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  1. Lessons Learned Cortisol

  2. 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

  3. What Medium to Use? • Urine • Blood (serum or plasma) • Saliva • Hair • Pros and Cons for each

  4. 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

  5. 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)

  6. 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

  7. 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?

  8. 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

  9. Measurement and Analysis • A single sample • unreliable unless: • Collected accurately at a specific time of day for all subjects or • 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

  10. 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

  11. Diurnal Rhythm

  12. Awakening Response • Awakening Response (Pruessner, 1997) [30 min post awakening] – [awakening] [awakening]

  13. 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

  14. Measurement and Analysis • Must validate correct collection times • Self-report • Phone calls • MEMs Caps (electronic monitoring)

  15. 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

  16. Thank you! • Questions?

  17. References • 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.

  18. 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.

  19. Conversion Factor • To change cortisol from • Microgram to nanomolar ; • Microgram x 2.76