Prognostic value of dehydroepiandrosterone-sulfate and other parameters of adrenal function in acute ischemic stroke

Claudine A Blum, Cornelia Mueller, Philipp Schuetz, Felix Fluri, Michael Trummler, Beat Mueller, Mira Katan, Mirjam Christ-Crain, Claudine A Blum, Cornelia Mueller, Philipp Schuetz, Felix Fluri, Michael Trummler, Beat Mueller, Mira Katan, Mirjam Christ-Crain

Abstract

Background and purpose: Acute stroke has a high morbidity and mortality. We evaluated the predictive value of adrenal function testing in acute ischemic stroke.

Methods: In a cohort of 231 acute ischemic stroke patients, we measured dehydroepiandrosterone (DHEA), DHEA-Sulfate (DHEAS), cortisol at baseline and 30 minutes after stimulation with 1 ug ACTH. Delta cortisol, the amount of rise in the 1 ug ACTH-test, was calculated. Primary endpoint was poor functional outcome defined as modified Rankin scale 3-6 after 1 year. Secondary endpoint was nonsurvival after 1 year.

Results: Logistic regression analysis showed that DHEAS (OR 1.21, 95% CI 1.01-1.49), but not DHEA (OR 1.01, 95% CI 0.99-1.04), was predictive for adverse functional outcome. Neither DHEA (OR 0.99, 95% CI 0.96-1.03) nor DHEAS (OR 1.10, 95% CI 0.82-1.44) were associated with mortality. Baseline and stimulated cortisol were predictive for mortality (OR 1.41, 95% CI 1.20-1.71; 1.35, 95% CI 1.15-1.60), but only basal cortisol for functional outcome (OR 1.20, 95% CI 1.04-1.38). Delta cortisol was not predictive for functional outcome (OR 0.86, 95% CI 0.71-1.05) or mortality (OR 0.92, 95% CI 0.72-1.17). The ratios cortisol/DHEA and cortisol/DHEAS discriminated between favorable outcome and nonsurvival (both p<0.0001) and between unfavorable outcome and nonsurvival (p = 0.0071 and 0.0029), but are not independent predictors for functional outcome or mortality in multivariate analysis (adjusted OR for functional outcome for both 1.0 (95% CI 0.99-1.0), adjusted OR for mortality for both 1.0 (95% CI 0.99-1.0 and 1.0-1.01, respectively)).

Conclusion: DHEAS and the cortisol/DHEAS ratio predicts functional outcome 1 year after stroke whereas cortisol levels predict functional outcome and mortality.

Trial registration: ClinicalTrials.gov NCT00390962 (Retrospective analysis of this cohort).

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Kaplan Meier Survival Curves.
Figure 1. Kaplan Meier Survival Curves.
A. Survival in relation to median cortisol level of 475 nmol/L. p = 0.0014, Hazard Ratio 0.35, 95% CI 0.19–0.67. B. Survival in relation to median stimulated cortisol level of 742 nmol/L. p = 0.015, Hazard Ratio 0.4496, 95% CI 0.24–0.86. C. Survival in relation to median dehydroepiandrosterone level of 15.5 nmol/L. p = 0.0236, Hazard Ratio 2.09, 95% CI 1.104 to 3.955. D. Survival in relation to median dehydroepiandrosterone-sulfate level of 2.4 umol/L. p = 0.1490, Hazard Ratio 1.60, 95% CI 0.85–3.80. E. Survival in relation to median cortisol/DHEA level of 27 nmol/nmol. p = 0.0002, Hazard Ratio 0.32, 95% CI 0.17–0.61. F: Survival in relation to median cortisol/DHEAS level of 203 nmol/micromol. p = 0.0004, Hazard Ratio 0.31, 95% CI 0.17–0.59.
Figure 2. ROC of adrenal values.
Figure 2. ROC of adrenal values.
Dehydroepiandrosterone (DHEA): Area 0.59, Std. Error 0.05, 95% CI 0.49–0.69, p = 0.07 Dehydroepiandrosterone-sulfate (DHEAS): Area 0.60, Std. Error 0.04, 95% CI 0.51–0.69, p = 0.048. Basal cortisol: Area 0.71, Std. Error 0.05, 95% CI 0.61–0.80, p

