HPA Axis

Cortisol

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Description
Cortisol is a steroid hormone produced by the adrenal cortex. As a stress induced hormone, cortisol secretion to an immediate challenge is a healthy response, while consistently high cortisol reactivity to repeated familiar challenges is an atypical response that may reflect chronic physiological stress (Epel et al., 2000) and is associated with negative health outcomes in old age (Seeman et al., 1997).

Cortisol has a strong diurnal variation, generally high early in the morning and falling during the day. Cortisol typically increases over the first few minutes of the day, reaching a peak 20-30 minutes after waking (http://labtestsonline.org/understanding/analytes/cortisol/test.html).

Levels of cortisol and its antagonist dehydroepiandrosterone sulfate (DHEAS) are indicators of HPA activity. As an individual interacts with his/her environment, the stimuli encountered can serve as challenges or stressors that elicit responses from the HPA axis as well as other internal homeostatic regulatory systems. Heat, cold, infection, trauma, exercise, obesity, pregnancy, and debilitating disease influence cortisol secretion (http://labtestsonline.org/understanding/analytes/cortisol/test.html).

Drugs that can increase cortisol measurements include estrogen and synthetic glucocorticoids, like prednisone and prednisolone (http://labtestsonline.org/understanding/analytes/cortisol/test.html). Drugs that can decrease cortisol measurements include androgens and phenytoin (http://labtestsonline.org/understanding/analytes/cortisol/test.html).

Significance of Measurement
Cortisol levels have been shown to be greater among individuals experiencing chronic stress from work or emotional strain (Steptoe et al., 2000).

Health consequences of exposure to elevated cortisol include increased cardiovascular risk (Henry, 1983), poorer cognitive functioning (Lupien et al., 1994; Seeman et al., 1997), and increased risks for fractures (Greendale et al., 1999). Higher levels of urinary catecholamine excretion have also been shown to predict functional disability and mortality (Reuben et al., 2000).

Method of Measurement
Cortisol level is usually assessed using a blood test, however it can be measured using saliva or urine. Urine is collected over a 12 or 24-hour period in order to represent a daily level. Researchers can be interested in the profile of cortisol change over the day; or change in the cortisol level after waking in the morning or the pattern of change over the day. To determine cortisol pattern over the day, it may be measured as much as four or fie time times – upon waking, shortly afterward, afternoon, evening and night.

Normal levels of cortisol in the bloodstream range from 6-23 mcg/dl (micrograms per deciliter). Normal 24-hour urinary cortisol levels range from 10-100 micrograms/ 24 hours (http://labtestsonline.org/understanding/analytes/cortisol/test.html).

In the MacArthur Study the cut off of urinary cortisol was =25.69 ug/g creatinine (Seeman et al., 2004).

References
· Epel, E.S., McEwen, B., Seeman, T., Matthews, K., Castellazzo, G., Brownell, K.D., et al. (2000). Stress and body shape: Stress-induced cortisol secretion is consistently greater among women with central fat. Psychosomatic Medicine, 62(5), 623-632.
· Greendale, G., Unger, J.B., Rowe, J.W., & Seeman, T. (1999). The relation between cortisol excretion and fractures in healthy older people: Results from the MacArthur Studies of Successful Aging. Journal of the American Geriatrics Society, 47(7), 799-803.
· Henry, J. (1983). Coronary heart disease and arousal of the adrenal cortical axis. In T. Dembrosk, T. Schmidt, & G. Blumchen (Eds.), Biobehavioral Bases of Coronary Heart Disease (pp. 365-381). Basel: Karger. .
· Lab Tests Online. (2004). Cortisol. Retrieved March 25, 2005, from http://labtestsonline.org/understanding/analytes/cortisol/test.html).
· Lupien, S., LeCours, A., Lussier, I., Schwartz, G., Nair, N., & Meaney, M. (1994). Basal cortisol levels and cognitive deficits in human aging. Journal of Neuroscience, 14, 2893-2903.
· Reuben, D.B., Talvi, S.L., Rowe, J.W., & Seeman, T.E. (2000). High urinary catecholamine excretion predicts mortality and functional decline in high-functioning, community-dwelling older persons: MacArthur Studies of Successful Aging. Journal of Gerontology: Medical Sciences, 55(10), M618-M624.
· Seeman, T.E., Crimmins, E., Huang, M.H., Singer, B., Bucur, A., Gruenewald, T., et al. (2004). Cumulative biological risk and socio-economic differences in mortality: MacArthur studies of successful aging. Social Science and Medicine, 58(10), 1985-1997.
· Seeman, T., McEwen, B., Singer, B., Albert, M., & Rowe, J. (1997). Increase in urinary cortisol excretion and declines in memory: MacArthur Studies of Successful Aging. Journal of Clinical Endocrinology and Metabolism, 82, 2458-2465.
· Steptoe, A., Cropley, M., Griffith, J., & Kirschbaum, C. (2000). Job strain and anger expression predict early morning elevations in salivary cortisol. Psychosomatic Medicine, 62, 286-292.
· Please refer to the Research Network on Socioeconomic Status and Health website for details. http://www.macses.ucsf.edu/Research/Allostatic/notebook/salivarycort.html

Adrenocotricotropic hormone (ACTH)

Dehydroepiandrosterone-Sulphate(DHEA-S)

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Description
Dehydroepiandrosterone (DHEA) is a hormone produced by the adrenal gland. DHEA sulfate (DHEA-S) is synthesized from DHEA and converted into other hormones (vitacost.com). Tests measure DHEA-S instead of DHEA because DHEA-S is less rapidly cleared from the blood stream and has less diurnal variation (Kroboth et al., 1999; Longcope, 1996; Rosenfeld et al., 1971, 1975).

Production of DHEA stops at birth, then begins again around age seven and peaks when a person is in their mid-20s. From the early 30s on there is a steady decline (about 2 percent each year) until around age 75 and older when the level of DHEA in the body is about 5 percent of peak. Because DHEA-S is known to decrease with age and is related to longevity (Kalimi, & Regelson, 1999; Lopez, 1984; Roth et al., 2002; Rotter et al., 1985; Rudman et al., 1990; Thomas et al., 1994; Yen, 2001), DHEA-S has attracted attention for the possible “anti-aging” effects.

Normal values for serum DHEA-S vary with sex and age. Normal values may vary slightly among different laboratories. Normal ranges are 800-5600 mcg/l for men, 350-4300 mcg/l for women (Note: mcg/dl = microgram per deciliter).

Significance of Measurement
The level of DHEA-S is an indicator of hypothalamic-pituitary axis activity. As an individual interacts with his/her environment, the stimuli encountered can serve as challenges or stressors that elicit responses from the HPA axis as well as other internal homeostatic regulatory systems. DHEA-S has been hypothesized to serve as a functional antagonist to HPA axis activity and thus is an important indicator of overall activity in the HPA axis (Kimonides et al., 1998; Svec, & Lopez, 1989).

While there are mixed results by gender (Glei et al., 2004), the literature generally documents a positive relationship between low DHEA-S and health outcomes. Lower level of DHEA-S is related to a history of heart disease and mortality (Barrett- Connor, & Goodman-Gruen, 1995; Beer et al., 1996; Feldman et al., 1998; Jansson et al., 1998). DHEA-S is thought to be protective against heart disease because of its anticlotting and antiproliferative properties (Beer et al., 1996; Jesse et al., 1994). It is also known to be related to physical and mental functioning (Crimmins et al., 2003; Ravaglia et al., 1997; Seplaki et al., 2004). Low DHEA-S has been included as one component of allostatic load (Seeman et al., 2001, 2004). DHEA-S is one of the four primary mediators in allostatic load measures that predict mortality and secondary outcomes such as systolic and diastolic blood pressure, waist-to-hip ratio (WHR), HDL and total cholesterol and glycosylated hemoglobin (McEwen, 2000; Seeman et al. 1997). In addition, studies have found that DHEA-S is a marker for bone turnover predicting bone mineral density (Gurlek, & Gedik, 2001). Low levels have also been linked to Alzheimer’s disease (Bicikova et al., 2004).

Method of Measurement
The test can be performed on blood, saliva or urine samples.

