The Effect of Calcium and Vitamin D Supplements on Metabolic and Hormonal Disturbances in Polycystic Ovary Syndrome Patients
Primary Purpose
Polycystic Ovary Syndrome, Vitamin D Deficiency/Insufficiency
Status
Completed
Phase
Phase 3
Locations
Syrian Arab Republic
Study Type
Interventional
Intervention
Vitamin D3
Calcium Carbonate
Metformin
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Polycystic Ovary Syndrome focused on measuring Polycystic Ovary Syndrome, Calcium, Vitamin D, Metformin
Eligibility 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.
Sites / Locations
- Damascus University of Obstetrics and Gynecology Hospital
- Orient Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Placebo Comparator
Experimental
Arm Label
Metformin + Placebo
Calcium carbonate + Vitamin D3 + Metformin
Arm Description
Outcomes
Primary Outcome Measures
Change in quantitative insulin sensitivity check index (QUICKI).
Assessment of QUICKI index at baseline and after 8 weeks of intervention.
Change in Raynaud's index.
Assessment of Raynaud's index at baseline and after 8 weeks of intervention.
Change in McAuley Index.
Assessment of McAuley Index at baseline and after 8 weeks of intervention.
Secondary Outcome Measures
Change in glucose concentration.
Assessment of serum concentration of glucose at baseline and after 8 weeks of intervention.
Change in insulin concentration.
Assessment of serum concentration of insulin at baseline and after 8 weeks of intervention.
Change in homeostasis model assessment of insulin resistance index (HOMA-IR).
Assessment of HOMA-IR index at baseline and after 8 weeks of intervention.
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.
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.
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).
Change in free testosterone concentration
Assessment of serum free testosterone concentration at baseline and after 8 weeks of intervention.
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.
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.
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.
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.
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.
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.
Change in serum concentration of C-reactive protein (CRP)
Assessment of serum concentration of CRP at baseline and after 8 weeks of intervention.
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.
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.
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.
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.
Change in calcium concentration.
Assessment of serum concentration of calcium at baseline and after 8 weeks of intervention.
Change in 25-OH-vitamin D concentration.
Assessment of serum concentration of 25-OH-vitamin D at baseline and after 8 weeks of intervention.
Change in phosphorus concentration.
Assessment of serum concentration of phosphorus at baseline and after 8 weeks of intervention.
Change in alanine transaminase (ALT) concentration.
Assessment of serum concentration of ALT at baseline and after 8 weeks of intervention.
Change in aspartate transaminase (AST) concentration.
Assessment of serum concentration of AST at baseline and after 8 weeks of intervention.
Change in urea concentration.
Assessment of serum concentration of urea at baseline and after 8 weeks of intervention.
Change in creatinine concentration.
Assessment of serum concentration of creatinine at baseline and after 8 weeks of intervention.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03792984
Brief Title
The Effect of Calcium and Vitamin D Supplements on Metabolic and Hormonal Disturbances in Polycystic Ovary Syndrome Patients
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
Study Type
Interventional
2. Study Status
Record Verification Date
December 2018
Overall Recruitment Status
Completed
Study Start Date
December 1, 2016 (Actual)
Primary Completion Date
October 1, 2017 (Actual)
Study Completion Date
December 30, 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Damascus University
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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).
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Polycystic Ovary Syndrome, Vitamin D Deficiency/Insufficiency
Keywords
Polycystic Ovary Syndrome, Calcium, Vitamin D, Metformin
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
Participant
Allocation
Randomized
Enrollment
40 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Metformin + Placebo
Arm Type
Placebo Comparator
Arm Title
Calcium carbonate + Vitamin D3 + Metformin
Arm Type
Experimental
Intervention Type
Dietary Supplement
Intervention Name(s)
Vitamin D3
Intervention Description
Vitamin D3 (Cholecalciferol) (6000 IU/daily). PO for 8 weeks.
Intervention Type
Dietary Supplement
Intervention Name(s)
Calcium Carbonate
Intervention Description
Calcium carbonate (1000 mg/daily). PO for 8 weeks.
Intervention Type
Drug
Intervention Name(s)
Metformin
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
PO for 8 weeks.
Primary Outcome Measure Information:
Title
Change in quantitative insulin sensitivity check index (QUICKI).
Description
Assessment of QUICKI index at baseline and after 8 weeks of intervention.
Time Frame
baseline, 8 weeks weeks.
Title
Change in Raynaud's index.
Description
Assessment of Raynaud's index at baseline and after 8 weeks of intervention.
Time Frame
baseline, 8 weeks weeks.
Title
Change in McAuley Index.
Description
Assessment of McAuley Index at baseline and after 8 weeks of intervention.
Time Frame
baseline, 8 weeks weeks.
Secondary Outcome Measure Information:
Title
Change in glucose concentration.
Description
Assessment of serum concentration of glucose at baseline and after 8 weeks of intervention.
Time Frame
baseline, 8 weeks.
Title
Change in insulin concentration.
Description
Assessment of serum concentration of insulin at baseline and after 8 weeks of intervention.
Time Frame
baseline, 8 weeks.
Title
Change in homeostasis model assessment of insulin resistance index (HOMA-IR).
Description
Assessment of HOMA-IR index at baseline and after 8 weeks of intervention.
Time Frame
baseline, 8 weeks.
Title
Change in homeostasis model assessment of β-cell function index (HOMA-B).
Description
Assessment of HOMA-B index at baseline and after 8 weeks of intervention.
Time Frame
baseline, 8 weeks.
Title
Change in menstrual cycle abnormalities.
Description
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.
Time Frame
up to 8 weeks.
Title
Change in hirsutism score
Description
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).
Time Frame
baseline, 8 weeks.
Title
Change in free testosterone concentration
Description
Assessment of serum free testosterone concentration at baseline and after 8 weeks of intervention.
Time Frame
baseline, 8 weeks.
Title
Change in serum concentration of follicle-stimulating hormone (FSH)
Description
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.
Time Frame
baseline, 8 weeks or the next spontaneous menstrual cycle depending on menstrual cycle status.
Title
Change in serum concentration of luteinizing hormone (LH) .
Description
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.
Time Frame
baseline, 8 weeks or the next spontaneous menstrual cycle depending on menstrual cycle status.
Title
Change in serum concentration of Insulin-like growth factor-1 (IGF-1).
Description
Assessment of serum concentration of IGF-1 at baseline and after 8 weeks of intervention.
Time Frame
baseline, 8 weeks.
Title
Change in serum concentration of Insulin-like growth factor binding protein-1 (IGFBP-1).
Description
Assessment of serum concentration of IGFBP-1 at baseline and after 8 weeks of intervention.
Time Frame
baseline, 8 weeks.
Title
Change in IGF-1 to IGFBP-1 ratio.
Description
Assessment of serum concentration of IGF-1 to IGFBP-1 ratio at baseline and after 8 weeks of intervention.
Time Frame
baseline, 8 weeks.
Title
Change in lipid profile.
Description
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.
Time Frame
baseline, 8 weeks.
Title
Change in serum concentration of C-reactive protein (CRP)
Description
Assessment of serum concentration of CRP at baseline and after 8 weeks of intervention.
Time Frame
baseline, 8 weeks.
Title
Change in Body mass index (BMI).
Description
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.
Time Frame
baseline, 8 weeks.
Title
Change in waist circumference.
Description
Assessment of waist circumference in an overnight fasting status without shoes with light clothes at baseline and after 8 weeks of intervention.
Time Frame
baseline, 8 weeks.
Title
Change in Hip circumference.
Description
Assessment of Hip circumference in an overnight fasting status without shoes with light clothes at baseline and after 8 weeks of intervention.
Time Frame
baseline, 8 weeks.
Title
Change in waist to hip ratio.
Description
Assessment of waist to hip ratio in an overnight fasting status without shoes with light clothes at baseline and after 8 weeks of intervention.
Time Frame
baseline, 8 weeks.
Title
Change in calcium concentration.
Description
Assessment of serum concentration of calcium at baseline and after 8 weeks of intervention.
Time Frame
baseline, 8 weeks.
Title
Change in 25-OH-vitamin D concentration.
Description
Assessment of serum concentration of 25-OH-vitamin D at baseline and after 8 weeks of intervention.
Time Frame
baseline, 8 weeks.
Title
Change in phosphorus concentration.
Description
Assessment of serum concentration of phosphorus at baseline and after 8 weeks of intervention.
Time Frame
baseline, 8 weeks.
Title
Change in alanine transaminase (ALT) concentration.
Description
Assessment of serum concentration of ALT at baseline and after 8 weeks of intervention.
Time Frame
baseline, 8 weeks.
Title
Change in aspartate transaminase (AST) concentration.
Description
Assessment of serum concentration of AST at baseline and after 8 weeks of intervention.
Time Frame
baseline, 8 weeks.
Title
Change in urea concentration.
Description
Assessment of serum concentration of urea at baseline and after 8 weeks of intervention.
Time Frame
baseline, 8 weeks.
Title
Change in creatinine concentration.
Description
Assessment of serum concentration of creatinine at baseline and after 8 weeks of intervention.
Time Frame
baseline, 8 weeks.
10. Eligibility
Sex
Female
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
30 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sally Kadoura, B Pharm, MD
Organizational Affiliation
Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Damascus University, Damascus, Syria
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Abdul Hakim Nattouf, MD, PhD
Organizational Affiliation
Professor at Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Damascus University, Damascus, Syria
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Marwan Alhalabi, MD, PhD
Organizational Affiliation
Professor at Department of Embryology and Reproductive Medicine, Faculty of Medicine, Damascus University, Damascus, Syria.
Official's Role
Study Director
Facility Information:
Facility Name
Damascus University of Obstetrics and Gynecology Hospital
City
Damascus
Country
Syrian Arab Republic
Facility Name
Orient Hospital
City
Damascus
Country
Syrian Arab Republic
12. IPD Sharing Statement
Plan to Share IPD
Undecided
Citations:
PubMed Identifier
23789983
Citation
Ameri P, Giusti A, Boschetti M, Murialdo G, Minuto F, Ferone D. Interactions between vitamin D and IGF-I: from physiology to clinical practice. Clin Endocrinol (Oxf). 2013 Oct;79(4):457-63. doi: 10.1111/cen.12268. Epub 2013 Aug 9.
Results Reference
background
PubMed Identifier
17177140
Citation
Hahn S, Haselhorst U, Tan S, Quadbeck B, Schmidt M, Roesler S, Kimmig R, Mann K, Janssen OE. Low serum 25-hydroxyvitamin D concentrations are associated with insulin resistance and obesity in women with polycystic ovary syndrome. Exp Clin Endocrinol Diabetes. 2006 Nov;114(10):577-83. doi: 10.1055/s-2006-948308.
Results Reference
background
PubMed Identifier
24933120
Citation
Irani M, Merhi Z. Role of vitamin D in ovarian physiology and its implication in reproduction: a systematic review. Fertil Steril. 2014 Aug;102(2):460-468.e3. doi: 10.1016/j.fertnstert.2014.04.046. Epub 2014 Jun 3.
Results Reference
background
PubMed Identifier
24044903
Citation
Krul-Poel YH, Snackey C, Louwers Y, Lips P, Lambalk CB, Laven JS, Simsek S. The role of vitamin D in metabolic disturbances in polycystic ovary syndrome: a systematic review. Eur J Endocrinol. 2013 Oct 23;169(6):853-65. doi: 10.1530/EJE-13-0617. Print 2013 Dec.
Results Reference
background
PubMed Identifier
21550088
Citation
Li HW, Brereton RE, Anderson RA, Wallace AM, Ho CK. Vitamin D deficiency is common and associated with metabolic risk factors in patients with polycystic ovary syndrome. Metabolism. 2011 Oct;60(10):1475-81. doi: 10.1016/j.metabol.2011.03.002. Epub 2011 May 6.
Results Reference
background
PubMed Identifier
22330149
Citation
Ott J, Wattar L, Kurz C, Seemann R, Huber JC, Mayerhofer K, Vytiska-Binstorfer E. Parameters for calcium metabolism in women with polycystic ovary syndrome who undergo clomiphene citrate stimulation: a prospective cohort study. Eur J Endocrinol. 2012 May;166(5):897-902. doi: 10.1530/EJE-11-1070. Epub 2012 Feb 13.
Results Reference
background
PubMed Identifier
27186859
Citation
Pal L, Zhang H, Williams J, Santoro NF, Diamond MP, Schlaff WD, Coutifaris C, Carson SA, Steinkampf MP, Carr BR, McGovern PG, Cataldo NA, Gosman GG, Nestler JE, Myers E, Legro RS; Reproductive Medicine Network. Vitamin D Status Relates to Reproductive Outcome in Women With Polycystic Ovary Syndrome: Secondary Analysis of a Multicenter Randomized Controlled Trial. J Clin Endocrinol Metab. 2016 Aug;101(8):3027-35. doi: 10.1210/jc.2015-4352. Epub 2016 May 17.
Results Reference
background
PubMed Identifier
20711952
Citation
Parikh G, Varadinova M, Suwandhi P, Araki T, Rosenwaks Z, Poretsky L, Seto-Young D. Vitamin D regulates steroidogenesis and insulin-like growth factor binding protein-1 (IGFBP-1) production in human ovarian cells. Horm Metab Res. 2010 Sep;42(10):754-7. doi: 10.1055/s-0030-1262837. Epub 2010 Aug 13.
Results Reference
background
PubMed Identifier
10487660
Citation
Thierry van Dessel HJ, Lee PD, Faessen G, Fauser BC, Giudice LC. Elevated serum levels of free insulin-like growth factor I in polycystic ovary syndrome. J Clin Endocrinol Metab. 1999 Sep;84(9):3030-5. doi: 10.1210/jcem.84.9.5941.
Results Reference
background
PubMed Identifier
31354810
Citation
Kadoura S, Alhalabi M, Nattouf AH. Effect of Calcium and Vitamin D Supplements as an Adjuvant Therapy to Metformin on Menstrual Cycle Abnormalities, Hormonal Profile, and IGF-1 System in Polycystic Ovary Syndrome Patients: A Randomized, Placebo-Controlled Clinical Trial. Adv Pharmacol Sci. 2019 Jul 1;2019:9680390. doi: 10.1155/2019/9680390. eCollection 2019.
Results Reference
derived
Learn more about this trial
The Effect of Calcium and Vitamin D Supplements on Metabolic and Hormonal Disturbances in Polycystic Ovary Syndrome Patients
We'll reach out to this number within 24 hrs