This Phase II clinical trial translates both animal studies and human observational research into public health relevant research. We will investigate vitamin D’s influence on the hypothalamic-pituitary-ovarian axis by careful evaluation of hormonal and ovulatory menstrual cycle changes that occur with vitamin D supplementation. Vitamin D supplementation may be a low-cost intervention that improves menstrual cycle function and fertility.
After recruitment, there will be two phases to this study: Phase 1 will follow all women for at least one menstrual cycle prior to supplementation, the “pre-supplementation cycle”. During Phase 1, blood will be drawn and assayed for 25-hydroxyvitamin D (25OHD). If their level is less than 20 ng/ml (deficiency), they will be invited to participate in Phase 2. A small sample of participants with a level >= 20 ng/ml will also be invited to participate in Phase 2, to maintain participant blinding. Participation ends for the remaining women whose level is 20 ng/ml or higher. During Phase 2, deficient women will receive a blinded dose of 50,000 IU of vitamin D supplementation per week. The small group of sufficient women will receive a placebo. Participants will not be told what their 25OHD level was or what group they are in. Women will be followed for three more menstrual cycles. In the pre-supplementation cycle and in the last of these three cycles, the “supplemented cycle”, women will collect daily urine specimens. Hormone levels will be compared between the pre-and post-supplementation cycles as the primary analysis. A secondary analysis will compare the supplemented cycles in the deficient women who received 50,000 IU and the sufficient women who received placebo.
The original design of this trial included a low-dose (4,200 IU) vitamin D supplementation arm. At entry into Phase 2, participants were randomized to receive the 4,200 IU vitamin D supplement or 50,000 IU vitamin D supplement in a 2:3 ratio. The low-dose arm of the trial has been discontinued for cost and efficiency purposes. As of 12/13/22, 16 participants were randomized to receive the low-dose vitamin D supplement. On approval of the current document, this information will be updated to reflect the final count of participants who received the low-dose vitamin D supplement and the specific date at which the low-dose arm was discontinued via a future amendment. Study data for women who received the low-dose vitamin D supplement will be retained for research and analysis. Specific analyses, biospecimen use, and statistical comparisons will not differ from those described below for the participants who receive the 50,000 IU vitamin D supplement or the placebo. All data handling and security procedures described in this document equivalently apply to data collected from participants receiving the low-dose vitamin D supplement.
The primary aim of this trial will test the following hypotheses by comparing vitamin D supplemented cycles to the pre-supplementation cycles, within-woman: (1) Mid-luteal progesterone is higher in vitamin D supplemented cycles; (2) Rate of estrogen rise is higher in vitamin D supplemented cycles; (3) Pre-ovulatory LH is higher in vitamin D supplemented cycles.