Lessons Learned: Cortisol

Hyper-cortisolism or hypo-cortisolism
associated with several disease conditions
Cushing’s Disease
Addison’s Disease
Congenital Adrenal Hyperplasia
Thyroid Disease
Cortisol is an objective marker of the stress
Blood (serum or plasma)
◦ Pros and Cons for each
◦ Pros:
 Non-invasive
 24-hr urine cortisol/creatinine ratio excellent
diagnostic for disease states. Not influenced by diurnal
◦ 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
 Can collect diurnal data or after stress exposure
 Best measure for diagnosing certain hyper-cortisol states
(e.g., Cushing’s via dex suppression test)
 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
◦ 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
◦ 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)
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)
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)
◦ 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?
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
A single sample
◦ unreliable unless:
 Collected accurately at a specific time of day for all
 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
Diurnal Rhythm
◦ Usually collect between 3-6 samples over the
course of 1-3 days to evaluate:
 Awakening level – considered a measure of allostatic
 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
(Pruessner, 1997)
[30 min post awakening] – [awakening]
◦ 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
Must validate correct collection times
◦ Self-report
◦ Phone calls
◦ MEMs Caps (electronic monitoring)
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
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.
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,
Walter, Corwin, Ulbrecht, Demers, Bennett,
Whetzel, & Klein (2012). Thyroid Research.
To change cortisol from
◦ Microgram to nanomolar
 Microgram x 2.76

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