Vitamin D Treatment, Pharmacogenetics and Glucose Metabolism

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.

Polycystic ovarian syndrome (PCOS) is associated with increased androgen levels, cysts in the ovaries and with an irregular menstrual cycle. This common endocrine disorder affects about 10-15% of all women of childbearing age. Women with PCOS are also at an increased risk of metabolic changes such as type 2 diabetes mellitus. The results of our project suggest that vitamin D supplementation leads to an improvement of various metabolic parameters in PCOS women and thus may possibly reduce the risk of developing type 2 diabetes mellitus. In women without PCOS vitamin D treatment seems to have a rather unfavorable effect on metabolic parameters. Vitamin D is well known for its effects on calcium and bone metabolism. There is accumulating evidence that vitamin D also plays a role in metabolic processes as well as in fertility and the production of reproductive hormones in women and men. We therefore performed a randomized placebo controlled study to investigate the effects of vitamin D treatment on metabolic and endocrine parameters in 180 women with and 150 women without PCOS. All women had insufficient or deficient vitamin D levels at baseline. Study participants received 20,000 International Units of vitamin D3 (50 drops of Oleovit D3) per week or placebo over a 24-week period. In women with PCOS and low vitamin D levels, vitamin D treatment seems to have a beneficial effect on various metabolic parameters after 3 and 6 months and may therefore decrease the risk of metabolic changes such as type 2 diabetes mellitus. Endocrine parameters (such as testosterone) and the menstrual cycle were unaffected by vitamin D treatment. In women without PCOS and low vitamin D levels, vitamin D treatment seems to have a rather unfavorable effect on metabolic parameters. In summary, vitamin D supplementation in women with PCOS and vitamin D deficiency may be a good therapeutic option with regard to various metabolic parameters. In contrast, in women without PCOS, no favorable effect of vitamin D treatment on metabolism could be demonstrated.