References

    1. Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD, et al. (2013) Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380: 2197–2223.
    1. Truelsen T, Piechowski-Jozwiak B, Bonita R, Mathers C, Bogousslavsky J, et al. (2006) Stroke incidence and prevalence in Europe: a review of available data. Eur J Neurol 13: 581–598.
    1. Widmer IE, Puder JJ, Konig C, Pargger H, Zerkowski HR, et al. (2005) Cortisol response in relation to the severity of stress and illness. J Clin Endocrinol Metab 90: 4579–4586.
    1. Hamrahian AH, Oseni TS, Arafah BM (2004) Measurements of serum free cortisol in critically ill patients. N Engl J Med 350: 1629–1638.
    1. Marklund N, Peltonen M, Nilsson TK, Olsson T (2004) Low and high circulating cortisol levels predict mortality and cognitive dysfunction early after stroke. J Intern Med 256: 15–21.
    1. Michalaki M, Margeli T, Tsekouras A, Gogos CH, Vagenakis AG, et al. (2010) Hypothalamic-pituitary-adrenal axis response to the severity of illness in non-critically ill patients: does relative corticosteroid insufficiency exist? Eur J Endocrinol 162: 341–347.
    1. Christensen H, Boysen G, Johannesen HH (2004) Serum-cortisol reflects severity and mortality in acute stroke. J Neurol Sci 217: 175–180.
    1. Katan M, Fluri F, Morgenthaler NG, Schuetz P, Zweifel C, et al. (2009) Copeptin: a novel, independent prognostic marker in patients with ischemic stroke. Ann Neurol 66: 799–808.
    1. Neidert S, Katan M, Schuetz P, Fluri F, Ernst A, et al. (2011) Anterior pituitary axis hormones and outcome in acute ischaemic stroke. J Intern Med 269: 420–432.
    1. Anne M, Juha K, Timo M, Mikko T, Olli V, et al. (2007) Neurohormonal activation in ischemic stroke: effects of acute phase disturbances on long-term mortality. Curr Neurovasc Res 4: 170–175.
    1. Slowik A, Turaj W, Pankiewicz J, Dziedzic T, Szermer P, et al. (2002) Hypercortisolemia in acute stroke is related to the inflammatory response. J Neurol Sci 196: 27–32.
    1. Rosenfeld RS, Hellman L, Roffwarg H, Weitzman ED, Fukushima DK, et al. (1971) Dehydroisoandrosterone is secreted episodically and synchronously with cortisol by normal man. J Clin Endocrinol Metab 33: 87–92.
    1. Pavlov EP, Harman SM, Chrousos GP, Loriaux DL, Blackman MR (1986) Responses of plasma adrenocorticotropin, cortisol, and dehydroepiandrosterone to ovine corticotropin-releasing hormone in healthy aging men. J Clin Endocrinol Metab 62: 767–772.
    1. Beishuizen A, Thijs LG, Vermes I (2002) Decreased levels of dehydroepiandrosterone sulphate in severe critical illness: a sign of exhausted adrenal reserve? Crit Care 6: 434–438.
    1. Arlt W, Hammer F, Sanning P, Butcher SK, Lord JM, et al. (2006) Dissociation of serum dehydroepiandrosterone and dehydroepiandrosterone sulfate in septic shock. J Clin Endocrinol Metab 91: 2548–2554.
    1. Marx C, Petros S, Bornstein SR, Weise M, Wendt M, et al. (2003) Adrenocortical hormones in survivors and nonsurvivors of severe sepsis: diverse time course of dehydroepiandrosterone, dehydroepiandrosterone-sulfate, and cortisol. Crit Care Med 31: 1382–1388.
    1. Baulieu EE, Robel P (1998) Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) as neuroactive neurosteroids. Proc Natl Acad Sci U S A 95: 4089–4091.
    1. Phillips AC, Carroll D, Gale CR, Lord JM, Arlt W, et al. (2010) Cortisol, DHEA sulphate, their ratio, and all-cause and cause-specific mortality in the Vietnam Experience Study. Eur J Endocrinol 163: 285–292.
