Stress-Axis Regulation by Vitamin D3 in Multiple Sclerosis

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 (4,000 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 (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 min 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).

Keywords: Cortisol; HPA-axis; multiple sclerosis; supplementation; vitamin D.

Figures

Figure 1

Flow diagram of the study process. MP, methylprednisolone; Analyzed = included in the primary endpoint analysis; Received allocated intervention = included in the safety analysis.

Figure 2

Effect of vitamin D3 supplements on serum 25(OH)D levels. (A) Within group comparisons of serum 25(OH)D levels at T0 (baseline) and T1 (week 16) in the vitamin D3 supplemented arm (n = 22), (B) within group comparisons of serum 25(OH)D levels at T0 and T1 in the placebo arm (n = 19), (C) between group comparisons of the serum 25(OH)D level differences between T1 and T0. (D) group comparisons of serum 25(OH)D levels < and >100 nmol/L at T0 and T1. p-Values calculated with (A,B) Wilcoxon signed ranks, (C) Mann–Whitney U or (D) χ2 test.

Figure 3

Association of vitamin D3 supplements with HPA-axis activity. Within group comparisons of the cortisol day curves (CDC) at T0 (baseline) and T1 (week 16) in the placebo arm [(A); n = 19] and in the vitamin D3 arm [(B); n = 21], and within group comparisons cortisol awakening responses (CAR) at T0 and T1 in the placebo arm [(D); n = 19] and in the vitamin D3 arm [(E); n = 22]. Between group comparison for the CDC [(C); T1–T0] and CAR [(F); T1–T0]. Data-points show median values with corresponding interquartile ranges. p-Value shows difference in area under the curve between vitamin D and placebo group tested with the Mann–Whitney U test.