Nutritional Fundamentals for Health

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Vitamin D - Think Functional Fatigue and Low Grade Cervical Dysplasia

Vitamin D can Improve Fatigue in Otherwise Healthy Individuals
Fatigue is a very common complaint in men and women, and can lead to obvious impacts on quality of life, work performance, home life, moods and more. There is a check off list for fatigue that a clinician will assess both in the history and in laboratory testing that includes anemias, hypothyroid, depression, poor nutrition, protein deficiency, celiac disease, food or airborne allergies, blood sugar issues, poor or not enough sleep and then a more serious investigation if needed into chronic diseases/cancers.

Vitamin D insufficiency or deficiency is common in the United States, and has been associated with fatigue, headache, depression, muscle pains/weakness, impaired cognition and more.

The current study investigated a single vitamin D dose to see if it improves fatigue after 30 days among individuals who were vitamin D deficient and had fatigue, but were otherwise healthy.

This randomized double-blind clinical trial was conducted at the University of Zurich. Study participants with fatigue were enrolled and were between the ages of 20-50, of normal body weight, fatigued, not suffering from other physical or mental illness and a serum vitamin D level below 20 mcg/L. Fifty three % of the participants were women. One hundred twenty eight individuals were enrolled in the study and a total of 122 participants underwent the baseline visit and took the study medication or the placebo.

The primary endpoint was intra-individual change in the fatigue assessment scale (FAS) at 4 weeks after the treatment. The FAS is a self-reported 10 item scale evaluating symptoms of chronic fatigue with lower scores indicating less fatigue. A negative change from the baseline indicates improvement. The FAS score also includes two subscales of physical fatigue and mental fatigue. There are 5 response options for each of the 10 items (never, sometimes, regularly, often or always). The secondary endpoint was the efficacy of vitamin D administration on fatigue using a short fatigue test called a fatigue course assessment (FCA). This is a 5 item self report where patients categorize their current level of fatigue as compared with its level at baseline: options include completely resolved, improved, unchanged, worse or much worse. Those who met the enrollment criteria for fatigue completed a validated 4 item basic questionnaire for fatigue (BQF) which was used to confirm fatigue symptoms at baseline and they were eligible if 2 or more points were reached.

Patients were randomized to receive a single oral dose of 100,000 units of vitamin D or placebo. The follow-up visit was 4 weeks after the baseline visit and ingestion of the vitamin D.

Over 4 weeks, the mean FAS decreased significantly more in the vitamin D group compared with the placebo (-3.3 vs -0.8) and was considered to improve significantly in the vitamin D group only. Resolution of fatigue was reported more frequently in the vitamin D group vs the placebo group (72% vs 50%). A greater improvement of FAS was associated with a greater increase in the 25 (OH) D level. Improvement in fatigue at the 4 week follow-up visit as assessed by the self reporting FCA was 48% in the vitamin D treated group vs 37% in the placebo group. A significant increase in 25 OH vitamin D was observed in vitamin D treated individuals but not in the placebo treated participants.

Commentary: This appears to be the first double-blind randomized clinical trial that tested a one time dose in individuals with fatigue due to no known physical or mental illness. While the mechanism by which vitamin D may improve fatigue is unknown, we do know that the vitamin D receptor is present in many parts of the brain. Central fatigue may arise from a dopamine imbalance within the central nervous system and we know that vitamin D has dopaminergic effects. Vitamin D has also been shown to regulate brain serotonin synthesis and a defect in serotonergic function might also be associated with fatigue. This 100,000 IU one time dose led to a significant improvement in fatigue in the vitamin D treated group which correlated significantly with the change in serum levels of vitamin D. Patients with fatigue for no other reason other than serum vitamin D level less than 20 mcg/L is going to be a meaningful number of patients in a primary care practice. While this study is limited by its short-term follow-up, I will take this study into my clinical practice. I will also be interested to see if this approach would help those with vitamin D insufficiency (20-30 mcg/L serum OH D) rather than deficiency—an even larger group.

Reference: Nowak A, Boesch L, Andres E, et al. Effect of vitamin D3 on self-perceived fatigue. A double-blind randomized placebo-controlled trial. Medicine 2016;95:52.

Vitamin D and Regression of Cervical Intraepithelial Neoplasia
This randomized double-blind clinical trial was conducted in Kashan, Iran. Patients with cervical intraepithelial neoplasia (CIN) 1, diagnosed by colposcopy, biopsy and pathology were randomly assigned to receive 50,000 IU of a vitamin D supplement (n=29) or placebo (n=29) every 2 weeks for 6 months. All women provided three dietary records and three physical activity records at month 2,4 and 6 of the intervention to assure their usual diet and physical activity during the study period.

To be included in the study, women were aged 18-55 with CIN 1 diagnosed by colposcopy, biopsy and pathology assessment. Women received colposcopy if they had an abnormal pap smear, abnormal cervical cytology, abnormal cervical appearance, postcoital bleeding, intermenstrual bleeding, chronic vaginal discharge or were positive for high risk human papilloma virus (HPV). Women were excluded if they were pregnant, had a history of cervical cancer or other lower genital tract cancer, had a had hysterectomy or a previous destructive therapy of the cervix. Women were advised not to change their diet or exercise 2 months prior to or during the study.

Three patients in the treatment group and 3 in the placebo group did not complete the trial which left 26 in each group who completed the trial. After 6 months of vitamin D supplementation, a greater percentage of women in the vitamin D group had a regression of their CIN I compared to placebo (84.6 % vs 53.8%). One patient in the placebo group progressed to CIN II.

Long-term vitamin D supplementation increased serum 25 (OH)D levels in the intervention group of 12.3 + 11.4 ng/mL vs -0.1 + 3.7 ng/mL in the placebo group.

Commentary: This is the first study I have seen on the effects of oral vitamin D supplementation as an intervention for CIN. There are previous studies documenting vitamin D and anticancer effects. And in a study specific to cervical infections and CIN , vitamin D vaginal suppositories at 12,5000 IU, three nights a week for 6 weeks resulted in some benefits for both those with CIN I and those with bacterial and/or fungal cervitis. (Ref: Schulte-Uebbing C, Schlett S, Craiut ID, Antal L, Olah H. Chronical cervical infections and dysplasia (CIN I, CIN II)-vaginal vitamin D (high dose) treatment: a new effective method. Arch Gynecol Obstet. 2011 Feb 12. )

It would have been useful information to test women for their serum vitamin D levels prior to entry into the study… to see if there were different responses to intervention based on vitamin D deficiency, insufficiency or sufficiency. If I were to include this rather simple addition to my CIN I protocols, it is important to remember that approximately 60% of women with CIN I regress to normal cytology on their own. I might also prefer to test serum levels, and if not too high, say not above 50 ng/ML, I would proceed with this intervention.

Reference: Vahedoor A, Jamilian M, Bahmani F, et al. Effects of long term vitamin D supplementation on regression and metabolic status of cervical intraepithelial neoplasia: a randomized, double-blind, placebo-controlled trial. Horm Canc; published online Springer, January 3, 2017