Basal cortisol levels and the relationship with clinical symptoms in multiple sclerosis: a systematic review

Pereira, Gabriela Magalhães; Soares, Nayron Medeiros; Souza, Andreo Rysdyk de; Becker, Jefferson; Finkelsztejn, Alessandro; Almeida, Rosa Maria Martins de

doi:10.1590/0004-282X20180091

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Arquivos de Neuro-Psiquiatria

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View and Review • Arq. Neuro-Psiquiatr. 76 (9) • Sept 2018 • https://doi.org/10.1590/0004-282X20180091 copy

Basal cortisol levels and the relationship with clinical symptoms in multiple sclerosis: a systematic review

Níveis de cortisol basal e a relação com sintomas clínicos na esclerose múltipla: uma revisão sistemática

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Multiple sclerosis (MS) is a demyelinating, progressive and neurodegenerative disease. A disturbance on the hypothalamic-pituitary-adrenal axis can be observed in patients with MS, showing altered cortisol levels. We aimed to identify basal cortisol levels and verify the relationship with clinical symptoms in patients with MS. A systematic search was conducted in the databases: Pubmed, Web of Science and SCOPUS. Both higher and lower cortisol levels were associated with MS. Higher cortisol levels were associated with depression and anxiety, while lower levels were associated with depression, fatigue and urinary dysfunction. Higher cortisol levels may be associated with the progression and severity of MS.

Keywords:
Multiple sclerosis; hydrocortisone; pituitary-adrenal system; neurologic manifestations; general symptoms

Authors, year	Objective	Subjects	Groups (n)	EDSS	Age (years)	Assessment	Sample type	Basal cortisol	Main results
Authors, year	Objective	(n)	Groups (n)	EDSS	Age (years)	Assessment	Sample type	Basal cortisol	Main results
Akcali et al., 2017⁵⁰50. Akcali A, Zengin F, Aksoy SN, Zengin O. Fatigue in Multiple Sclerosis: is it related to cytokines and hypothalamic-pituitaryadrenal axis? Mult Scler Relat Disord. 2017 Jul;15:37-41. https://doi.org/10.1016/j.msard.2017.03.004 https://doi.org/10.1016/j.msard.2017.03....	To compare Fatigue Severity Scale and Neurological Fatigue Index-MS and assess the relation between fatigue and serum biomarkers in patients with MS	80	MS Fatigued = 26	1.34 ± 1.09 0.98 ± 1.15	34.6 ± 8.5	Fatigue Severity Scale, Neurological Fatigue Index-MS, serum IL-1β, TNF-α, IL-35, IL-2, IL-10, ACTH, cortisol, α-MSH, β-MSH, γ-MSH and CLIP	Serum	22.26 ± 8.43 μg/dl	Cortisol levels were elevated in fatigued and non-fatigued patients in comparison to control group. Cortisol was similar in fatigued and non-fatigued patient groups.
		F= 42	MS Non-fatigued = 28		33.9 ± 7.4			20.90 ± 6.68 μg/dl
		M = 38	Control = 26		32.4 ± 4.0			15.38 ± 9.57 μg/dl
Villoslada et al., 2017⁴⁹49. Villoslada P, Alonso C, Agirrezabal I, Kotelnikova E, Zubizarreta I, Pulido-Valdeolivas I et al. Metabolomic signatures associated with disease severity in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2017 Jan;4(2):e321. https://doi.org/10.1212/NXI.0000000000000321 https://doi.org/10.1212/NXI.000000000000...	To identify biomarkers to severity of MS.	312	MS = 238	1.5 (0-.5.)	33.6 ± 8.7	Retrospective cohort study.	Serum	–	Cortisol levels showed just a trend of association with disability and severity measured two years later.
		F = 196	Control = 74	2.0 (0-7.5)	33.2 ± 4.2	Cortisol assessment in the first meeting and 2 years later.
		M = 116
Najafi; Moghadasi, 2017⁴³43. Najafi P, Moghadasi M. The effect of yoga training on enhancement of Adrenocorticotropic hormone (ACTH) and cortisol levels in female patients with multiple sclerosis. Complement Ther Clin Pract. 2017 Feb;26:21-5. https://doi.org/10.1016/j.ctcp.2016.11.006 https://doi.org/10.1016/j.ctcp.2016.11.0...	To assess training effect of yoga on cortisol and ACTH levels in MS females.	24	MS yoga = 14	1 to 5.5	29 to 50	90 minutes of yoga, 3 times a week, for 8 weeks. Assessment done 48h before first training and 48h after last training.	Plasma	3.56 ± 1.22 µg/dL	Post-training cortisol levels decreased in comparison to pre-training, also when compared with control group.
		F = 24	MS control = 10	1 to 5.5	29 to 50		Plasma	11.69 ± 1.25 µg/dL
Melief et al., 2016²⁴24. Melief J, Koper JW, Endert E, Møller HJ, Hamann J, Uitdehaag BM et al. Glucocorticoid receptor haplotypes conferring increased sensitivity (BclI and N363S) are associated with faster progression of multiple sclerosis. J Neuroimmunol. 2016 Oct;299:84-9. https://doi.org/10.1016/j.jneuroim.2016.08.019 https://doi.org/10.1016/j.jneuroim.2016....	To explore prognostic relevance of assessment of GR haplotype and cortisol levels and sCD163 in CSF of patients with MS.	137^* * 104 for cortisol analysis (17 excluded);	SPMS = 77	6.0	55 to 78	Postmortem assessment, CSF from lateral ventricles centrifuged.	CSF	–	Cortisol was correlated with sCD163, especially in GS-L group. There was no correlation of cortisol with time of progress and duration of MS according to EDSS 6,0.
		M = 46	PPMS = 34
		F = 91	RRMS = 26
Arata; Sternber, 2016⁵¹51. Arata M, Sternberg Z. Neuroendocrine responses to transvascular autonomic modulation: a modified balloon angioplasty in multiple sclerosis patients. Horm Metab Res. 2016 Feb;48(2):123-9. https://doi.org/10.1055/s-0035-1547235 https://doi.org/10.1055/s-0035-1547235...	To examine effects from TVAM of the HPA axis in patients with MS and to determine any relationship between the autonomic nervous system function and the HPA axis.	72	RRMS = 61	–	49.6 ± 11	Measurement of cortisol, ACTH, systolic and diastolic pressures, cardiac frequency variability, 24h before and after TVAM.	Serum	10.7 ± 0.6 pg/ml	Decrease of cortisol and ACTH before TVAM in 18% and 25% of the patients. There was a significant reduction in cortisol levels and ACTH after TVAM. Cortisol was correlated with systolic pressure.
		M = 26	PPMS = 6
		F = 44	SPMS = 5
Koutsis et al., 2016⁵²52. Koutsis G, Evangelopoulos ME, Sfagos C, Markianos M. Neurochemical and neuroendocrine correlates of overactive bladder at first demyelinating episode. Neurourol Urodyn. 2016 Nov;35(8):955-8. https://doi.org/10.1002/nau.22834 https://doi.org/10.1002/nau.22834...	To investigate neuroendocrine correlations with bladder dysfunction at the beginning of MS.	101	Overactive bladder-yes = 15	1.93 ± 0.9	33.9 ± 11.4	Cortisol sample collected within 12 first months since the first demyelination episode.	Serum	139 ± 68 ng/ml	Cortisol levels significantly lower in overactive bladder -Yes group. No correlation between cortisol levels and MS duration.
		M = 37	Overactive bladder-no = 86	1.37 ± 1.07	35.3 ± 8.5			92 ± 42 ng/ml
		F = 64
Baranowska-Bik et al., 2015³¹31. Baranowska-Bik A, Kochanowski J, Uchman D, Litwiniuk A, Kalisz M, Martynska L et al. Association of copeptin and cortisol in newly diagnosed multiple sclerosis patients. J Neuroimmunol. 2015 May;282:21-4. https://doi.org/10.1016/j.jneuroim.2015.03.011 https://doi.org/10.1016/j.jneuroim.2015....	To evaluate cortisol plasma levels and copeptin in recently-diagnosed patients.	82	MS = 40	1.56 ± 0.89	34.43 ± 8.5	Blood samples were collected 8h after overnight fasting. BMI was measured to subdivide groups into lean and overweight/obese individuals.	Plasma	348.58 ± 158 nmol/l	Cortisol levels were significantly higher in the MS overweight/obese group in comparison with the overweight/obese controls and MS lean group. There was positive correlation between cortisol and copeptin, and between cortisol and C reactive protein.
