CoChat
Sign Up
Cited by 28Vitamin D Research StudiesMultiple Sclerosis Research StudiesStress Responses and Cortisol

Stress-Axis Regulation by Vitamin D3 in Multiple Sclerosis

Open access
Rolf, Linda, Damoiseaux, Jan, Huitinga, Inge, Kimenai, Dorien, van den Ouweland, Jody, Hupperts, Raymond, Smolders, Joost·2018·Frontiers in Neurology
DOI 10.3389/fneur.2018.00263PMC PMC5933207
Open this paper in CoChat — free accountOpen PDF

Abstract

INTRODUCTION: Multiple sclerosis (MS) has been associated with both a poor vitamin D status and hyperactivity of the hypothalamus-pituitary-adrenal (HPA) axis. Since nuclear receptor ligands may regulate each other, we explored the association of vitamin D3 supplements with circadian cortisol levels in a double-blind and placebo-controlled supplementation study. METHODS: Female patients with relapsing-remitting MS received vitamin D3 supplements (4000 IU/day; n=22) or placebo (n=19) during 16 weeks. Salivary cortisol levels, repeatedly measured during the day, and serum 25(OH)D levels were assessed before (T0) and after (T1) this treatment period. RESULTS: Median 25(OH)D levels at T1 were 139.9 nmol/L (interquartile range 123.5 – 161.2) and 74.5 nmol/L (58.6 – 88.1) in the vitamin D3 and placebo group, respectively (p<0.001). Comparisons within and between groups showed no differences in area under the curve (AUC) and slope of the cortisol day curve. Although the AUC of the cortisol awakening response (CAR, sampling each 15 minutes the first hour after awakening) showed a reduction over time in the vitamin D3 group (39.16 nmol/L (27.41 – 42.07) at T0 to 33.37 nmol/L (26.75 – 38.08) at T1) compared to the placebo group (33.90 nmol/L (25.92 – 44.61) at T0 to 35.00 nmol/L (25.46 – 49.23) at T1; p= 0.044), there was no significant difference in AUC of CAR at T1 corrected for baseline AUC of CAR (P=0.066). CONCLUSION: Suppression of HPA-axis activity by vitamin D3 supplements in non-depressed MS patients may be best reflected by CAR as primary outcome measure. Further studies should address this interaction and its potential implications for the disease course of MS. REGISTRATION: This study was registered on ClinicalTrials.gov (NCT02096133) and EudraCT (2014-000728-97).

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3389/fneur.2018.00263

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Results of studies in genetically modified mice without vitamin D receptor show gonadal failure leading to hyper-gonadotrophic hypogonadism and reduced sperm count and motility.

    “this hypothesis was supported by the results of studies in genetically modified mice, which have no receptor for vitamin D and have suffered gonadal failure leading to hyper-gonadotrophic hypogonadism as well as reduced sperm count and motility.”

    From Influence of Sunlight and Oral D3 Supplementation on Serum 25(OH)D Concentration and Exercise Performance in Elite Soccer Players (2020) · cites this paper as [40]

    The Materials and Methods (Participants) describe a trial in female patients with multiple sclerosis, and the Discussion addresses vitamin D3 and stress-axis outcomes. Searches for vitamin D receptor–deficient mice, gonadal failure, hypogonadism, and sperm count or motility found no passage addressing the claim. Page numbers were not available in our copy. (LLM, conf=0.74)

    Experimental — accuracy not yet measured

  • There is a positive correlation between levels of vitamin D and testosterone levels.

    “The study authors conclude that their results support the results of several previous works, which exhibit a positive correlation between levels of vitamin D and testosterone levels [39,40].”

