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

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ClinicalTrials.gov Identifier: NCT03792984
Recruitment Status : Completed
First Posted : January 4, 2019
Last Update Posted : June 6, 2019
Sponsor:
Information provided by (Responsible Party):
Damascus University

Brief Summary:
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).

Condition or disease Intervention/treatment Phase
Polycystic Ovary Syndrome Vitamin D Deficiency/Insufficiency Dietary Supplement: Vitamin D3 Dietary Supplement: Calcium Carbonate Drug: Metformin Drug: Placebo Phase 3

Detailed Description:
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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Official Title: The Effect of Calcium and Vitamin D Supplements as an Adjuvant Therapy to Metformin on Metabolic and Hormonal Disturbances in Polycystic Ovary Syndrome Patients
Actual Study Start Date : December 1, 2016
Actual Primary Completion Date : October 1, 2017
Actual Study Completion Date : December 30, 2017


Arm Intervention/treatment
Placebo Comparator: Metformin + Placebo Drug: Metformin
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.

Drug: Placebo
PO for 8 weeks.

Experimental: Calcium carbonate + Vitamin D3 + Metformin Dietary Supplement: Vitamin D3
Vitamin D3 (Cholecalciferol) (6000 IU/daily). PO for 8 weeks.

Dietary Supplement: Calcium Carbonate
Calcium carbonate (1000 mg/daily). PO for 8 weeks.

Drug: Metformin
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.




Primary Outcome Measures :
  1. Change in quantitative insulin sensitivity check index (QUICKI). [ Time Frame: baseline, 8 weeks weeks. ]
    Assessment of QUICKI index at baseline and after 8 weeks of intervention.

  2. Change in Raynaud's index. [ Time Frame: baseline, 8 weeks weeks. ]
    Assessment of Raynaud's index at baseline and after 8 weeks of intervention.

  3. Change in McAuley Index. [ Time Frame: baseline, 8 weeks weeks. ]
    Assessment of McAuley Index at baseline and after 8 weeks of intervention.


Secondary Outcome Measures :
  1. Change in glucose concentration. [ Time Frame: baseline, 8 weeks. ]
    Assessment of serum concentration of glucose at baseline and after 8 weeks of intervention.

  2. Change in insulin concentration. [ Time Frame: baseline, 8 weeks. ]
    Assessment of serum concentration of insulin at baseline and after 8 weeks of intervention.

  3. Change in homeostasis model assessment of insulin resistance index (HOMA-IR). [ Time Frame: baseline, 8 weeks. ]
    Assessment of HOMA-IR index at baseline and after 8 weeks of intervention.

  4. Change in homeostasis model assessment of β-cell function index (HOMA-B). [ Time Frame: baseline, 8 weeks. ]
    Assessment of HOMA-B index at baseline and after 8 weeks of intervention.

  5. Change in menstrual cycle abnormalities. [ Time Frame: up to 8 weeks. ]
    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.

  6. Change in hirsutism score [ Time Frame: baseline, 8 weeks. ]
    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).

  7. Change in free testosterone concentration [ Time Frame: baseline, 8 weeks. ]
    Assessment of serum free testosterone concentration at baseline and after 8 weeks of intervention.

  8. Change in serum concentration of follicle-stimulating hormone (FSH) [ Time Frame: baseline, 8 weeks or the next spontaneous menstrual cycle depending on menstrual cycle status. ]
    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.

  9. Change in serum concentration of luteinizing hormone (LH) . [ Time Frame: baseline, 8 weeks or the next spontaneous menstrual cycle depending on menstrual cycle status. ]
    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.

  10. Change in serum concentration of Insulin-like growth factor-1 (IGF-1). [ Time Frame: baseline, 8 weeks. ]
    Assessment of serum concentration of IGF-1 at baseline and after 8 weeks of intervention.

  11. Change in serum concentration of Insulin-like growth factor binding protein-1 (IGFBP-1). [ Time Frame: baseline, 8 weeks. ]
    Assessment of serum concentration of IGFBP-1 at baseline and after 8 weeks of intervention.