		M = 17	Control = 42	–	32.28 ± 8.1			337.04 ± 265.3 nmol/l
		F = 65
Powell et al., 2015²⁵25. Powell DJ, Moss-Morris R, Liossi C, Schlotz W. Circadian cortisol and fatigue severity in relapsing-remitting multiple sclerosis. Psychoneuroendocrinology. 2015 Jun;56:120-31. https://doi.org/10.1016/j.psyneuen.2015.03.010 https://doi.org/10.1016/j.psyneuen.2015....	To explore the relationship between cortisol and fatigue in RRMS.	76	RRMS = 38	4.3 5 ±1.40	41.89 ± 7.53	Ecological momentary assessment performed 4 consecutive days in two projects: one based in events (CAR) – collection performed at awakening; 30 and 45 minutes later; based in time (DCS) — 6 quasi-random samples distributed in 1000h and 2000h.	Saliva	13.57 ± 3.77 nmol/L/min	CAR was higher in RRMS than in the control group. Accumulated fatigue in RRMS was associated with lower cortisol levels at awakening and higher CAR. The CAR was not associated with fatigue on the same day.
		M = 14	Control = 38	–	40.34 ± 8.16			13.57 ± 3.77 nmol/L/min
		F = 62						11.78 ± 2.95 nmol/L/min
Eftekhari et al., 2014⁴⁴44. Eftekhari E, Etemadifar M, Mostahfezian M, Zafari A. Effects of resistance training and vibration on hormonal changes in female patients with multiple sclerosis. Neurol Asia. 2014;19:63-7.	To determine if a resistance training program and whole body vibration has any effect on hormone changes in female MS patients.	24	RRMS = 12	2.87 ± 0.82	35.08 ± 6.89	Resistance training and vibration, 3 weekly sessions for 8 weeks. Cortisol was measured before and after intervention, between the 8^th and 10^th day of the follicular phase of the menstrual cycle.	Serum	12.32 ± 4.1 ng/ml	Significant reduction in cortisol concentrations after training in RRMS compared with control group.
		F = 24	Control = 12	2.79 ± 0.65	33.75 ± 5.32		Serum	9.51 ± 3.4 ng/ml
Melief et al., 2013³⁰30. Melief J, Wit SJ, Eden CG, Teunissen C, Hamann J, Uitdehaag BM et al. HPA axis activity in multiple sclerosis correlates with disease severity, lesion type and gene expression in normal-appearing white matter. Acta Neuropathol. 2013 Aug;126(2):237-49. https://doi.org/10.1007/s00401-013-1140-7 https://doi.org/10.1007/s00401-013-1140-...	To investigate how activity of the HPA axis in MS is related to severity, neurodegeneration, depression, lesions and genic expression in normal-appearing white matter.	49	–	3 to 9	32 a 83	Postmortem study. Normal-appearing white matter and hypothalamus were dissected and stored for 30 days. CSF collected to analyze cortisol. Corticotropinreleasing hormone expressing neurons counted.	CSF	236 nmol/l	Higher cortisol levels are associated with delay in MS progression, above all in women with SPMS. Lower cortisol was related to higher number of active lesions and smaller remyelinated plates, and related to quick progression of MS. No differences in lower and higher cortisol levels with humor disorders.
		M = 13
		F = 36
Kern et al., 2013⁴⁵45. Kern S, Krause I, Horntrich A, Thomas K, Aderhold J, Ziemssen T. Cortisol awakening response is linked to disease course and progression in multiple sclerosis. PLoS One. 2013 Apr;8(4):e60647. https://doi.org/10.1371/journal.pone.0060647 https://doi.org/10.1371/journal.pone.006...	To measure cortisol daily release, including CAR under basal conditions.	111	RRMS = 55	2.71	36.56	EDSS, CES-D and TICS.	Saliva	–	Circadian release of cortisol in RRMS was different in the control group. There was no difference in CAR in treated and never treated patients. Follow-up groups with progression of EDSS showed a significant increase in CAR when compared with the controls. Stress and depression did not correlate with CAR in RRMS.
