The Effect of Calcium and Vitamin D Supplements on Metabolic and Hormonal Disturbances in Polycystic Ovary Syndrome Patients

Study Overview
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Brief Summary
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The aim of this study is to investigate the safety and metabolic-hormonal efficiency of supplementation vitamin D deficient/insufficient PCOS women with (calcium +vitamin D + metformin) for 8 weeks compared to (placebo+ metformin).

Detailed Description
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Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among females of reproductive age. The main manifestations of this syndrome are ovulatory dysfunction, hyperandrogenism, and polycystic ovarian morphology. Noticeably, PCOS is associated with several metabolic disturbances such as insulin resistance, compensatory hyperinsulinemia, dyslipidemia and central obesity, which increase the risk for long-term complications like type 2 diabetes mellitus, metabolic syndrome, and cardiovascular diseases. Moreover, previous data demonstrated that, compared to normo-ovulatory women, PCOS patients might exhibit a dysregulation in the IGF system represented as an elevation in the serum levels of free Insulin-like growth factor-1 (IGF-1) and a reduction in the serum levels of Insulin-like growth factor binding protein-1 (IGFBP-1). However, the exact aetiology of PCOS remains unclear and current treatments are only moderately effective at controlling PCOS symptoms and preventing its complications. Growing evidence suggests a role of vitamin D in female reproductive diseases as the expression of Vitamin D Receptors (VDR) was identified in many organs throughout the female reproductive tract. On the top of that, vitamin D regulates over 300 genes, including genes that are important for glucose and lipid metabolism. Moreover, vitamin D deficiency is a common condition among women with PCOS, and several studies indicated an association between low levels of serum 25-hydroxyvitamin D (25-OH-Vitamin D) and manifestations of PCOS including insulin resistance, hyperandrogenism, and infertility. Further, a recent in-vitro study showed that vitamin D regulated steroidogenesis and IGFBP-1 production in cultured human ovarian cells, and many reports have suggested an interrelation between IGF-1 and vitamin D.

Official Title
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The Effect of Calcium and Vitamin D Supplements as an Adjuvant Therapy to Metformin on Metabolic and Hormonal Disturbances in Polycystic Ovary Syndrome Patients

Conditions
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Polycystic Ovary Syndrome, Vitamin D Deficiency/Insufficiency

