Abstract
Abstract. Vitamin D is a secosteroid hormone that plays a pivotal role in several metabolic and reproductive pathways in humans. Increasing evidence supports the role of vitamin D deficiency in metabolic disturbances and infertility in women with polycystic ovary syndrome (PCOS). Indeed, supplementation with vitamin D seems to have a beneficial role on insulin resistance (IR) and endometrial receptivity. On the other hand, exceedingly high levels of vitamin D appear to play a detrimental role on oocytes development and embryo quality. In the current review, we summarize the available evidence about the topic, aiming to suggest the best supplementation strategy in women with PCOS or, more generally, in those with metabolic disturbances and infertility. Based on the retrieved data, vitamin D seems to have a beneficial role on IR, insulin sensitivity and endometrial receptivity, but high levels and incorrect timing of administration seem to have a detrimental role on oocytes development and embryo quality. Therefore, we encourage a low dose supplementation (400–800 IU/day) particularly in vitamin D deficient women that present metabolic disturbances like PCOS. As far as the reproductive health, we advise vitamin D supplementation in selected populations, only during specific moments of the ovarian cycle, to support the luteal phase. However, ambiguities about dosage and timing of the supplementation still emerge from the clinical studies published to date and further studies are required.
References
1 . Epidemiology, diagnosis, and management of polycystic ovary syndrome. Clin Epidemiol. 2013;6:1–13.
2 . Polycystic ovary syndrome: a complex condition with psychological, reproductive and metabolic manifestations that impacts on health across the lifespan. BMC Med. 2010;8:41.
3 Association of hypovitaminosis D with metabolic disturbances in polycystic ovary syndrome. Eur J Endocrinol. 2009;161:575–82.
4 . Vitamin D in the aetiology and management of polycystic ovary syndrome. Clin Endocrinol. 2012;77:343–50.
5 . Type 2 diabetes and other metabolic outcomes: A systematic review and meta-analysis of prospective studies. Proc Nutr Soc. 2013;72:89–97.
6 Blood 25-hydroxy vitamin D levels and incident type 2 diabetes: A meta-analysis of prospective studies. Diabetes Care. 2013;36:1422–8.
7 The role of vitamin D in metabolic disturbances in polycystic ovary syndrome: A systematic review. Eur J Endocrinol. 2013;169:853–65.
8 . Role of vitamin D in insulin secretion and insulin sensitivity for glucose homeostasis. Int J Endocrinol. 2010;2010:351–85.
9 . Vitamin D-associated polymorphisms are related to insulin resistance and vitamin D deficiency in polycystic ovary syndrome. Eur J Endocrinol. 2011;164(5):741–9.
10 . Role of vitamin D in ovarian physiology and its implication in reproduction: a systematic review. Fertil Steril. 2014;102(2):460–468.e3.
11 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;101:3027–35.
12 . The role of vitamin D oral supplementation in insulin resistance in women with polycystic ovary syndrome: A systematic review and meta-analysis of randomized controlled trials. Nutrients. 2018;10:1637.
13 . Effect of two different doses of vitamin D supplementation on metabolic profiles of insulin-resistant patients with polycystic ovary syndrome. Nutrients. 2017;12(9):E1280.
14 Effects of vitamin D supplementation on metabolic and endocrine parameters in PCOS: a randomized-controlled trial. Eur J Nutr. 2018;58(5):2019–28.
15 . Differential rate in decline in ovarian reserve markers in polycysctic ovary syndrome compared to controls: Results of a longitudinal study. Fertil Steril. 2018;109:526–31.
16 . Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Human Reproduction. 2004;81(1):19–25.
17 . 1 alpha, 25-Dihydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 in vitro synthesis by human decidua and placenta. Nature. 1979;281:317–9.
18 Vitamin D regulates steroidogenesis and insulin-like growth factor binding protein-1 (IGFBP-1) production in human ovarian cells. Horm Metab Res. 2010;42:754–7.
19 Cycling and early pregnant endometrium as a site of regulated expression of the vitamin D system. J Mol Endocrinol. 2006;36:415–24.
20 . Vitamin D receptor gene expression in human pituitary gland. Life Sci. 1997;60:35–42.
21 Effects of 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 on cytokine production by human decidual cells. Biol Reprod. 2006;75:816–22.
22 . Relevance of vitamin D in reproduction. Hum Reprod. 2012;27:3015–27.
23 Is there a link between premature ovarian failure and serum concentrations of vitamin D, zinc, and copper? Menopause. 2013;20:94–9.
24 . Vitamin D and Infertility: The Evidence. Fertil Reprod. 2019;1(1):31–3.
25 . Vitamin D alters genes involved in follicular development and steroidogenesis in human cumulus granulosa cells. J Clin Endocrinol Metab. 2014;99(6):E1137–45.
26 . Anti-Müllerian hormone: a new marker for ovarian function. Reproduction. 2006;13(1):1–9.
27 . Estradioland progesterone synthesis in human placenta is stimulated by calcitriol. J Steroid Biochem Mol Biol. 2007;103:529–32.
28 . Vitamin D as a follicular marker of human oocyte quality and a serum marker of in vitro fertilization outcome. J Assist Reprod Genet. 2018;35(7):1265–76.
29 Calcitriol affects hCG gene transcription in cultured human syncytiotrophoblasts. Reprod Biol Endocrinol. 2008;6:3.
30 . Direct regulation of HOXA10 by 1,25-(OH)2D3 in human myelomonocytic cells and human endometrial stromal cells. Mol Endocrinol. 2005;19:2222–33.
31 . Alteration of maternal Hoxa10 expression by in vivo gene transfection affects implantation. Gene Ther. 2000;7:1378–84.
32 . A conserved Hox axis in the mouse and human female reproductive system: late establishment and persistent adult expression of the Hoxa cluster genes. Biol Reprod. 1997;57:1338–45.
33 Effect of vitamin D3 on production of progesterone in porcine granulosa cells by regulation of steroidogenic enzymes. J Biomed Res. 2016;30:203–8.
34 . Vitamin D in human reproduction: the more, the better? An evidence-based critical appraisal. Eur Rev Med Pharmacol Sci. 2017;21(18):4243–51.
35 Replete vitamin D stores predict reproductive success following in vitro fertilization. Fertil Steril. 2010;94:1314–9.
36 Vitamin D deficiency and infertility: Insights from in vitro fertilization cycles. J Clin Endocrinol Metab. 2014;99:E2372–6.
37 . Influence of vitamin D levels on in vitro fertilization outcomes in donorrecipient cycles. Fertil Steril. 2014;101:447–52.
38 . Effect of vitamin D status on clinical pregnancy rates following in vitro fertilization. C Open. 2013;1:E77–82.
39 Prognostic value of follicular fluid 25-OH vitamin D and glucose levels in the IVF outcome. Reprod Biol Endocrinol RB&E. 2010;8:91.
40 Cycling and early pregnant endometrium as a site of regulated expression of the vitamin D system. J Mol Endocrinol. 2006;36(3):415–24.
41 . Scientific opinion on dietary reference values for iodine. EFSA J. 2014;12(5):3660.
42 . Vitamin D and assisted reproductive treatment outcome: a systematic review and meta-analysis. Hum Reprod. 2018;33(1):65–80.