		M = 46	SPMS = 22	4.86	45.91	Cortisol collected 6 times over 24h (on awakening, 20, 45, 60 minutes later, 3 pm and 10pm, on 2 separate days within 2 weeks.
		F = 65	Control = 34		35.56
Wipfler et al., 2013⁴⁶46. Wipfler P, Heikkinen A, Harrer A, Pilz G, Kunz A, Golaszewski SM et al. Circadian rhythmicity of inflammatory serum parameters: a neglected issue in the search of biomarkers in multiple sclerosis. J Neurol. 2013 Jan;260(1):221-7. https://doi.org/10.1007/s00415-012-6622-3 https://doi.org/10.1007/s00415-012-6622-...	To investigate a potential circadian periodicity of expression levels of several cytokines relevant to MS, adhesion molecules and cytokine receptors.	68	RRMS = 34 (12 PAD; 22 PNAD)	1.75 (0.0–5.0)	36.7 ± 7.6	Blood collection at 7am, 11am, 2:30pm, 6pm and 9:30pm. Cortisol.	Serum	22.00 lg/dl – 7.30am	No significant differences in cortisol levels during the day. There was a decrease in cortisol between 7:30am and 9:30pm in both MS groups. Cortisol was higher in PAD if compared to PNAD.
		M = 16	Control = 34					3.60 lg/dl – 9.30 pm
		F = 52		–	36.8 ± 7.2
Kern et al., 2011⁵5. Kern S, Schultheiss T, Schneider H, Schrempf W, Reichmann H, Ziemssen T. Circadian cortisol, depressive symptoms and neurological impairment in early multiple sclerosis. Psychoneuroendocrinology. 2011 Nov;36(10):1505-12. https://doi.org/10.1016/j.psyneuen.2011.04.004 https://doi.org/10.1016/j.psyneuen.2011....	To examine circadian function of the HPA axis and CAR in patients with RRMS, with maximal duration of 36 months.	48	RRMS = 32	–	30.53	CAR assessed on two different days in a week. Sample collected on awakening, 30, 45, 60 minutes later, at 3pm and 10pm. EDSS and BDI.	Saliva	Low BDI 1299.92 ± 394.33 nmol/l	RRMS showed higher CAR levels than the control group. Only RRMS patients with moderately higher BDI had different levels compared to controls.
		M = 11	Control = 16	–	30.37			High BDI 1486.40 ± 435.29 nmol/l
		F = 37
Gold et al., 2011³⁷37. Gold SM, Krüger S, Ziegler KJ, Krieger T, Schulz KH, Otte C et al. Endocrine and immune substrates of depressive symptoms and fatigue in multiple sclerosis patients with comorbid major depression. J Neurol Neurosurg Psychiatry. 2011 Jul;82(7):814-8. https://doi.org/10.1136/jnnp.2010.230029 https://doi.org/10.1136/jnnp.2010.230029...	To examine the role of the HPA axis activity in subpopulations of T-cells from patients with RRMS and MDD.	44	RRMS = 34	2.2 ± 0.2	35.8 ± 0.7	Circadian profile collected on 2 consecutive days at awakening, 11am, 3pm, 8pm and 10pm. EDSS and Hospital.	Saliva	–	Patients with MDD showed HPA axis hyperactivity, with elevated cortisol levels at night. No differences observed in CAR between groups. Decrease in cortisol levels was not associated with CAR but was a significant predictor of severity in depression.