Intervention / Treatment
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* Dietary Supplement: Vitamin D3
* Dietary Supplement: Calcium Carbonate
* Drug: Metformin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: PCOS women aged 18-30 years diagnosed according to the Rotterdam criteria. Vitamin D deficiency or insufficiency according to the Endocrine Society Clinical Practice Guideline. Normal liver function. Normal kidney function. Exclusion Criteria: Pregnant, postpartum or breastfeeding women. Females aged <18 or >30 years old. Patients who were diagnosed with androgen-secreting tumours, Cushing's syndrome, congenital adrenal hyperplasia, hyperprolactinemia, hypercalcemia, malabsorption disorders, diabetes mellitus, thyroid disorders, liver disease, renal disease, epilepsy, cardiovascular disease. History of kidney stones. Usage of any hormonal therapy, corticosteroids (other than topical corticosteroids forms), insulin sensitizers, hypolipidemic agents, anti-obesity medications, vitamin D or calcium supplements, anti-epileptic drugs, or any other drugs known to affect endocrine parameters, carbohydrate metabolism, or calciotropic hormone concentrations during the last 3 months.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 30 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Metformin + Placebo<br> | Drug: Metformin<br>* Metformin (1500 mg/daily; the metformin dose was increased stepwise, starting with 500 mg once daily for the 1st week, 500 mg twice daily in the 2nd week, followed by 500 mg 3 times daily from the 3rd week onward). PO for 8 weeks.<br>Drug: Placebo<br>* PO for 8 weeks.<br>|
| Experimental: Calcium carbonate + Vitamin D3 + Metformin<br> | Dietary Supplement: Vitamin D3<br>* Vitamin D3 (Cholecalciferol) (6000 IU/daily). PO for 8 weeks.<br>Dietary Supplement: Calcium Carbonate<br>* Calcium carbonate (1000 mg/daily). PO for 8 weeks.<br>Drug: Metformin<br>* Metformin (1500 mg/daily; the metformin dose was increased stepwise, starting with 500 mg once daily for the 1st week, 500 mg twice daily in the 2nd week, followed by 500 mg 3 times daily from the 3rd week onward). PO for 8 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in quantitative insulin sensitivity check index (QUICKI). | Assessment of QUICKI index at baseline and after 8 weeks of intervention. | baseline, 8 weeks weeks. | 
| Change in Raynaud's index. | Assessment of Raynaud's index at baseline and after 8 weeks of intervention. | baseline, 8 weeks weeks. | 
| Change in McAuley Index. | Assessment of McAuley Index at baseline and after 8 weeks of intervention. | baseline, 8 weeks weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in glucose concentration. | Assessment of serum concentration of glucose at baseline and after 8 weeks of intervention. | baseline, 8 weeks. | 
| Change in insulin concentration. | Assessment of serum concentration of insulin at baseline and after 8 weeks of intervention. | baseline, 8 weeks. | 
| Change in homeostasis model assessment of insulin resistance index (HOMA-IR). | Assessment of HOMA-IR index at baseline and after 8 weeks of intervention. | baseline, 8 weeks. | 
| Change in homeostasis model assessment of β-cell function index (HOMA-B). | Assessment of HOMA-B index at baseline and after 8 weeks of intervention. | baseline, 8 weeks. | 
| Change in menstrual cycle abnormalities. | Assessment of menstrual cycles regularity (having normal menstrual cycle 21-35 days) was done at baseline and during the study period using a calendar by recording the time of the onset of the menstrual periods and the duration of menses. | up to 8 weeks. | 
| Change in hirsutism score | Assessment of modified Ferriman-Gallwey score for hirsutism at baseline and after 8 weeks of intervention. (The score represents the hair growth in a male pattern on a woman shown in four different degrees of severity ( 0= no hair growth; 1= light hair growth; 2= moderate hair growth; 4= severe hair growth) in 9 different body parts; namely the upper lip, chin, chest, upper back, lower back, upper abdomen, lower abdomen, upper arms and thighs. The score is the sum of each region sub-score. Thus, it ranges between 0 and 36, where a score ≥ 6 was considered as a cut off Hirsutism). | baseline, 8 weeks. | 
| Change in free testosterone concentration | Assessment of serum free testosterone concentration at baseline and after 8 weeks of intervention. | baseline, 8 weeks. | 
| Change in serum concentration of follicle-stimulating hormone (FSH) | Assessment of serum concentration of FSH during the early follicular phase of menses at baseline and after 8 weeks of intervention if menstrual cycle regularity was reached during treatment period, or at baseline and the next spontaneous menstrual cycle after finishing the treatment if menstrual cycle regularity was not reached during treatment period. | baseline, 8 weeks or the next spontaneous menstrual cycle depending on menstrual cycle status. | 
| Change in serum concentration of luteinizing hormone (LH) . | Assessment of serum concentration of LH during the early follicular phase of menses at baseline and after 8 weeks of intervention if menstrual cycle regularity was reached during treatment period, or at baseline and the next spontaneous menstrual cycle after finishing the treatment if menstrual cycle regularity was not reached during treatment period. | baseline, 8 weeks or the next spontaneous menstrual cycle depending on menstrual cycle status. | 
| Change in serum concentration of Insulin-like growth factor-1 (IGF-1). | Assessment of serum concentration of IGF-1 at baseline and after 8 weeks of intervention. | baseline, 8 weeks. | 
| Change in serum concentration of Insulin-like growth factor binding protein-1 (IGFBP-1). | Assessment of serum concentration of IGFBP-1 at baseline and after 8 weeks of intervention. | baseline, 8 weeks. | 
| Change in IGF-1 to IGFBP-1 ratio. | Assessment of serum concentration of IGF-1 to IGFBP-1 ratio at baseline and after 8 weeks of intervention. | baseline, 8 weeks. | 
| Change in lipid profile. | Assessment of serum concentration of total cholesterol (TC), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), triglyceride (TG) and non-HDL cholesterol (non-HDL) at baseline and after 8 weeks of intervention. | baseline, 8 weeks. | 
| Change in serum concentration of C-reactive protein (CRP) | Assessment of serum concentration of CRP at baseline and after 8 weeks of intervention. | baseline, 8 weeks. | 
| Change in Body mass index (BMI). | Assessment of weight and height in an overnight fasting status without shoes with light clothes at baseline and after 8 weeks of intervention. Weight and height will be combined to report BMI in kg/m^2. | baseline, 8 weeks. | 
| Change in waist circumference. | Assessment of waist circumference in an overnight fasting status without shoes with light clothes at baseline and after 8 weeks of intervention. | baseline, 8 weeks. | 
| Change in Hip circumference. | Assessment of Hip circumference in an overnight fasting status without shoes with light clothes at baseline and after 8 weeks of intervention. | baseline, 8 weeks. | 
| Change in waist to hip ratio. | Assessment of waist to hip ratio in an overnight fasting status without shoes with light clothes at baseline and after 8 weeks of intervention. | baseline, 8 weeks. | 
| Change in calcium concentration. | Assessment of serum concentration of calcium at baseline and after 8 weeks of intervention. | baseline, 8 weeks. | 
| Change in 25-OH-vitamin D concentration. | Assessment of serum concentration of 25-OH-vitamin D at baseline and after 8 weeks of intervention. | baseline, 8 weeks. | 
| Change in phosphorus concentration. | Assessment of serum concentration of phosphorus at baseline and after 8 weeks of intervention. | baseline, 8 weeks. | 
| Change in alanine transaminase (ALT) concentration. | Assessment of serum concentration of ALT at baseline and after 8 weeks of intervention. | baseline, 8 weeks. | 
| Change in aspartate transaminase (AST) concentration. | Assessment of serum concentration of AST at baseline and after 8 weeks of intervention. | baseline, 8 weeks. | 
| Change in urea concentration. | Assessment of serum concentration of urea at baseline and after 8 weeks of intervention. | baseline, 8 weeks. | 
| Change in creatinine concentration. | Assessment of serum concentration of creatinine at baseline and after 8 weeks of intervention. | baseline, 8 weeks. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Polycystic Ovary Syndrome, Calcium, Vitamin D, Metformin