The Investigation of Vitamin D and Menstrual Cycles Trial, the inVitD Trial: A Phase II Randomized Trial
Study Details
Study Description
Brief Summary
Background:
About 1.5 million U.S. women of reproductive age are estimated to be infertile. Many more have difficulty getting pregnant. Menstrual cycles are an indicator of a woman s general health. Menstrual cycle changes may predict difficulties in getting pregnant. Researchers want to see what role vitamin D may play in menstrual cycle health.
Objective:
To examine the effect of vitamin D supplementation on the hormones that come from the brain and the ovary during a menstrual cycle.
Eligibility:
Women aged 19-40 who have spontaneous menstrual cycles (are not taking any hormones) less than 50 days in length.
Design:
Participants will fill out a screening survey about their demographics and health history. It will take 5-10 minutes to complete.
Participants will have 3 study visits. Participants who are deficient will be randomized to receive either a lower or higher dose of vitamin D supplements. Participants who are sufficient will receive placebo. If they are vitamin D deficient, they will not get the placebo. They will take the capsules by mouth, once per week, for 3 menstrual cycles (or about 90 days).
Participants will have physical exams. Their height, weight, body fat percentage, blood pressure, and waist-hip ratio will be measured. They will give blood samples. They will have vaginal and oral swabs.
Participants will keep a daily menstrual diary. They will do daily home ovulation testing. They will collect urine at home. Some women may collect menstrual blood at home.
Participants will fill out an online survey. It will ask about their health, diet, and physical activity; birth control use; pregnancy history; menstrual cycle; smoking and drinking habits; education; and occupation. It will take 20-30 minutes to complete.
Participation will last for four menstrual cycles (about 4 months).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
Detailed Description
Study Description:
This Phase II randomized, dose-ranging 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 be randomized (2:3) to receive a blinded dose of either 4,200 IU or 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 presupplementation 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 postsupplementation cycles as the primary analysis. A secondary analysis will compare the supplemented cycles in the deficient women who received 50,000 IU and the deficient women who received 4,200 IU
The primary aim of this trial will test the following hypotheses by comparing vitamin D supplemented cycles to the presupplementation 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.
Objectives:
Primary objective:
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To examine the effect of vitamin D supplementation on hypothalamic-pituitary-ovarian axis hormones. We will evaluate the extent to which vitamin D supplementation:
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Increases urinary mid-luteal progesterone (an indicator of healthy, fertile follicle development)
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Increases the rate of rise in urinary follicular phase estrogen (an indicator of follicular development)
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Increases urinary pre-ovulatory LH (an indicator of healthy ovarian-hypothalamic interaction)
Secondary objectives:
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Determine the impact of vitamin D supplementation in reproductive-aged women by assaying the metabolome before and after vitamin D supplementation
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To quantify the increase in 25OHD and the fraction who achieve a level of 40 ng/ml after 1.5 and 3 months of supplementation, in response to either 4,200 or 50,000 IU/week of vitamin D.
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To examine the effects of vitamin D supplementation on endometrial stromal cell decidualization
Tertiary/Exploratory objectives:
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To examine the change in whole blood metals levels in response to vitamin D supplementation.
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To examine the change in vaginal or oral microbiome in response to vitamin D supplementation.
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To investigate the extent to which vitamin D reduces the incidence of
--delayed ovulation (follicular phase >20 days), 2) short luteal phase (<=10 days), and 3) long cycles (>34 days)
- To investigate the association between 25OHD levels, sleep measures, physical activity, exposure to white/red/green/blue light, and hypothalamic-pituitary-ovarian axis hormones.
Endpoints:
Primary Endpoint: Mid-luteal progesterone, follicular estrogen, preovulatory LH
Secondary Endpoints: Untargeted metabolomics, 25OHD, endometrial stromal cell function,
Tertiary Endpoints: metals, microbiome, ovulation, menstrual cycle length, sleep
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: 1/High Dose Vitamin D Deficient women will be randomized to either the IOM recommended RDA, 4,200 IU/week, or the Endocrine Society recommendation for deficiency, 50,000 IU/week. |
Dietary Supplement: Vitamin D
This is a Phase II randomized, dose-ranging clinical trial including 1) a within-woman comparison of hormones pre- and post-supplementation and 2) a comparison across women of two different dose levels. After recruitment, there will be two phases: Phase 1 will follow all women for one menstrual cycle prior to supplementation; blood will be assayed for 25OHD. Phase 2 includes only: 1) women with less than 20 ng/ml 25OHD ("deficient") OR 2) a small ~10% sample of women with >20 ng/ml 25OHD ("sufficient") as the placebo group. During Phase 2, deficient women will be randomized (2:3) to receive a blinded dose of either 4,200 IU or 50,000 IU of vitamin D supplementation per week and followed for three more menstrual cycles. Hormone levels will be compared between the pre-and post-supplementation cycles as the primary analysis. The primary aim will test: if mid-luteal progesterone, rate of estrogen rise and pre-ovulatory LH are higher in vitamin D supplemented cycles.
|
| Experimental: 2/Low Dose Vitamin D Deficient women will be randomized to either the IOM recommended RDA, 4,200 IU/week, or the Endocrine Society recommendation for deficiency, 50,000 IU/week. |
Dietary Supplement: Vitamin D
This is a Phase II randomized, dose-ranging clinical trial including 1) a within-woman comparison of hormones pre- and post-supplementation and 2) a comparison across women of two different dose levels. After recruitment, there will be two phases: Phase 1 will follow all women for one menstrual cycle prior to supplementation; blood will be assayed for 25OHD. Phase 2 includes only: 1) women with less than 20 ng/ml 25OHD ("deficient") OR 2) a small ~10% sample of women with >20 ng/ml 25OHD ("sufficient") as the placebo group. During Phase 2, deficient women will be randomized (2:3) to receive a blinded dose of either 4,200 IU or 50,000 IU of vitamin D supplementation per week and followed for three more menstrual cycles. Hormone levels will be compared between the pre-and post-supplementation cycles as the primary analysis. The primary aim will test: if mid-luteal progesterone, rate of estrogen rise and pre-ovulatory LH are higher in vitamin D supplemented cycles.
|
| Placebo Comparator: 3/Placebo Sufficient women who will receive placebo instead of Vitamin D supplementation. |
Dietary Supplement: Vitamin D
This is a Phase II randomized, dose-ranging clinical trial including 1) a within-woman comparison of hormones pre- and post-supplementation and 2) a comparison across women of two different dose levels. After recruitment, there will be two phases: Phase 1 will follow all women for one menstrual cycle prior to supplementation; blood will be assayed for 25OHD. Phase 2 includes only: 1) women with less than 20 ng/ml 25OHD ("deficient") OR 2) a small ~10% sample of women with >20 ng/ml 25OHD ("sufficient") as the placebo group. During Phase 2, deficient women will be randomized (2:3) to receive a blinded dose of either 4,200 IU or 50,000 IU of vitamin D supplementation per week and followed for three more menstrual cycles. Hormone levels will be compared between the pre-and post-supplementation cycles as the primary analysis. The primary aim will test: if mid-luteal progesterone, rate of estrogen rise and pre-ovulatory LH are higher in vitamin D supplemented cycles.
|
Outcome Measures
Primary Outcome Measures
- To examine the effect of vitamin D supplementation on hypothalamic-pituitary-ovarian axis hormones. [60 months]
We will evaluate the extent to which vitamin D supplementation: 1) Increases urinary mid-luteal progesterone (an indicator of healthy, fertile follicle development) 2) Increases the rate of rise in urinary follicular phase estrogen (an indicator of follicular development) 3) Increases urinary pre-ovulatory LH (an indicator of healthy ovarian-hypothalamic interaction)
Secondary Outcome Measures
- To examine the change in whole blood metals levels in response to vitamin D supplementation. [60 months]
Whole blood lead
- To investigate the effect of vitamin D supplementation on the microbiome [60 months]
Untargeted microbiome profiling
- To quantify the increase in 25OHD and the fraction who achieve a level of 40 ng/ml after 1.5 and 3 months of supplementation, in response to either 4,200 or 50,000 IU/week of vitamin D. [60 months]
25OHD
- To investigate the effect of vitamin D supplementation on endometrial stromal cell function. [60 months]
Endometrial stromal cells isolated from menstrual effluent.
- Determine the impact of Vitamin D supplementation in reproductive-aged women by assaying the metabolome before and after vitamin D supplementation. [60 months]
Untargeted metabolomics
Eligibility Criteria
Criteria
- INCLUSION CRITERIA:
In order to be eligible to participate in this study, an individual must meet all of the following criteria:
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Provision of signed and dated informed consent form
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Stated willingness to comply with all study procedures and availability for the duration of the study
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Having natural, spontaneous menstrual cycles (no hormonal therapy) less than 50 days in length.
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Aged 19-40 years
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Ability to take a vitamin D capsule and willing to adhere to the weekly regimen
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If sexually active, use of a non-hormonal contraceptive method.
EXCLUSION CRITERIA:
An individual who meets any of the following criteria will be excluded from participation in this study:
- No menstrual period in the last 50 days, or, a typical menstrual cycle length <16 or
49 days.
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Use of a vitamin D supplement for more than one month and on more than 15 days out of each month. Volunteers will be asked to check their supplement label for vitamin D content.
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Unwilling to abstain from taking non-study vitamin D supplements during the study or if already taking a medically-advised vitamin D supplement.
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Use of a calcium supplement (including certain antacids) and unwilling to abstain from taking a calcium supplement during the study.
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Known polycystic ovarian syndrome
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Depo-provera use in the previous 12 months
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Current use of any hormones, including birth control
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Current use of a hormonal intrauterine device (IUD)
- thyroid medications with hormones are allowed as there are no safety concerns associated with supplementation and these medications
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Current pregnancy or lactation, trying to become pregnant, or planning to try in the next four menstrual cycles or 5 months.
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History of seizure disorders
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Celiac disease
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Crohn s Disease
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Body mass index >35
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Aged <19 or > 40 years
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Presence of known contraindications for vitamin D supplementation, history of any of the following: calcium disorder or hypercalcemia, tuberculosis or granulomatous disease, metastatic bone disease, sarcoidosis, Williams syndrome, kidney disease (kidney stones, renal failure or dialysis, lupus nephritis)
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Known liver disease (cirrhosis)
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History of cancer other than skin cancer.
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History of anorexia nervosa, bulimia or an eating disorder
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Use within the past 60 days, of exogenous hormones
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Type 1 or Type 2 diabetes
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Known heart disease
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Gastric bypass surgery
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Unwilling or unable to complete study activities, e.g. collect daily urine specimens, have blood drawn, complete daily diaries, attend in person study visits
- Non-English speaking
- Due to the complexity of daily/weekly diaries, testing and procedurerequirements, all consents, instructions and questionnaires are provided in English. Therefore, all participants must be able to able to read and speak English.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | National Institute of Environmental Health Sciences (NIEHS) | Bethesda | Maryland | United States | 20892 |
| 2 | Henry Ford Health System | Detroit | Michigan | United States | 48187 |
Sponsors and Collaborators
- National Institute of Environmental Health Sciences (NIEHS)
Investigators
- Principal Investigator: Anne Marie Z Jukic, Ph.D., National Institute of Environmental Health Sciences (NIEHS)
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 10000476
- 000476-E