		F = 44	RRMS-MDD = 10	3.3 ± 0.3	37.2 ± 2.2	Anxiety and Depression Scale.	Saliva	–
Lombardi et al., 2011⁵³53. Lombardi G, Celso M, Bartelli M, Cilotti A, Del Popolo G. Female sexual dysfunction and hormonal status in multiple sclerosis patients. J Sex Med. 2011 Apr;8(4):1138-46. https://doi.org/10.1111/j.1743-6109.2010.02161.x https://doi.org/10.1111/j.1743-6109.2010...	To investigate the correlation between blood hormones and SD in women of reproductive age with MS.	55	MS-SD = 31	2.9 (1.5-6)	34.7 (26-44)	Hormone assessment, including cortisol on the third day of menstrual cycle. FSFI, EDSS.	Serum	232.14 (180–366) nmol/l	No alteration in cortisol levels in comparison to standard laboratory levels and no correlation with the FSFI.
		F = 55	EM = 24	–	–		Serum	232.14 (180–366) nmol/l
Gold et al., 2010⁴⁷47. Gold SM, Kern KC, O’Connor MF, Montag MJ, Kim A, Yoo YS et al. Smaller cornu ammonis 2-3/dentate gyrus volumes and elevated cortisol in multiple sclerosis patients with depressive symptoms. Biol Psychiatry. 2010 Sep;68(6):553-9. https://doi.org/10.1016/j.biopsych.2010.04.025 https://doi.org/10.1016/j.biopsych.2010....	To explore if specific sub-regional volumes of hippocampus can be linked to alterations in daytime cortisol secretion.	49	RRMS = 29	2.5 ± 0.2	37.5 ± 1.6	BDI-II, BAI, MRI of hippocampus, dentate gyrus, subiculum and entorhinal cortex. Diurnal cortisol was collected at awakening, 4pm and 9pm on two consecutive days.	Saliva	–	Patients with RRMS and depressive symptoms showed higher cortisol levels and a smaller CA23DG. The volume of CA23DG was correlated cortisol levels.
		M = 6	Control = 20	–	35.1 ± 1.9
		F = 43
Heidbrink et al., 2010⁴⁸48. Heidbrink C, Häusler SF, Buttmann M, Ossadnik M, Strik HM, Keller A et al. Reduced cortisol levels in cerebrospinal fluid and differential distribution of 11beta-hydroxysteroid dehydrogenases in multiple sclerosis: implications for lesion pathogenesis. Brain Behav Immun. 2010 Aug;24(6):975-84. https://doi.org/10.1016/j.bbi.2010.04.003 https://doi.org/10.1016/j.bbi.2010.04.00...	To determine DHEA and cortisol levels in CSF and blood of patients with MS, OIND and NIND.	78	MS = 34	–	41 (16-65)	Blood and CSF collected consecutively between 1pm and 3pm.	CSF and Serum	–	Serum cortisol in MS was just as observed in NIND. CSF cortisol levels in MS were significantly lower. There was positive correlation between MS and OIND in paired CSF and blood analysis. Cortisol levels were lower in CSF and normal in blood during an acute relapse.
		M = 33	OIND = 16	–	42 (20-86)
		F = 45	NIND = 28	–	49 (22-81)
Mackereth et al., 2009⁵⁴54. Mackereth PA, Booth K, Hillier VF, Caress AL. Reflexology and progressive muscle relaxation training for people with multiple sclerosis: a crossover trial. Complement Ther Clin Pract. 2009 Feb;15(1):14-21. https://doi.org/10.1016/j.ctcp.2008.07.002 https://doi.org/10.1016/j.ctcp.2008.07.0...	To compare the effects of muscle relaxing and reflexology training in people with MS.	50	Group 1 = 25	–	48.1 ± 11.06	Six weekly session of progressive muscular relaxation; followed by 4 weeks of washout and six-weekly reflexology sessions. SF-36, QHG 28, SAI, cortisol, systolic and diastolic pressure.	Saliva	7.88 ± 5.35	Diminished cortisol levels after one and six weeks. Reduction of anxiety symptoms and systolic pressure.
		M = 12	Group 2 = 25	–	52.5 ± 11.6			8.49 ± 5.11
		F = 38
Ysrraelit et al., 2008³²32. Ysrraelit MC, Gaitán MI, Lopez AS, Correale J. Impaired hypothalamic-pituitary-adrenal axis activity in patients with multiple sclerosis. Neurology. 2008 Dec;71(24):1948-54. https://doi.org/10.1212/01.wnl.0000336918.32695.6b https://doi.org/10.1212/01.wnl.000033691...	To investigate HPA activity in MS subgroups.	233	PPMS = 40	4.3 ± 1.6	49.5 ± 12.7	EDSS, BDI, HDS, MFIS. Cortisol, ACTH, DHEAS.	Plasma	µg/dL^* * 104 for cortisol analysis (17 excluded);	Statistically higher cortisol levels in all groups with MS patients. RRMS relapse group showed higher hyperactivity. There was no correlation between fatigue and depression with cortisol levels.
		M = 79	SPMS = 41	5.6 ± 1.4	51.2 ± 10.1			23.0 ± 7
		F = 154	RRMS = 58	1.3 ± 1.1	36.8 ± 10			18.4 ± 4.1
			RRMS relapse = 34	2 ± 1.4	37.5 ± 8.4			18.4 ± 5.1
			Control = 60	–	49.0 ± 5.0			24.6 ± 5.5
							Urine	µg/24h
								348.3 ± 115.6
								271.8 ± 65.7
								294.1 ± 7
								441.5 ± 67.9
Téllez et al., 2006⁴⁰40. Téllez N, Comabella M, Julià E, Río J, Tintoré M, Brieva L, et al. Fatigue in progressive multiple sclerosis is associated with low levels of dehydroepiandrosterone. Mult Scler. 2006;12(4):487-94. https://doi.org/10.1191/135248505ms1322oa https://doi.org/10.1191/135248505ms1322o...	To test if fatigue in MS is associated to endocrine biomarkers.	38	MS with fatigue = 29	6.0 (6.5-4.0)	50.1 ± 8.1	FSS, cortisol, DHEAS and basal DHEA.	Serum	–	No differences in cortisol levels between groups.
		F = 25	MS without fatigue = 9	6.0 (6.0-3.5)	45.0 ± 7.7
		M = 13

Study, Year	Sample randomization	Pharmacologic Therapy	Cortisol storage time	Cortisol storage temperature	Assessment kit
Akcali et al., 2017⁵⁰50. Akcali A, Zengin F, Aksoy SN, Zengin O. Fatigue in Multiple Sclerosis: is it related to cytokines and hypothalamic-pituitaryadrenal axis? Mult Scler Relat Disord. 2017 Jul;15:37-41. https://doi.org/10.1016/j.msard.2017.03.004 https://doi.org/10.1016/j.msard.2017.03....	No	Without DMT or corticosteroids – 3 months	–	-80 °C	Electrochemiluminescence Cobas^® 8000 modular system
Villoslada et al. 2017⁴⁹49. Villoslada P, Alonso C, Agirrezabal I, Kotelnikova E, Zubizarreta I, Pulido-Valdeolivas I et al. Metabolomic signatures associated with disease severity in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2017 Jan;4(2):e321. https://doi.org/10.1212/NXI.0000000000000321 https://doi.org/10.1212/NXI.000000000000...	Yes	DMT	–	-80 °C	Ultra-high pressure liquid chromatography-MS
Najafi; Moghadasi, 2017⁴³43. Najafi P, Moghadasi M. The effect of yoga training on enhancement of Adrenocorticotropic hormone (ACTH) and cortisol levels in female patients with multiple sclerosis. Complement Ther Clin Pract. 2017 Feb;26:21-5. https://doi.org/10.1016/j.ctcp.2016.11.006 https://doi.org/10.1016/j.ctcp.2016.11.0...	Yes	Without corticosteroids – 3 months	–	–	Radioimmunoassay
Melief et al., 2016²⁴24. Melief J, Koper JW, Endert E, Møller HJ, Hamann J, Uitdehaag BM et al. Glucocorticoid receptor haplotypes conferring increased sensitivity (BclI and N363S) are associated with faster progression of multiple sclerosis. J Neuroimmunol. 2016 Oct;299:84-9. https://doi.org/10.1016/j.jneuroim.2016.08.019 https://doi.org/10.1016/j.jneuroim.2016....	No	–	–	-80 °C	Radioimmunoassay
Koutsis et al., 2016⁵²52. Koutsis G, Evangelopoulos ME, Sfagos C, Markianos M. Neurochemical and neuroendocrine correlates of overactive bladder at first demyelinating episode. Neurourol Urodyn. 2016 Nov;35(8):955-8. https://doi.org/10.1002/nau.22834 https://doi.org/10.1002/nau.22834...	No	Drug-free	3 months	-30 °C	Radioimmunoassay
Baranowska-Bik et al., 2015³¹31. Baranowska-Bik A, Kochanowski J, Uchman D, Litwiniuk A, Kalisz M, Martynska L et al. Association of copeptin and cortisol in newly diagnosed multiple sclerosis patients. J Neuroimmunol. 2015 May;282:21-4. https://doi.org/10.1016/j.jneuroim.2015.03.011 https://doi.org/10.1016/j.jneuroim.2015....	No	Naive	–	-70 °C	Radioimmunoassay
Powell et al., 2015²⁵25. Powell DJ, Moss-Morris R, Liossi C, Schlotz W. Circadian cortisol and fatigue severity in relapsing-remitting multiple sclerosis. Psychoneuroendocrinology. 2015 Jun;56:120-31. https://doi.org/10.1016/j.psyneuen.2015.03.010 https://doi.org/10.1016/j.psyneuen.2015....	No	Without corticosteroids – 3 months	–	-20 °C	Immunoassay with fluorescent detection
Arata; Sternberg, 2016⁵¹51. Arata M, Sternberg Z. Neuroendocrine responses to transvascular autonomic modulation: a modified balloon angioplasty in multiple sclerosis patients. Horm Metab Res. 2016 Feb;48(2):123-9. https://doi.org/10.1055/s-0035-1547235 https://doi.org/10.1055/s-0035-1547235...	No	–	–	–	Electrochemiluminescence assay
Melief et al., 2013³⁰30. Melief J, Wit SJ, Eden CG, Teunissen C, Hamann J, Uitdehaag BM et al. HPA axis activity in multiple sclerosis correlates with disease severity, lesion type and gene expression in normal-appearing white matter. Acta Neuropathol. 2013 Aug;126(2):237-49. https://doi.org/10.1007/s00401-013-1140-7 https://doi.org/10.1007/s00401-013-1140-...	No	Without corticosteroids – 8 weeks	–	-70 °C	Radioimmunoassay
Kern et al., 2013⁴⁵45. Kern S, Krause I, Horntrich A, Thomas K, Aderhold J, Ziemssen T. Cortisol awakening response is linked to disease course and progression in multiple sclerosis. PLoS One. 2013 Apr;8(4):e60647. https://doi.org/10.1371/journal.pone.0060647 https://doi.org/10.1371/journal.pone.006...	No	Naive and DMT	–	-20 °C	Immunoluminescence assay
Wipfler et al., 2013⁴⁶46. Wipfler P, Heikkinen A, Harrer A, Pilz G, Kunz A, Golaszewski SM et al. Circadian rhythmicity of inflammatory serum parameters: a neglected issue in the search of biomarkers in multiple sclerosis. J Neurol. 2013 Jan;260(1):221-7. https://doi.org/10.1007/s00415-012-6622-3 https://doi.org/10.1007/s00415-012-6622-...	No	Without immunomodulatory/ immunosuppressive therapy (3/6 months)	–	–	ELISA enzymatic immunoassay
Kern et al., 2011⁵5. Kern S, Schultheiss T, Schneider H, Schrempf W, Reichmann H, Ziemssen T. Circadian cortisol, depressive symptoms and neurological impairment in early multiple sclerosis. Psychoneuroendocrinology. 2011 Nov;36(10):1505-12. https://doi.org/10.1016/j.psyneuen.2011.04.004 https://doi.org/10.1016/j.psyneuen.2011....	No	Within DMT/without glucocorticoids – 4 weeks	–	-20 °C	Immunoluminescence assay