    From Influence of Sunlight and Oral D3 Supplementation on Serum 25(OH)D Concentration and Exercise Performance in Elite Soccer Players (2020) · cites this paper as [40]

    The Results section reports changes in vitamin D levels, while Materials and Methods > Laboratory Assays describes vitamin D and cortisol measurements; neither addresses testosterone. Searches for testosterone and for androgen or sex-steroid associations found no passage reporting a positive vitamin D–testosterone correlation. Page numbers were not available in our copy. (LLM, conf=0.75)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 33

  1. [1]Smolders J Menheere P Kessels A Damoiseaux J Hupperts R. Association of vitamin D metabolite levels with relapse rate and disability in multiple sclerosis. Mult Scler (2008) 14: 1220– 4. 10.1177/1352458508094399 18653736 · DOI
  2. [2]Simpson S Jr Taylor B Blizzard L Ponsonby AL Pittas F Tremlett H Higher 25-hydroxyvitamin D is associated with lower relapse risk in multiple sclerosis. Ann Neurol (2010) 68: 193– 203. 10.1002/ana.22043 20695012 · DOI
  3. [3]Mowry EM Waubant E McCulloch CE Okuda DT Evangelista AA Lincoln RR Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis. Ann Neurol (2012) 72: 234– 40. 10.1002/ana.23591 22926855 PMC3430977 · DOI
  4. [4]Loken-Amsrud KI Holmoy T Bakke SJ Beiske AG Bjerve KS Bjornara BT Vitamin D and disease activity in multiple sclerosis before and during interferon-beta treatment. Neurology (2012) 79: 267– 73. 10.1212/WNL.0b013e31825fdf01 22700809 · DOI
  5. [5]Ascherio A Munger KL White R Kochert K Simon KC Polman CH Vitamin D as an early predictor of multiple sclerosis activity and progression. JAMA Neurol (2014) 71: 306– 14. 10.1001/jamaneurol.2013.5993 24445558 PMC4000029 · DOI
  6. [6]Muris AH Smolders J Rolf L Klinkenberg LJ van der Linden N Meex S Vitamin D status does not affect disability progression of patients with multiple sclerosis over three year follow-up. PLoS One (2016) 11: e0156122 10.1371/journal.pone.0156122 27276080 PMC4898831 · DOI
  7. [7]Knippenberg S Bol Y Damoiseaux J Hupperts R Smolders J. Vitamin D status in patients with MS is negatively correlated with depression, but not with fatigue. Acta Neurol Scand (2011) 124: 171– 5. 10.1111/j.1600-0404.2010.01447.x 20880265 · DOI
  8. [8]Soilu-Hanninen M Aivo J Lindstrom BM Elovaara I Sumelahti ML Farkkila M A randomised, double blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon beta-1b in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry (2012) 83: 565– 71. 10.1136/jnnp-2011-301876 22362918 · DOI
  9. [9]Rolf L Damoiseaux J Hupperts R Huitinga I Smolders J. Network of nuclear receptor ligands in multiple sclerosis: common pathways and interactions of sex-steroids, corticosteroids and vitamin D3-derived molecules. Autoimmun Rev (2016) 15: 900– 10. 10.1016/j.autrev.2016.07.002 27395031 · DOI
  10. [10]Rose AS Kuzma JW Kurtzke JF Namerow NS Sibley WA Tourtellotte WW Cooperative study in the evaluation of therapy in multiple sclerosis. ACTH vs. placebo – final report. Neurology (1970) 20: 1– 59. 10.1212/WNL.20.5_Part_2.1 4314823 · DOI
  11. [11]Michelson D Stone L Galliven E Magiakou MA Chrousos GP Sternberg EM Multiple sclerosis is associated with alterations in hypothalamic-pituitary-adrenal axis function. J Clin Endocrinol Metab (1994) 79: 848– 53. 10.1210/jcem.79.3.8077372 8077372 · DOI
  12. [12]Ysrraelit MC Gaitan MI Lopez AS Correale J. Impaired hypothalamic-pituitary-adrenal axis activity in patients with multiple sclerosis. Neurology (2008) 71: 1948– 54. 10.1212/01.wnl.0000336918.32695.6b 19064876 · DOI
  13. [13]Heesen C Gold SM Raji A Wiedemann K Schulz KH. Cognitive impairment correlates with hypothalamo-pituitary-adrenal axis dysregulation in multiple sclerosis. Psychoneuroendocrinology (2002) 27: 505– 17. 10.1016/S0306-4530(01)00071-3 11912002 · DOI
  14. [14]Reder AT Lowy MT Meltzer HY Antel JP. Dexamethasone suppression test abnormalities in multiple sclerosis: relation to ACTH therapy. Neurology (1987) 37: 849– 53. 10.1212/WNL.37.5.849 3033547 · DOI
  15. [15]Then Bergh F Kumpfel T Trenkwalder C Rupprecht R Holsboer F. Dysregulation of the hypothalamo-pituitary-adrenal axis is related to the clinical course of MS. Neurology (1999) 53: 772– 7. 10.1212/WNL.53.4.772 10489039 · DOI
  16. [16]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) 8: e60647. 10.1371/journal.pone.0060647 23613736 PMC3628870 · DOI · Paper page