References
· Barrett-Connor, E., & Goodman-Gruen, D. (1995). The epidemiology of DHEAS and cardiovascular disease. Annals of the New York Academy of Sciences, 774, 259-270.
· Beer, N., Jakubowicz, D.J., Matt, D.W., Beer, R.M., & Nestler, J.E. (1996). Dehydroepiandrosterone reduces plasma plasminogen activator inhibitor type I and tissue plasminogen activator antigen in men. American Journal of the Medical Sciences, 311, 205-210.
· Bicikova, M., Ripova, D., Hill, M., Jirak, R., Havlikova, H., Tallova, J., et al. (2004). Plasma levels of 7-hydroxylated dehydroepiandrosterone (DHEA) metabolites and selected amino-thiols as discriminatory tools of Alzheimer’s disease and vascular dementia. Clinical Chemistry and Laboratory Medicine, 42(5), 518-524.
· Crimmins, E.M., Johnston, M., Hayward, M., & Seeman, T. (2003). Age differences in allostatic load: An index of physiological dysregulation. Experimental Gerontology, 38, 731-734.
· Feldman, H., Johannes, C., McKinlay, J., & Longcope, C. (1998). Low dehydroepiandrosterone sulfate and heart disease in middle-aged men: Cross-sectional results from the Massachusetts Male Aging Study. Annals of Epidemiology, 8, 217-228.
· Glei, D., Goldman, N., Weinstein, M., & Liu, I. (2004). Dehydroepiandrosterone sulfate (DHEAS) and health: Does the relationship differ by sex. Experimental Gerontology, 39, 321-331.
· Gurlek, A., & Gedik, O. (2001). Endogenous sex steroid, GH and IGF-I levels in normal elderly men: Relationships with bone mineral density and markers of bone turnover. Journal of Endocrinological Investigation, 24(6), 408-414.
· Jansson, J.H., Nilsson, T.K., & Johnson, O. (1998). von Willebrand factor, tissue plasminogen activator, and dehydroepiandrosterone sulphate predict cardiovascular death in a 10 year follow up of survivors of acute myocardial infarction. Heart, 80(4), 334-337.
· Jesse, R.L., Loesser, K., Eich, D.M., Qian, Y.Z., Hess, M.L., & Nestler, J.E. (1994). Dehydroepiandrosterone inhibits human platelet aggregation in vitro and in vivo. Annals of the New York Academy of Sciences, 774, 281-290.
· Kalimi, M., & Regelson, W. (Eds.). (1999). Dehydroepiandrosterone (DHEA): Biochemical, physiological, and clinical aspects. New York: Walter de Gruyter, Inc.
· Kimonides, V., Khatibi, N., Sofroniew, M., & Herbert, J. (1998). Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS) protect hippocampal neurons against excitatory amino acid-induced neurotoxicity. Proceedings of the National Academy of Sciences of the United States of America, 95, 1852-1857.
· Kroboth, P.D., Salek, F.S., Pittenger, A.L., Fabian, T.J., & Frye, R.F. (1999). DHEA and DHEAS: A review. Journal of Clinical Pharmacology, 39, 327–348.
· Longcope, C. (1996). Dehydroepiandrosterone metabolism. Journal of Endocrinology, 150, S107–S118.
· Lopez, S.A. (1984). Metabolic and endocrine factors in aging. In H. Rothschild (Ed.), Risk Factors for Senility (pp. 205-219). New York: Oxford University Press.
· McEwen, B. (2000). Allostasis and allostatic load: Implications for neuropsychopharmacology. Neuropsychopharmacology, 22(2), 108-124.
· Ravaglia, G., Forti, P., Maioli, F., Boschi, F., Cicognani, A., Bernardi, M., et al. (1997). Determinants of functional status in healthy Italian nonagenarians and centenarians: A comprehensive functional assessment by the instruments of geriatric practice. Journal of the American Geriatrics Society, 45(10), 1196-1202.
· Rosenfeld, R.S., Hellman, L., Roffwarg, H., Weitzman, E.D., Fukushima, D.K., & Gallagher, T.F. (1971). Dehydroepiandrosterone is secreted episodically and synchronously with cortisol by normal man. Journal of Clinical Endocrinology and Metabolism, 33, 87–92.
· Rosenfeld, R.S., Rosenberg, B.J., Fukushima, D.K., & Hellman, L. (1975). 24-hour secretory pattern of dehydroepiandrosterone and dehydroepiandrosterone sulfate. Journal of Clinical Endocrinology and Metabolism, 40, 850–855.
· Roth, G.S., Lane, M.A., Ingram, D.K., Mattison, J.A., Elahi, D., Tobin, J.D., et al. (2002). Biomarkers of caloric restriction may predict longevity in humans. Science, 297, 811.
· Rotter, J.I., Wong, F.L., Lifrak, E.T., & Parker, L.N. (1985). A genetic component to the variation of dehydroepiandrosterone. Metabolism, 34(8), 731–736.
· Rudman, D., Shetty, K.R., & Mattson, D.E. (1990). Plasma dehydroepiandrosterone sulfate in nursing home men. Journal of the American Geriatrics Society, 38, 421–427.
· Seeman, T., Glei, D., Goldman, N., Weinstein, M., Singer, B., & Lin, Y.-H. (2004). Social relationships and allostatic load in Taiwanese elderly and near elderly. Social Science and Medicine, 59, 2245-2257.
· Seeman, T., McEwen, B.S., Rowe, J.W., & Singer, B.H. (2001). Allostatic load as a marker of cumulative biological risk: MacArthur studies of successful aging. Proceedings of the National Academy of Sciences of the United States of America, 98(8), 4770-4775.
· Seeman, T.E., Singer, B.H., Rowe, J.W., Horwitz, R.I., & McEwen B.S. (1997) Price of adaptation—allostatic load and its health consequences: MacArthur studies of successful aging. Archives of Internal Medicine, 157, 2259–2268.
· Seplaki, C., Goldman, N., Weinstein, M., & Lin, Y.-H. (2004). How are biomarkers related to physical and mental well-being? Journal of Gerontology: Biological Sciences, 59, B201-B217.
· Svec, S., & Lopez, A. (1989). Antiglucocorticoid actions of dehydroepiandrosterone and low concentrations in Alzheimer’s disease. Lancet, 2, 1335-1336.
· Thomas, G., Frenoy, N., Legrain, S., Sebag-Lanoe, R., Baulieu, E.E., Debuire, B. (1994). Serum dehydroepiandrosterone sulfate levels as an individual marker. Journal of Clinical Endocrinology and Metabolism, 79, 1273–1276.
· Yen, S.S.C. (2001). Dehydroepiandrosterone sulfate and longevity: new clues for an old friend. Proceedings of the National Academy of Sciences of the United States of America, 98(15), 8167–8169.