  12. Change in IGF-1 to IGFBP-1 ratio. [ Time Frame: baseline, 8 weeks. ]
    Assessment of serum concentration of IGF-1 to IGFBP-1 ratio at baseline and after 8 weeks of intervention.

  13. Change in lipid profile. [ Time Frame: baseline, 8 weeks. ]
    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.

  14. Change in serum concentration of C-reactive protein (CRP) [ Time Frame: baseline, 8 weeks. ]
    Assessment of serum concentration of CRP at baseline and after 8 weeks of intervention.

  15. Change in Body mass index (BMI). [ Time Frame: baseline, 8 weeks. ]
    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.

  16. Change in waist circumference. [ Time Frame: baseline, 8 weeks. ]
    Assessment of waist circumference in an overnight fasting status without shoes with light clothes at baseline and after 8 weeks of intervention.

  17. Change in Hip circumference. [ Time Frame: baseline, 8 weeks. ]
    Assessment of Hip circumference in an overnight fasting status without shoes with light clothes at baseline and after 8 weeks of intervention.

  18. Change in waist to hip ratio. [ Time Frame: baseline, 8 weeks. ]
    Assessment of waist to hip ratio in an overnight fasting status without shoes with light clothes at baseline and after 8 weeks of intervention.

  19. Change in calcium concentration. [ Time Frame: baseline, 8 weeks. ]
    Assessment of serum concentration of calcium at baseline and after 8 weeks of intervention.

  20. Change in 25-OH-vitamin D concentration. [ Time Frame: baseline, 8 weeks. ]
    Assessment of serum concentration of 25-OH-vitamin D at baseline and after 8 weeks of intervention.

  21. Change in phosphorus concentration. [ Time Frame: baseline, 8 weeks. ]
    Assessment of serum concentration of phosphorus at baseline and after 8 weeks of intervention.

  22. Change in alanine transaminase (ALT) concentration. [ Time Frame: baseline, 8 weeks. ]
    Assessment of serum concentration of ALT at baseline and after 8 weeks of intervention.

  23. Change in aspartate transaminase (AST) concentration. [ Time Frame: baseline, 8 weeks. ]
    Assessment of serum concentration of AST at baseline and after 8 weeks of intervention.

  24. Change in urea concentration. [ Time Frame: baseline, 8 weeks. ]
    Assessment of serum concentration of urea at baseline and after 8 weeks of intervention.

  25. Change in creatinine concentration. [ Time Frame: baseline, 8 weeks. ]
    Assessment of serum concentration of creatinine at baseline and after 8 weeks of intervention.



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Ages Eligible for Study:   18 Years to 30 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03792984


Locations
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Syrian Arab Republic
Damascus University of Obstetrics and Gynecology Hospital
Damascus, Syrian Arab Republic
Orient Hospital
Damascus, Syrian Arab Republic
Sponsors and Collaborators
Damascus University
Investigators
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Principal Investigator: Sally Kadoura, B Pharm, MD Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Damascus University, Damascus, Syria
Study Director: Abdul Hakim Nattouf, MD, PhD Professor at Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Damascus University, Damascus, Syria
Study Director: Marwan Alhalabi, MD, PhD Professor at Department of Embryology and Reproductive Medicine, Faculty of Medicine, Damascus University, Damascus, Syria.

Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Damascus University
ClinicalTrials.gov Identifier: NCT03792984    
Other Study ID Numbers: Ph-CT-2685
First Posted: January 4, 2019    Key Record Dates
Last Update Posted: June 6, 2019
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Damascus University:
Polycystic Ovary Syndrome
Calcium
Vitamin D
Metformin
Additional relevant MeSH terms:
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Polycystic Ovary Syndrome
Vitamin D Deficiency
Syndrome
Disease
Pathologic Processes
Ovarian Cysts
Cysts
Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Gonadal Disorders
Endocrine System Diseases
Avitaminosis
Deficiency Diseases
Malnutrition
Nutrition Disorders
Vitamin D
Ergocalciferols
Calcium, Dietary
Cholecalciferol
Vitamins
Metformin
Calcium Carbonate
Calcium
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs
Hypoglycemic Agents