  17. [17]Schumann EM Kumpfel T Then Bergh F Trenkwalder C Holsboer F Auer DP. Activity of the hypothalamic-pituitary-adrenal axis in multiple sclerosis: correlations with gadolinium-enhancing lesions and ventricular volume. Ann Neurol (2002) 51: 763– 7. 10.1002/ana.10187 12112083 · DOI
  18. [18]Eyles DW Smith S Kinobe R Hewison M McGrath JJ. Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain. J Chem Neuroanat (2005) 29: 21– 30. 10.1016/j.jchemneu.2004.08.006 15589699 · DOI · Paper page
  19. [19]Smolders J Schuurman KG van Strien ME Melief J Hendrickx D Hol EM Expression of vitamin D receptor and metabolizing enzymes in multiple sclerosis-affected brain tissue. J Neuropathol Exp Neurol (2013) 72: 91– 105. 10.1097/NEN.0b013e31827f4fcc 23334593 · DOI
  20. [21]Gold SM Kruger S Ziegler KJ Krieger T Schulz KH Otte C Endocrine and immune substrates of depressive symptoms and fatigue in multiple sclerosis patients with comorbid major depression. J Neurol Neurosurg Psychiatry (2011) 82: 814– 8. 10.1136/jnnp.2010.230029 21296901 · DOI
  21. [22]Polman CH Reingold SC Banwell B Clanet M Cohen JA Filippi M Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol (2011) 69: 292– 302. 10.1002/ana.22366 21387374 PMC3084507 · DOI · Paper page
  22. [23]Bao AM Ji YF Van Someren EJ Hofman MA Liu RY Zhou JN. Diurnal rhythms of free estradiol and cortisol during the normal menstrual cycle in women with major depression. Horm Behav (2004) 45: 93– 102. 10.1016/j.yhbeh.2003.09.004 15019795 · DOI
  23. [25]Kimball SM Ursell MR O’Connor P Vieth R. Safety of vitamin D3 in adults with multiple sclerosis. Am J Clin Nutr (2007) 86: 645– 51. 10.1093/ajcn/86.3.645 17823429 · DOI
  24. [26]Van den Ouweland JM Beijers AM van DH. Overestimation of 25-hydroxyvitamin D3 by increased ionisation efficiency of 3-epi-25-hydroxyvitamin D3 in LC-MS/MS methods not separating both metabolites as determined by an LC-MS/MS method for separate quantification of 25-hydroxyvitamin D3, 3-epi-25-hydroxyvitamin D3 and 25-hydroxyvitamin D2 in human serum. J Chromatogr B Analyt Technol Biomed Life Sci (2014) 967: 195– 202. 10.1016/j.jchromb.2014.07.021 25125396 · DOI
  25. [27]Gold SM Mohr DC Huitinga I Flachenecker P Sternberg EM Heesen C. The role of stress-response systems for the pathogenesis and progression of MS. Trends Immunol (2005) 26: 644– 52. 10.1016/j.it.2005.09.010 16214415 · DOI
  26. [28]Erkut ZA Hofman MA Ravid R Swaab DF. Increased activity of hypothalamic corticotropin-releasing hormone neurons in multiple sclerosis. J Neuroimmunol (1995) 62: 27– 33. 10.1016/0165-5728(95)00098-M 7499489 · DOI
  27. [29]Huitinga I Erkut ZA van Beurden D Swaab DF. The hypothalamo-pituitary-adrenal axis in multiple sclerosis. Ann N Y Acad Sci (2003) 992: 118– 28. 10.1111/j.1749-6632.2003.tb03143.x 12794052 · DOI
  28. [30]Mirhosseini N Brunel L Muscogiuri G Kimball S. Physiological serum 25-hydroxyvitamin D concentrations are associated with improved thyroid function-observations from a community-based program. Endocrine (2017) 58: 563– 73. 10.1007/s12020-017-1450-y 29067607 PMC5693977 · DOI
  29. [31]Knippenberg S Damoiseaux J Bol Y Hupperts R Taylor BV Ponsonby AL Higher levels of reported sun exposure, and not vitamin D status, are associated with less depressive symptoms and fatigue in multiple sclerosis. Acta Neurol Scand (2014) 129: 123– 31. 10.1111/ane.12155 23763464 · DOI
  30. [32]Rolf L Muris AH Bol Y Damoiseaux J Smolders J Hupperts R Vitamin D supplementation in multiple sclerosis: symptoms and biomarkers of depression. J Neurol Sci (2017) 378: 30– 5. 10.1016/j.jns.2017.04.017 28566173 · DOI
  31. [34]Vrshek-Schallhorn S Doane LD Mineka S Zinbarg RE Craske MG Adam EK. The cortisol awakening response predicts major depression: predictive stability over a 4-year follow-up and effect of depression history. Psychol Med (2013) 43: 483– 93. 10.1017/S0033291712001213 22652338 PMC3500423 · DOI · Paper page
  32. [35]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) 36: 1505– 12. 10.1016/j.psyneuen.2011.04.004 21621332 · DOI
  33. [36]Amato MP Derfuss T Hemmer B Liblau R Montalban X Soelberg Sørensen P Environmental modifiable risk factors for multiple sclerosis: report from the 2016 ECTRIMS focused workshop. Mult Scler (2017): 1– 14. 10.1177/1352458516686847 28671487 · DOI

