrinology, 28, 35-47.

    • Pruessner, J., C., Wolf, O.T., Hellhammer, D. H., et al. (1997). Free cortisol levels after awakening: a reliable biological marker for the assessment of adrenocortical activity. Life Science, 61, 2539-2549.

    • Russell, E., Koren, G., Rieder, M., & Van Uum. (2012). Hair cortisol as a biological marker of chronic stress: current status, future directions and unanswered questions. Psychoneuroendocrinology, 37, 589-601.

    Thyroid stimulating hormone and cortisol concentration
    Thyroid Stimulating Hormone and Cortisol Concentration

    • Serum cortisol levels among individuals with TSH levels >2.0 uIU/L (N=31) were significantly higher than among those individuals with TSH levels ≤ 2.0 uIU/L (N=20) [13.83 ± 0.93 ug/dL vs. 8.66 ± 0.59 ug/dL, respectively, F(1,48)=14.24, p<0.0001].

    • Walter, Corwin, Ulbrecht, Demers, Bennett, Whetzel, & Klein (2012). Thyroid Research.

    Conversion factor
    Conversion Factor

    • To change cortisol from

      • Microgram to nanomolar ;

        • Microgram x 2.76