The Investigation of Vitamin D and Menstrual Cycles Trial (the inVitD Trial): A clinical trial of vitamin D supplementation on the hypothalamic-pituitary-ovarian axis

Abstract

Background: While there is evidence that vitamin D deficiency is associated with long menstrual cycles, delayed ovulation, and reduced fertility, it is yet unknown if increasing vitamin D levels can regulate menstrual cycles, and thus possibly improve fertility. The primary objective of this randomized clinical trial (RCT) is to test the hypothesis that vitamin D supplementation influences the hypothalamic-pituitary-ovarian axis.

Methods: This two-site RCT (NCT05050916) required participants to be aged 19-40 years old, having spontaneous menstrual cycles, and without certain chronic diseases or contraindications for vitamin D supplementation. At baseline participants provided information on their demographics and health history. Blood was drawn at the first clinic visit after which participants collected daily urine samples for one menstrual cycle (phase 1). Those with a 25-hydroxyvitamin D level less than 20 ng/ml ("low") received cholecalciferol supplementation (randomized to either 4200 IU/week or 50,000 IU/week). A random sample of those without low vitamin D received placebo. Supplement (or placebo) was taken for three menstrual cycles which included collection of daily urine samples and home ovulation testing (phase 2). Participants collected self-administered vaginal and oral swabs and a subset collected menstrual effluent samples. Finally, participants kept a daily menstrual diary and weekly behavior diaries. The primary endpoints were mid-luteal progesterone, rate of estrogen rise, and pre-ovulatory luteinizing hormone.

Discussion: Findings from this RCT will provide insight into the relationship between vitamin D supplementation and menstrual cycle hormones. Vitamin D shows promise as a low-cost, non-hormonal intervention to regulate menstrual cycles.

Keywords: Hormone levels; Hypothalamic-pituitary-ovarian axis; Menstrual cycles; Ovulation; Subfertility; Vitamin D supplementation.

Figure 1.

The inVitD Trial participant flow diagram.

Figure 2.

Description of study activities. Eligible participants were invited to complete a baseline questionnaire and schedule an in-person visit. After the study visit she collects urine samples and completes daily diaries until she has two menstrual periods in the study, this will be a different amount of time for each woman depending on her cycle lengths. Randomization occurred when there were two treatment arms - low dose and high dose. Following the discontinuation of the low dose arm, no randomization occurred, as participants received high dose or placebo based on their baseline levels of 25OHD. Phase 2 begins at the onset of second menses. If participants opted to collect ME they did so before taking their first supplement (or placebo). Participants had one more blood draw two months after beginning supplementation. A final clinic visit was scheduled for after three cycles of supplementation. Phase 2 lasted 3 -4 months depending on their cycle lengths.