Cited by

Sorted by citations

Authors
Rolf, L., Damoiseaux, J., Huitinga, I., Kimenai, D., van den Ouweland, J., Hupperts, R., & Smolders, J.
Affiliations
  • Maastricht University (NL)
  • Maastricht University Medical Centre (NL)
  • Netherlands Institute for Neuroscience (NL)
Corresponding author
Smolders, Joost
ORCID
Venue
Frontiers in Neurology
Publisher
Frontiers Media SA
Published
2018-04-26
Volume
9
Pages
263-263
ISSN
1664-2295 (ISSN-L)
DOI
10.3389/fneur.2018.00263
PMC
PMC5933207
OpenAlex
W2799606874
Cited by
28
References
1
Citations by year
2026: 1 · 2025: 1 · 2024: 4 · 2023: 2 · 2022: 3 · 2021: 1 · 2020: 9 · 2019: 5 · 2018: 2
FWCI
3.23
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Neurology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Publications (Maastricht University) (publishedVersion, cc-by)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (submittedVersion, other-oa)
  • KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (submittedVersion, other-oa)
  • Research Publications (Maastricht University) (submittedVersion, cc-by)
Funders
Merck KGaA
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Vitamin D Research Studies
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
multiple sclerosis, vitamin D3 supplementation, hypothalamic-pituitary-adrenal axis, cortisol, cortisol awakening response, diurnal cortisol rhythm, 25-hydroxyvitamin D, relapsing-remitting multiple sclerosis, salivary cortisol, nuclear receptor regulation, women with multiple sclerosis, vitamin D deficiency

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review