Impact of Vitamin D Supplementation on Cardiometabolic Status and Androgen Profile in Polycystic Ovary Syndrome

• ClinicalTrials.gov Identifier: NCT04117750
• Recruitment Status: Completed
• First Posted: October 7, 2019
• Last Update Posted: October 8, 2019
• Sponsor: Zagazig University
• Information provided by (Responsible Party): Nearmeen M.Rashad, Zagazig University

Study Description

Brief Summary:

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder of reproductive, endocrine and metabolic functions. Vitamin D has an influence on metabolic and reproductive functions. This study was designed to explore the levels of free 25 hydroxy cholecalciferol [25(OH) D] in PCOS patients. We also aimed to clarify the impact of vitamin D supplementation on cardiometabolic status, androgen profile and clinical features of PCOS.

Condition or disease	Intervention/treatment	Phase
Evaluations, Diagnostic Self; Treatment Adherence	Dietary Supplement: cholecalciferol (vit D3)	Not Applicable

Detailed Description:

Background Polycystic ovarian syndrome (PCOS) is a heterogeneous disorder affecting 510% of women of reproductive age. It is a disorder that affects the reproductive, endocrine and metabolic functions and is the leading cause of chronic anovulation leading to infertility.

PCOS is characterized by hyperandrogenism, chronic oligo or anovulation, and polycystic ovaries. Hyperandrogenism, in particular, is a hallmark feature of PCOS because it is strongly implicated in the genesis of the disorder; and is also associated with metabolic derangements that contribute to the underlying pathophysiology. Also, it is associated with cardiovascular risk factors including obesity, insulin resistance (IR), dyslipidemia, endothelial dysfunction, and metabolic syndrome.

Vitamin D (VD) is a fat-soluble vitamin that is naturally present in very few foods and available as a dietary supplement. It is a steroid hormone with pleiotropic effects. In addition to the main effects of VD on bone and calcium metabolism, it has other roles in the body, including modulation of cell growth, neuromuscular and immune function, and reduction of inflammation.

VD deficiency is now recognized as pandemic disease. Its prevalence varies according to geographic location, season, ethnicity and the standard laboratory value; of what is considered normal, deficient and insufficient. VD deficiency is a risk factor for hypertension, diabetes, and various cancers . Accumulating evidence suggests that VD deficiency might be a causal factor in the pathogenesis of IR and the metabolic syndrome in PCOS. Carotid intima-media thickness (CIMT) measured by ultrasound is a noninvasive, safe, low-cost, reproducible, and well-validated marker of preclinical atherosclerosis.

PCOS is the most frequent endocrine disorder among women of reproductive age and VD deficiency is a key problem in PCOS patients conversely, the basic mechanisms underlying the favorable effects of vitamin D in PCOS are still obscure. Resolving this mechanism may provide insight into the pathophysiology of this syndrome. It can also offer a new therapeutic option for PCOS women. Thus, in the present study was designed to explore the levels of free 25 hydroxyvitamin D [25(OH) D] in PCOS patients. We also aimed to clarify the impact of vitamin D supplementation cardiometabolic status, androgen profile and clinical features of PCOS. Methods This placebo-controlled trial comprised 95 women with PCO recruited from Outpatient Clinics of the Endocrinology Unit of Internal Medicine and Obstetrics and Gynecology Departments, Faculty of Medicine, Zagazig University, Egypt and 50 healthy women matched to PCOS women as regard age and ethnic origin. The diagnosis of PCOS was based on the 2004 revised Rotterdam criteria .. All women underwent the menstrual history and thorough clinical examination. All patients were assessed at the study start on the third day of a spontaneous or progesterone-induced menstrual cycle. Anthropometric measures were estimated, including waist/hip ratio, height and weight then we calculated body mass index (BMI). We estimated the hirsutism score according to Ferriman and Gallwey. .Ovarian volume and antral follicular count (AFC) were evaluated by transvaginal ultrasound (TVS). PCOS patients were randomized divided to the intervention group (n=55) received vitamin D supplements (42,000 IU oral vitamin D per week and 500 mg calcium carbonate per day for 12-week), and non-intervention group (n=40) received 500 mg calcium carbonate per day for 12-week. The exclusion criteria for all women included a history of hyperandrogenic states (such as nonclassic congenital adrenal hyperplasia, androgen-secreting tumors, Cushing's syndrome, 21-hydroxylase deficiency, or hyperprolactinemia), DM, hypertension, liver, kidney, or thyroid diseases. In addition, subjects on non-steroidal anti-inflammatory drugs and multivitamin, as well as patients treated with hormone replacement therapy. At the start of the study, the participants were asked to maintain their usual diet and level of physical activity throughout the study period as well as not to receive any lipid-lowering medications and medications that might affect their reproductive physiology during the 12-week intervention. At baseline and at the endpoint of the 12 weeks of study, anthropometrical measurements were estimated as well as and blood samples were collected for biochemical analyses. Written informed consent was taken from all of the participants after explaining details and benefits as well as risks to them. The ethical committee of the Faculty of Medicine, Zagazig University approved our study protocol.

2.1. Sampling of blood Blood samples were drawn from all subjects during the early follicular phase of the menstrual cycles. One ml was collected into tubes containing fluoride for fasting plasma glucose (FPG). A second remaining part underwent immediate serum separation and was stored at -20 ◦C until analysis serum. calcium, phosphate, albumin were measured. Total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides levels were determined using routine enzymatic methods (Spinreact, Girona, Spain). Low-density lipoprotein (LDL) cholesterol levels were calculated using the Friedewald formula.

