Vitamin D Treatment, Pharmacogenetics and Glucose Metabolism

Phase 4CompletedNCT01721915

Medical University of Graz330 enrolled

Overview

Background: Polycystic ovary syndrome (PCOS) is as common as 5-10% of all women in Austria. PCOS women frequently present with metabolic disturbances, hyperandrogenism and infertility. New therapy concepts are warranted. In our recent pilot study, vitamin D (vitD) supplementation significantly improved glucose metabolism and fertility. However, the efficacy of vitD administration shows individual variability indicating endogenous influences on pharmacological effects. A recent genome-wide association study reported three loci (DHCR7, CYP2R1, and GC) associated with vitD insufficiency. Moreover, vitD receptor (VDR) gene variants have already been known to be associated with insulin resistance. Aim: To test the hypothesis that vitD is efficient in changing metabolic parameters in PCOS and non-PCOS women longitudinally and to generate data on pharmacogenetic effects of vitD related genetic determinants adjusted for environmental factors. Primary outcome: Change from baseline in AUCgluc after vitD treatment. Secondary outcome: To generate the hypothesis that changes in metabolic and endocrine parameters following vitD treatment are associated with vitD related gene variants. Methods: 150 PCOS women with 25-hydroxyvitamin D (cholecalciferol, \[25(OH)D\]) levels \<30 ng/ml will be treated with vitD (20,000 IU/wk) or placebo in a 2:1 randomized controlled trial over 24 weeks and investigated for metabolic and endocrine parameters as well as vitD related genetic variants. In addition, 150 non-PCOS women with 25(OH)D \<30 ng/ml will be treated with vitD (20,000 IU/wk) or placebo in a 2:1 randomized controlled trial over 24 weeks and investigated for metabolic and endocrine parameters as well as vitD related genetic variants. The response to vitD supplementation in both groups will be analysed according to genotype profiles. Significance: VitD might be a new therapeutic option without major side effects for PCOS patients. Exploring specific loci for pharmacogenetic vitD actions would open a new window for therapy modulation in PCOS and other metabolic diseases.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

Eligibility

Sex: FEMALEMin age: 18 YearsMax age: 44 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: PCOS women: * 25(OH)D levels below 30 ng/ml (measured at the baseline visit) * Polycystic ovary syndrome defined by the Androgen Excess Society (AES) criteria * Female, age of ≥ 18 and \<45 years * BMI status: 75 PCOS women with BMI ≤25 kg/m² and 75 PCOS women with BMI\>25 kg/m² * Written informed consent before study entry Control women: * 25(OH)D levels below 30 ng/ml (measured at the baseline visit) * Female, age of ≥ 18 and \<45 years * BMI status: 75 nonPCOS women with BMI ≤25 kg/m² and 75 nonPCOS women with BMI\>25 kg/m² * Written informed consent before study entry Exclusion Criteria: PCOS women: * Hypercalcemia defined as a serum calcium \> 2,7 mmol/L * Pregnancy or lactating women * Disorders associated with androgen excess and/or menstrual irregularities apart from PCOS (thyroid dysfunction, hyperprolactinemia, adrenal hyperplasia, androgen secreting tumors) * Prevalent type 2 diabetes * Regular intake of vitD supplements at any time before study entry * Intake of medication influencing metabolic or endocrine parameters (insulin sensitizers, oral contraceptives, …) in the last 3 months before study entry Control women: * Hypercalcemia defined as a serum calcium \> 2,7 mmol/L * Established PCOS or any of the AES criteria 29 (hyperandrogenism (clinical and/or biochemical), oligo- or anovulation, or polycystic ovaries on ultrasound) * Disorders associated with androgen excess and/or menstrual irregularities apart from PCOS (thyroid dysfunction, hyperprolactinemia, adrenal hyperplasia, androgen secreting tumors) * Prevalent type 2 diabetes * Pregnancy or lactating women * Regular intake of vitD supplements at any time before study entry * Intake of medication influencing metabolic or endocrine parameters (insulin sensitizers, oral contraceptives, …) in the last 3 months before study entry

Outcomes

Primary Outcomes

Metabolic response during an oral glucose tolerance test (oGTT) as defined by AUCgluc

Time frame: Change from Baseline in AUC gluc at 24 weeks

Secondary Outcomes

Insulin resistance assessed by homeostatic model assessment-insulin resistance (HOMA-IR)

Time frame: Change from Baseline in insulin resistance at 24 weeks

Lipid levels (total cholesterol)

Time frame: Change from Baseline in total cholesterol at 24 weeks

HbA1c

Time frame: Change from Baseline in HbA1c at 24 weeks

Testosterone

Time frame: Change from Baseline in testosterone at 24 weeks

Menstrual frequency

Time frame: Change from Baseline in menstrual frequency at 24 weeks

Insulin sensitivity assessed by Quantitative Insulin-sensitivity Check Index (QUICKI)

Time frame: Change from baseline in QUICKI at 24 weeks

Free testosterone (FT)

Time frame: Change from Baseline in FT at 4 weeks

Triglycerides

Time frame: Change from Baseline in triglycerides at 24 weeks

Vitamin D Treatment, Pharmacogenetics and Glucose Metabolism

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes