Clinical trial NCT03792984: 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
Overall status: COMPLETED
Phase: PHASE3
Conditions: Polycystic Ovary Syndrome
Vitamin D Deficiency/Insufficiency
Keywords: Polycystic Ovary Syndrome
Calcium
Vitamin D
Metformin
Lead sponsor: Damascus University
Sponsor class: OTHER
First posted: 2019-01-04
Enrollment: 40
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 30
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Change in quantitative insulin sensitivity check index (QUICKI).
timeFrame: baseline, 8 weeks weeks.
measure: Change in Raynaud's index.
timeFrame: baseline, 8 weeks weeks.
measure: Change in McAuley Index.
timeFrame: baseline, 8 weeks weeks.
Secondary outcomes:
measure: Change in glucose concentration.
timeFrame: baseline, 8 weeks.
measure: Change in insulin concentration.
timeFrame: baseline, 8 weeks.
measure: Change in homeostasis model assessment of insulin resistance index (HOMA-IR).
timeFrame: baseline, 8 weeks.
measure: Change in homeostasis model assessment of β-cell function index (HOMA-B).
timeFrame: baseline, 8 weeks.
measure: Change in menstrual cycle abnormalities.
timeFrame: up to 8 weeks.
measure: Change in hirsutism score
timeFrame: baseline, 8 weeks.
measure: Change in free testosterone concentration
timeFrame: baseline, 8 weeks.
measure: Change in serum concentration of follicle-stimulating hormone (FSH)
timeFrame: baseline, 8 weeks or the next spontaneous menstrual cycle depending on menstrual cycle status.
measure: Change in serum concentration of luteinizing hormone (LH) .
timeFrame: baseline, 8 weeks or the next spontaneous menstrual cycle depending on menstrual cycle status.
measure: Change in serum concentration of Insulin-like growth factor-1 (IGF-1).
timeFrame: baseline, 8 weeks.
measure: Change in serum concentration of Insulin-like growth factor binding protein-1 (IGFBP-1).
timeFrame: baseline, 8 weeks.
measure: Change in IGF-1 to IGFBP-1 ratio.
timeFrame: baseline, 8 weeks.
measure: Change in lipid profile.
timeFrame: baseline, 8 weeks.
measure: Change in serum concentration of C-reactive protein (CRP)
timeFrame: baseline, 8 weeks.
measure: Change in Body mass index (BMI).
timeFrame: baseline, 8 weeks.
measure: Change in waist circumference.
timeFrame: baseline, 8 weeks.
measure: Change in Hip circumference.
timeFrame: baseline, 8 weeks.
measure: Change in waist to hip ratio.
timeFrame: baseline, 8 weeks.
measure: Change in calcium concentration.
timeFrame: baseline, 8 weeks.
measure: Change in 25-OH-vitamin D concentration.
timeFrame: baseline, 8 weeks.
measure: Change in phosphorus concentration.
timeFrame: baseline, 8 weeks.
measure: Change in alanine transaminase (ALT) concentration.
timeFrame: baseline, 8 weeks.
measure: Change in aspartate transaminase (AST) concentration.
timeFrame: baseline, 8 weeks.
measure: Change in urea concentration.
timeFrame: baseline, 8 weeks.
measure: Change in creatinine concentration.
timeFrame: baseline, 8 weeks.
Other outcomes:
Locations:
city: Damascus
country: Syrian Arab Republic
facility: Damascus University of Obstetrics and Gynecology Hospital
city: Damascus
country: Syrian Arab Republic
facility: Orient Hospital
Study officials:
affiliation: Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Damascus University, Damascus, Syria
name: Sally Kadoura, B Pharm, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Professor at Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Damascus University, Damascus, Syria
name: Abdul Hakim Nattouf, MD, PhD
role: STUDY_DIRECTOR
affiliation: Professor at Department of Embryology and Reproductive Medicine, Faculty of Medicine, Damascus University, Damascus, Syria.
name: Marwan Alhalabi, MD, PhD
role: STUDY_DIRECTOR
References:
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.
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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.
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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.
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.
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.
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.