    1. Barrett-Connor E, Khaw KT, Yen SS (1986) A prospective study of dehydroepiandrosterone sulfate, mortality, and cardiovascular disease. N Engl J Med 315: 1519–1524.
    1. Wang L, Hao Q, Wang YD, Wang WJ, Li DJ (2011) Protective effects of dehydroepiandrosterone on atherosclerosis in ovariectomized rabbits via alleviating inflammatory injury in endothelial cells. Atherosclerosis 214: 47–57.
    1. Bologa L, Sharma J, Roberts E (1987) Dehydroepiandrosterone and its sulfated derivative reduce neuronal death and enhance astrocytic differentiation in brain cell cultures. J Neurosci Res 17: 225–234.
    1. Lapchak PA, Chapman DF, Nunez SY, Zivin JA (2000) Dehydroepiandrosterone sulfate is neuroprotective in a reversible spinal cord ischemia model: possible involvement of GABA(A) receptors. Stroke 31: 1953–1956; discussion 1957.
    1. Corpechot C, Robel P, Axelson M, Sjovall J, Baulieu EE (1981) Characterization and measurement of dehydroepiandrosterone sulfate in rat brain. Proc Natl Acad Sci U S A 78: 4704–4707.
    1. Wolf OT, Kirschbaum C (1999) Actions of dehydroepiandrosterone and its sulfate in the central nervous system: effects on cognition and emotion in animals and humans. Brain Res Brain Res Rev 30: 264–288.
    1. Baulieu EE (1999) Neuroactive neurosteroids: dehydroepiandrosterone (DHEA) and DHEA sulphate. Acta Paediatr Suppl 88: 78–80.
    1. Kancheva R, Hill M, Novak Z, Chrastina J, Kancheva L, et al. (2011) Neuroactive steroids in periphery and cerebrospinal fluid. Neuroscience 191: 22–27.
    1. Chehab O, Ouertani M, Chaieb K, Haouala F, Mahdouani K (2007) Hormonal status of cortisol and dehydroepiandrosterone sulfate in an elderly Tunisian population. C R Biol 330: 755–763.
    1. Thijs L, Fagard R, Forette F, Nawrot T, Staessen JA (2003) Are low dehydroepiandrosterone sulphate levels predictive for cardiovascular diseases? A review of prospective and retrospective studies. Acta Cardiol 58: 403–410.
    1. Ohlsson C, Labrie F, Barrett-Connor E, Karlsson MK, Ljunggren O, et al. (2010) Low serum levels of dehydroepiandrosterone sulfate predict all-cause and cardiovascular mortality in elderly Swedish men. J Clin Endocrinol Metab 95: 4406–4414.
    1. Jeckel CM, Lopes RP, Berleze MC, Luz C, Feix L, et al. (2010) Neuroendocrine and immunological correlates of chronic stress in ‘strictly healthy’ populations. Neuroimmunomodulation 17: 9–18.
    1. Armanini D, Vecchio F, Basso A, Milone FF, Simoncini M, et al. (2003) Alzheimer’s disease: pathophysiological implications of measurement of plasma cortisol, plasma dehydroepiandrosterone sulfate, and lymphocytic corticosteroid receptors. Endocrine 22: 113–118.
    1. D’Astous M, Morissette M, Tanguay B, Callier S, Di Paolo T (2003) Dehydroepiandrosterone (DHEA) such as 17beta-estradiol prevents MPTP-induced dopamine depletion in mice. Synapse 47: 10–14.
    1. Kumpfel T, Then Bergh F, Friess E, Uhr M, Yassouridis A, et al. (1999) Dehydroepiandrosterone response to the adrenocorticotropin test and the combined dexamethasone and corticotropin-releasing hormone test in patients with multiple sclerosis. Neuroendocrinology 70: 431–438.
    1. Wade CE, Lindberg JS, Cockrell JL, Lamiell JM, Hunt MM, et al. (1988) Upon-admission adrenal steroidogenesis is adapted to the degree of illness in intensive care unit patients. J Clin Endocrinol Metab 67: 223–227.
    1. Parker LN, Levin ER, Lifrak ET (1985) Evidence for adrenocortical adaptation to severe illness. J Clin Endocrinol Metab 60: 947–952.
    1. Pappa T, Vemmos K, Saltiki K, Mantzou E, Stamatelopoulos K, et al. (2012) Severity and outcome of acute stroke in women: relation to adrenal sex steroid levels. Metabolism 61: 84–91.
    1. Cooper MS, Stewart PM (2003) Corticosteroid insufficiency in acutely ill patients. N Engl J Med 348: 727–734.
    1. Olsson T, Marklund N, Gustafson Y, Nasman B (1992) Abnormalities at different levels of the hypothalamic-pituitary-adrenocortical axis early after stroke. Stroke 23: 1573–1576.
    1. Dimopoulou I, Tsagarakis S, Douka E, Zervou M, Kouyialis AT, et al. (2004) The low-dose corticotropin stimulation test in acute traumatic and non-traumatic brain injury: incidence of hypo-responsiveness and relationship to outcome. Intensive Care Med 30: 1216–1219.
    1. von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, et al. (2007) The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet 370: 1453–1457.
    1. Hatano S (1976) Experience from a multicentre stroke register: a preliminary report. Bull World Health Organ 54: 541–553.
    1. Bamford J, Sandercock P, Dennis M, Burn J, Warlow C (1991) Classification and natural history of clinically identifiable subtypes of cerebral infarction. Lancet 337: 1521–1526.
    1. Rankin J (1957) Cerebral vascular accidents in patients over the age of 60. II. Prognosis. Scott Med J 2: 200–215.
    1. Dickstein G, Shechner C, Nicholson WE, Rosner I, Shen-Orr Z, et al. (1991) Adrenocorticotropin stimulation test: effects of basal cortisol level, time of day, and suggested new sensitive low dose test. J Clin Endocrinol Metab 72: 773–778.
    1. Goldstein LB, Samsa GP, Matchar DB, Horner RD (2004) Charlson Index comorbidity adjustment for ischemic stroke outcome studies. Stroke 35: 1941–1945.
    1. Laughlin GA, Barrett-Connor E (2000) Sexual dimorphism in the influence of advanced aging on adrenal hormone levels: the Rancho Bernardo Study. J Clin Endocrinol Metab 85: 3561–3568.
    1. de Bruin VM, Vieira MC, Rocha MN, Viana GS (2002) Cortisol and dehydroepiandosterone sulfate plasma levels and their relationship to aging, cognitive function, and dementia. Brain Cogn 50: 316–323.
    1. Valenti G (2004) Neuroendocrine hypothesis of aging: the role of corticoadrenal steroids. J Endocrinol Invest 27: 62–63.
    1. Johansson A, Olsson T, Carlberg B, Karlsson K, Fagerlund M (1997) Hypercortisolism after stroke–partly cytokine-mediated? J Neurol Sci 147: 43–47.
    1. Kleindienst A, Brabant G, Morgenthaler NG, Dixit KC, Parsch H, et al... (2010) Following brain trauma, copeptin, a stable peptide derived from the AVP precusor, does not reflect osmoregulation but correlates with injury severity. Acta Neurochir Suppl 106: 221–224.
    1. Kolditz M, Halank M, Schulte-Hubbert B, Hoffken G (2010) Adrenal function is related to prognosis in moderate community-acquired pneumonia. Eur Respir J 36: 615–621.
    1. Arnlov J, Pencina MJ, Amin S, Nam BH, Benjamin EJ, et al. (2006) Endogenous sex hormones and cardiovascular disease incidence in men. Ann Intern Med 145: 176–184.
    1. Hougaku H, Fleg JL, Najjar SS, Lakatta EG, Harman SM, et al. (2006) Relationship between androgenic hormones and arterial stiffness, based on longitudinal hormone measurements. Am J Physiol Endocrinol Metab 290: E234–242.
    1. Creatsa M, Armeni E, Stamatelopoulos K, Rizos D, Georgiopoulos G, et al... (2011) Circulating androgen levels are associated with subclinical atherosclerosis and arterial stiffness in healthy recently menopausal women. Metabolism.
    1. Sanders JL, Boudreau RM, Cappola AR, Arnold AM, Robbins J, et al. (2010) Cardiovascular disease is associated with greater incident dehydroepiandrosterone sulfate decline in the oldest old: the cardiovascular health study all stars study. J Am Geriatr Soc 58: 421–426.