Gold et al., 2011³⁷37. Gold SM, Krüger S, Ziegler KJ, Krieger T, Schulz KH, Otte C et al. Endocrine and immune substrates of depressive symptoms and fatigue in multiple sclerosis patients with comorbid major depression. J Neurol Neurosurg Psychiatry. 2011 Jul;82(7):814-8. https://doi.org/10.1136/jnnp.2010.230029 https://doi.org/10.1136/jnnp.2010.230029...	No	Without steroid/immunosuppressive treatment – 4 weeks	–	–	Radioimmunoassay
Lombardi et al., 2011⁵³53. Lombardi G, Celso M, Bartelli M, Cilotti A, Del Popolo G. Female sexual dysfunction and hormonal status in multiple sclerosis patients. J Sex Med. 2011 Apr;8(4):1138-46. https://doi.org/10.1111/j.1743-6109.2010.02161.x https://doi.org/10.1111/j.1743-6109.2010...	No	Without corticosteroids – 2 months	–	–	Enzymatic immunoassay
Gold et al., 2010⁴⁷47. Gold SM, Kern KC, O’Connor MF, Montag MJ, Kim A, Yoo YS et al. Smaller cornu ammonis 2-3/dentate gyrus volumes and elevated cortisol in multiple sclerosis patients with depressive symptoms. Biol Psychiatry. 2010 Sep;68(6):553-9. https://doi.org/10.1016/j.biopsych.2010.04.025 https://doi.org/10.1016/j.biopsych.2010....	No	Without steroids – 3 months	–	-20 °C	Competitive bonding assay
Heidbrink et al., 2010⁴⁸48. Heidbrink C, Häusler SF, Buttmann M, Ossadnik M, Strik HM, Keller A et al. Reduced cortisol levels in cerebrospinal fluid and differential distribution of 11beta-hydroxysteroid dehydrogenases in multiple sclerosis: implications for lesion pathogenesis. Brain Behav Immun. 2010 Aug;24(6):975-84. https://doi.org/10.1016/j.bbi.2010.04.003 https://doi.org/10.1016/j.bbi.2010.04.00...	No	Without corticosteroids, immunosuppressants or immunomodulators (3 months)	–	-80 °C	Immunoluminescent assay
Mackereth et al., 2009⁵⁴54. Mackereth PA, Booth K, Hillier VF, Caress AL. Reflexology and progressive muscle relaxation training for people with multiple sclerosis: a crossover trial. Complement Ther Clin Pract. 2009 Feb;15(1):14-21. https://doi.org/10.1016/j.ctcp.2008.07.002 https://doi.org/10.1016/j.ctcp.2008.07.0...	Yes	–	–	–	–
Ysrraelit et al., 2008³²32. Ysrraelit MC, Gaitán MI, Lopez AS, Correale J. Impaired hypothalamic-pituitary-adrenal axis activity in patients with multiple sclerosis. Neurology. 2008 Dec;71(24):1948-54. https://doi.org/10.1212/01.wnl.0000336918.32695.6b https://doi.org/10.1212/01.wnl.000033691...	No	No steroids, immunosuppressants or immunomodulators (> 6 months)	–	–	–
Eftekhari et al., 2014⁴⁴44. Eftekhari E, Etemadifar M, Mostahfezian M, Zafari A. Effects of resistance training and vibration on hormonal changes in female patients with multiple sclerosis. Neurol Asia. 2014;19:63-7.	Yes	Without corticosteroids (6 months)	–	–	–
Téllez et al., 2006⁴⁰40. Téllez N, Comabella M, Julià E, Río J, Tintoré M, Brieva L, et al. Fatigue in progressive multiple sclerosis is associated with low levels of dehydroepiandrosterone. Mult Scler. 2006;12(4):487-94. https://doi.org/10.1191/135248505ms1322oa https://doi.org/10.1191/135248505ms1322o...	Yes	No steroids (6 months)	–	-80 °C	Immunoassay with chemiluminescence
	Yes	6-methylprednisolone (only 2 patients)	–	-80 °C	Immunoassay with chemiluminescence

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[1] Correspondence: Rosa Maria Martins de Almeida; Instituto de Ciências Básicas da Saúde da UFRGS; Rua Sarmento Leite, 500; 90050-170 Porto Alegre RS, Brasil; E-mail: rosa.almeida@ufrgs.br