2.2. Immunochemical assays: We measured prolactin, FSH, and LH levels via chemiluminescence immunoassays (CLIA) provided by (Immunospec Corporation, CA, USA). Serum high-sensitivity C-reactive protein (hs-CRP) concentrations were measured using high sensitivity enzyme-linked immunosorbent assays (ELISA) (Biosource, Nivelles, Belgium). We determined to fast insulin, FSH, LH, total and free testosterone, sex hormone-binding globulin (SHBG) levels using ELISA kits (DRG International, USA). We calculated insulin resistance (IR) with the homeostatic model assessment (HOMA-IR) index, which is defined as fasting serum insulin (FSI) value (µU/ml) × fasting plasma glucose value (mg/dl)/405. The B cell function was calculated using HOMA- B as (20× (fasting insulin µU/mL)/ (fasting glucose (mmol/l) - 3.5).

2.3.Determination of serum vitamin D levels Serum concentrations of 25(OH)-D were tested using enzyme-linked immunosorbent assay, [Cat No. EQ 6411-9601, Euroimmun Medizinische Labordiagnostika AG, Germany]. Current recommendations define VD deficiency as serum 25(OH)-D levels less than 20 ng/ml and VD insufficiency less than 30 ng/ml.

2.4. Carotid ultrasonography Carotid artery atherosclerosis was determined by one examiner for all patients across all six sites, using high-resolution B-mode ultrasound (M-Turbo®, SonoSite, Washington, Bothell, USA), according to American Society of Echocardiography protocol.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 145 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Investigator, Outcomes Assessor)
• Primary Purpose: Diagnostic
• Official Title: Impact of Vitamin D Supplementation on the Cardiometabolic Status and Androgen Profile in Women With Polycystic Ovary Syndrome: Placebo-Controlled Clinical Trial
• Actual Study Start Date: November 1, 2017
• Actual Primary Completion Date: April 1, 2018
• Actual Study Completion Date: July 1, 2018

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: intervention group; 55 female patients with PCO	Dietary Supplement: cholecalciferol (vit D3); 42,000 IU oral vitamin D per week and 500 mg calcium carbonate; Other Name: calcium carbonate
Placebo Comparator: non -intervention group; 40 female patients with PCO and 50 healthy women matched to PCOS women as regard age and ethnic origin.	Dietary Supplement: cholecalciferol (vit D3); 42,000 IU oral vitamin D per week and 500 mg calcium carbonate; Other Name: calcium carbonate

Outcome Measures

Primary Outcome Measures :

1. change of lipid profiles in intervention arm of PCOS patients who received vitamin d supplementation [ Time Frame: 12 weeks ]
   change of LDL (mg/dl), TG (mg/dl) TG (mg/dl) ,(mg/dl)
2. Improvement of fertility ;ovarian size [ Time Frame: 12 weeks ]
   Ovarian volume cm were evaluated by transvaginal ultrasound
3. change of vitamin D deficiency [ Time Frame: 12 weeks ]
   Serum concentrations of 25(OH)-D( ng/ml )
4. Change of androgenic levels in intervention arm of PCOS patients who received vitamin d [ Time Frame: 12 weeks ]
   total testosterone (ng/mL),
5. Change of inflammatory markers in intervention arm of PCOS patients who received vitamin d [ Time Frame: 12 weeks ]
   hs-CRP (µg/ml)
6. change of BMI [ Time Frame: 12 weeks ]
   weight in kilograms, height in meters
7. change of fertility , antral follicular count [ Time Frame: 12 weeks ]
   antral follicular count were evaluated by transvaginal ultrasound

Eligibility Criteria

• Ages Eligible for Study: 20 Years to 33 Years (Adult)
• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes
• Gender Eligibility Description: female patient with pco
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

1. women with PCO. The diagnosis of PCOS was based on the 2004 revised Rotterdam criteria
2. women must be able to swallow tablets

Exclusion Criteria:

1. a history of hyperandrogenic states (such as nonclassic congenital adrenal hyperplasia, androgen-secreting tumors, Cushing's syndrome, 21-hydroxylase deficiency, or hyperprolactinemia)
2. DM3-hypertension
3. liver diseases
4. kidney diseases
5. Insulin-dependent diabetes
6. thyroid diseases.
7. women received non-steroidal anti-inflammatory drugs , multivitamins, and hormone replacement therapy.

Contacts and Locations

Locations

Egypt

Zagazig University

Zagazig, El-Shakia, Egypt, 44519

Sponsors and Collaborators

Zagazig University

More Information

Publications:

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Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004 Jan;81(1):19-25. doi: 10.1016/j.fertnstert.2003.10.004.

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• Responsible Party: Nearmeen M.Rashad, ass.professor of internal medicine, Zagazig University
• ClinicalTrials.gov Identifier: NCT04117750
• Other Study ID Numbers: vitamin D and PCO
• First Posted: October 7, 2019
• Last Update Posted: October 8, 2019
• Last Verified: October 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: participants data without names
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code
• Time Frame: after the publication of the study

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Nearmeen M.Rashad, Zagazig University:

PCOS; VD supplementation; androgen level; cardio metabolic

Additional relevant MeSH terms:

Polycystic Ovary Syndrome; Ovarian Cysts; Cysts; Neoplasms; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine System Diseases; Cholecalciferol; Vitamin D; Calcium Carbonate; Calcium-Regulating Hormones and Agents; Physiological Effects of Drugs; Vitamins; Micronutrients; Bone Density Conservation Agents; Antacids; Molecular Mechanisms of Pharmacological Action; Gastrointestinal Agents