    1. Phillips AC, Carroll D, Gale CR, Lord JM, Arlt W, et al. (2010) Cortisol, DHEAS, their ratio and the metabolic syndrome: evidence from the Vietnam Experience Study. Eur J Endocrinol 162: 919–923.
    1. Shufelt C, Bretsky P, Almeida CM, Johnson BD, Shaw LJ, et al. (2010) DHEA-S levels and cardiovascular disease mortality in postmenopausal women: results from the National Institutes of Health–National Heart, Lung, and Blood Institute (NHLBI)-sponsored Women’s Ischemia Syndrome Evaluation (WISE). J Clin Endocrinol Metab 95: 4985–4992.
    1. Li Z, Cui S, Zhang Z, Zhou R, Ge Y, et al. (2009) DHEA-neuroprotection and -neurotoxicity after transient cerebral ischemia in rats. J Cereb Blood Flow Metab 29: 287–296.
    1. Miyajima M, Kusuhara H, Fujishima M, Adachi Y, Sugiyama Y (2011) Organic anion transporter 3 mediates the efflux transport of an amphipathic organic anion, dehydroepiandrosterone sulfate, across the blood-brain barrier in mice. Drug Metab Dispos 39: 814–819.
    1. Ohtsuki S (2004) New aspects of the blood-brain barrier transporters; its physiological roles in the central nervous system. Biol Pharm Bull 27: 1489–1496.
    1. Dickstein G (2005) On the term “relative adrenal insufficiency”–or what do we really measure with adrenal stimulation tests? J Clin Endocrinol Metab 90: 4973–4974.
    1. Marik PE, Pastores SM, Annane D, Meduri GU, Sprung CL, et al. (2008) Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med 36: 1937–1949.
    1. de Jong MF, Beishuizen A, van Schijndel RJ, Girbes AR, Groeneveld AB (2012) Risk factors and outcome of changes in adrenal response to ACTH in the course of critical illness. J Intensive Care Med 27: 37–44.
    1. Moraes RB, Czepielewski MA, Friedman G, Borba EL (2011) Diagnosis of adrenal failure in critically ill patients. Arq Bras Endocrinol Metabol 55: 295–302.
    1. Salluh JI, Shinotsuka CR, Soares M, Bozza FA, Lapa e Silva JR, et al... (2010) Cortisol levels and adrenal response in severe community-acquired pneumonia: a systematic review of the literature. J Crit Care 25: 541 e541–548.
    1. Urwyler SA, Schuetz P, Fluri F, Morgenthaler NG, Zweifel C, et al. (2010) Prognostic value of copeptin: one-year outcome in patients with acute stroke. Stroke 41: 1564–1567.
    1. Feibel JH, Hardy PM, Campbell RG, Goldstein MN, Joynt RJ (1977) Prognostic value of the stress response following stroke. JAMA 238: 1374–1376.
    1. Folan MM, Stone RA, Pittenger AL, Stoffel JA, Hess MM, et al. (2001) Dehydroepiandrosterone, dehydroepiandrosterone-sulfate, and cortisol concentrations in intensive care unit patients. Crit Care Med 29: 965–970.
    1. Kleindienst A, Brabant G, Bock C, Maser-Gluth C, Buchfelder M (2009) Neuroendocrine function following traumatic brain injury and subsequent intensive care treatment: a prospective longitudinal evaluation. J Neurotrauma 26: 1435–1446.
    1. Delahanty DL, Nugent NR, Christopher NC, Walsh M (2005) Initial urinary epinephrine and cortisol levels predict acute PTSD symptoms in child trauma victims. Psychoneuroendocrinology 30: 121–128.
    1. Levine A, Cohen D, Zadik Z (1994) Urinary free cortisol values in children under stress. J Pediatr 125: 853–857.
    1. Rasmuson S, Andrew R, Nasman B, Seckl JR, Walker BR, et al. (2001) Increased glucocorticoid production and altered cortisol metabolism in women with mild to moderate Alzheimer’s disease. Biol Psychiatry 49: 547–552.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever