Evaluation of the Clinical and Psychological Impact of Vitamin D Replacement in Adolescent Females at Risk for Polycystic Ovarian Syndrome (PCOS)

• ClinicalTrials.gov Identifier: NCT04355572
• Recruitment Status: Not yet recruiting
• First Posted: April 21, 2020
• Last Update Posted: January 11, 2023
• Sponsor: Yale University
• Information provided by (Responsible Party): Yale University

Study Description

Brief Summary:

This study is a double blind, placebo controlled, randomized trial of study subjects with PCOS and low vitamin D to 2 groups- placebo and vitamin D replacement. Participants and investigators will be blinded to treatment modality until the end of the trial period

Condition or disease	Intervention/treatment	Phase
Polycystic Ovarian Syndrome in Adolescent Females; Vitamin D Deficiency	Drug: Vitamin D 4000IU daily; Drug: Placebo	Not Applicable

Detailed Description:

Patients referred to the pediatric endocrinology clinic or adolescent gynecology clinic at Yale New Haven Children Hospital with a primary complaint of hirsutism, acne, or amenorrhea and/or oligomenorrhea persisting 2 years after their menarche will be evaluated for polycystic ovarian syndrome through history, physical exam, pelvic ultrasound, and laboratory evaluation, to include androgen testing, thyroid testing, female hormone testing, and diabetic risk testing (this is standard of care). A vitamin D level will also be drawn. While vitamin D level is not currently part of the diagnostic algorithm for PCOS, it is not unreasonable to check in patients in which there is concern for an endocrine disorder. If the patient meets Rotterdam criteria and their serum vitamin D level is between 6 and 29 ng/mL, the patient and their guardian(s) will be approached for inclusion in our study by the physician or dedicated research nursing staff.

If patient and guardian agree to participate and sign a consent / assent form, the patient will then be randomized to receive vitamin D supplement versus placebo and will be followed for 6 months on their randomized replacement with repeat laboratory testing of AMH, vitamin D, lipid profile, glucose and insulin testing, androgen testing, and female hormone testing at the randomization, 3 months and at the end of the course of the trial(6 months). Patients with vitamin D levels 5ng/mL or less will not be randomized, they will be given recommended treatment. Depressive symptoms will be assessed at time of randomization, 3 months post randomization, and 6 months post randomization using the Beck Depression Inventory-II, the gold standard self-report depression inventory. A depression screen is currently administered to all adolescents seen at Yale New Haven Children Hospital outpatient clinics with a protocol for patients who report clinically significant levels of depression. This protocol will remain in place and will not be altered during this research study.

After post-trial testing, patients will be unblinded and patients who still have vitamin D below threshold will be offered vitamin D treatment.

Aim 1: To investigate the effect of vitamin D replacement upon biochemical parameters of polycystic ovarian syndrome (PCOS) in adolescent female patients. Hypothesis: Replacement of vitamin D to normal levels in adolescents with PCOS and/or at risk for PCOS and low levels of vitamin D will lower serum androgen and anti-mullerian hormone (AMH) levels.

Aim 2: To investigate the effect of vitamin D replacement on clinical features of PCOS in adolescent female patients. Hypothesis: Replacement of vitamin D in adolescents with PCOS and/or at risk for PCOS and low levels of vitamin D will improve symptoms of menstrual irregularities, acne, and hirsutism.

Aim3: To investigate the effect of vitamin D replacement on depressive symptoms in adolescent female patients with PCOS. Hypothesis: Replacement of vitamin D in adolescents with PCOS or at risk for PCOS and low levels of serum vitamin D will improve symptoms of depression.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Masking Description: Participants and investigators will be blinded to treatment modality until the end of the trial period
• Primary Purpose: Treatment
• Official Title: Evaluation of the Clinical and Psychological Impact of Vitamin D Replacement in Adolescent Females at Risk for Polycystic Ovarian Syndrome (PCOS)
• Estimated Study Start Date: March 2023
• Estimated Primary Completion Date: May 2023
• Estimated Study Completion Date: May 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Vitamin D Supplement; Patients will take vitamin D tablet with 4,000IU daily for 6 months.	Drug: Vitamin D 4000IU daily; Randomized to receive vitamin D 4000IU daily
Placebo Comparator: Placebo; Patients will take placebo for 6 months	Drug: Placebo; Randomized to placebo daily

Outcome Measures

Primary Outcome Measures :

1. Change in oligomenorrhea [ Time Frame: 6 months ]
   The change in oligomenorrhea, i.e restoration of monthly menses or improvement in the menstrual pattern during 6 months while enrolled in the trial based on self report
2. Changes Vitamin D (25-hydroxyvitamin D) level [ Time Frame: at enrollment, at 3 months after randomization and 6 months after randomization ]
   25-hydroxyvitamin D level will be measured by liquid chromatography-mass spectrometry (LC-MS/MS) or immunoassay

Secondary Outcome Measures :

1. Change in DHEAS level [ Time Frame: at enrollment, at 3 months after randomization and 6 months after randomization ]
   The serum DHEA-S concentration is the traditional marker for adrenal androgen excession because it is produced almost exclusively by the adrenal glands and concentrations remain stable across the day and cycle. Preferred testing is done by immunoassay.
2. Changes in Androstenedione level [ Time Frame: at enrollment, at 3 months after randomization and 6 months after randomization ]
   Androstenedione concentration assesses for hyperandrogenemia as well, it is produced by the ovary and the adrenal cortex and serves as precursor of testosterone. Data suggests that levels are elevated in approximately 20% of women with PCOS. Evaluation is done by Liquid Chromatography/Tandem Mass Spectrometry
3. Change in Anti-Mullerian hormone (AMH) level [ Time Frame: at enrollment, at 3 months after randomization and 6 months after randomization ]
   AMH is a dimeric glycoprotein of the transforming growth factor-β superfamily that is involved in growth and differentiation of ovarian follicles. AMH is expressed in granulosa cells in the ovary and serves as a marker of ovarian reserve as well as marker of several ovarian pathologies such as PCOS, granulosa cell tumors and premature ovarian insufficiency. Level will be measured using Immunoassay (IA)
4. Change in testosterone level [ Time Frame: at enrollment, at 3 months after randomization and 6 months after randomization ]
   Testosterone levels are elevated in vast majority of adolescents with PCOS. The free testosterone level is more sensitive for diagnosis of hyperandrogenic disorders compared with the total testosterone. Evaluation is done by Chromatography/Mass Spectrometry
5. Change in Hirsutism [ Time Frame: at enrollment, at 3 months after randomization and 6 months after randomization ]
   Hirsutism is defined as excessive male-pattern facial and body hair. This will be measured by using the modified Ferriman Gallwey score by a provider with scores of less than 6 indicating no evidence of hirsutism, 6-8 indicating mild hirsutism, scores 8-15 indicating moderate hirsutism and scores greater than 15 indicating severe hirsutism.
6. Change Body Acne [ Time Frame: at enrollment, at 3 months after randomization and 6 months after randomization ]
   European Dermatology Forum Guidelines group (2011) grading system will be used to describe acne in 4 areas of the body- face, upper chest, upper back, upper arms: minimal - comedonal acne, mild to moderate: moderate papulopustular acne, severe: severe papulopustular acne, moderate nodular acne; severe nodular acne,conglobate acne
7. Change in Facial [ Time Frame: at enrollment, at 3 months after randomization and 6 months after randomization ]
   European Dermatology Forum Guidelines group (2011) grading system will be used to describe acne in 4 areas of the body- face, upper chest, upper back, upper arms: minimal - comedonal acne, mild to moderate: moderate papulopustular acne, severe: severe papulopustular acne, moderate nodular acne; severe nodular acne,conglobate acne

Eligibility Criteria

• Ages Eligible for Study: 13 Years to 21 Years (Child, Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

- Postmenarchal adolescent females aged 13-21 who meet modified Rotterdam criteria for PCOS, with a serum vitamin D level between 6-29 ng/mL.

Exclusion Criteria:

• Other causes for hyperandrogenism,
• Chronic renal diseases,
• Acquired or inherited calcium and vitamin D metabolic disorders.

Contacts and Locations

Contacts

Contact: Alla Vash-Margita, MD; 203-785-4010; alla.vash-margita@yale.edu

Sponsors and Collaborators

Yale University

Investigators

• Principal Investigator: Alla Vash-Margita, MD; Yale University

More Information

• Responsible Party: Yale University
• ClinicalTrials.gov Identifier: NCT04355572
• Other Study ID Numbers: 2000028054
• First Posted: April 21, 2020
• Last Update Posted: January 11, 2023
• Last Verified: January 2023

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Yale University:

Anti-Mullerian Hormone (AMH)

Additional relevant MeSH terms:

Polycystic Ovary Syndrome; Vitamin D Deficiency; Syndrome; Disease; Pathologic Processes; Avitaminosis; Deficiency Diseases; Malnutrition; Nutrition Disorders; Ovarian Cysts; Cysts; Neoplasms; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine System Diseases; Vitamin D; Vitamins; Micronutrients; Physiological Effects of Drugs; Bone Density Conservation Agents