Background: The important role of vitamin D3 in human health is well recognized. In this study, we measured serum concentrations of vitamin D3, vitamin B12 and B9 (folic acid) in 410 women undergoing in vitro fertilisation (IVF)/intracytoplasmatic sperm injection (ICSI) with dedicated focus on 3-month changes in consideration of patients’ BMI. Methods: Patients were of European origin and did not take any supplementation of D3. In preparing for pregnancy, patients took ≥4 weeks 400 µg folic acid combined with 9 µg vitamin B12 and 150 µg iodide as recommended. Results: We found a significant 3-month quartile change of D3 serum concentrations (p < 0.0001) with maximum levels in autumn and lowest in spring. D3 correlated significantly with B12 (p = 0.035, ρ = 0.102) and folic acid (p < 0.0001, ρ = 0.191). BMIs however showed a negative correlation with B12 (p = 0.031, ρ = –0.105) and folic acid (p = 0.012, ρ = –0.125). Conclusions: Our results suggest a model in which the sun exposure during summer months enables storage of D3 followed by a slow release as a major factor to maintain D3 levels throughout the year. Finally, our data indicate that B12 and folic acid uptake might be influenced by vitamin D receptor and D3, where D3 and the BMI appear to have an indirect relationship – via B12 and folic acid.

Keywords:
Vitamin D, Calcitriol, D3, Vitamin B12, Folic acid, In vitro fertilisation/Intracytoplasmatic sperm injection, Assisted reproductive therapies
1.
Holick MF: Vitamin D deficiency. N Engl J Med 2007; 357: 266–281.
2.
Nandi A, Sinha N, Ong E, Sonmez H, Poretsky L: Is there a role for vitamin D in human reproduction? Horm Mol Biol Clin Investig 2016; 25: 15–28.
3.
Pearce K, Gleeson K, Tremellen K: Serum anti-Mullerian hormone production is not correlated with seasonal fluctuations of vitamin D status in ovulatory or PCOS women. Hum Reprod 2015; 30: 2171–2177.
4.
Bouillon R, Carmeliet G, Daci E, Segaert S, Verstuyf A: Vitamin D metabolism and action. Osteoporos Int 1998; 8(suppl 2):S13–S19.
5.
Irani M, Merhi Z: Role of vitamin D in ovarian physiology and its implication in reproduction: a systematic review. Fertil Steril 2014; 102: 460–468. e463.
6.
Johnson LE, DeLuca HF: Reproductive defects are corrected in vitamin d-deficient female rats fed a high calcium, phosphorus and lactose diet. J Nutr 2002; 132: 2270–2273.
7.
Kinuta K, Tanaka H, Moriwake T, Aya K, Kato S, Seino Y: Vitamin D is an important factor in estrogen biosynthesis of both female and male gonads. Endocrinology 2000; 141: 1317–1324.
8.
Hurley WL, Doane RM: Recent developments in the roles of vitamins and minerals in reproduction. J Dairy Sci 1989; 72: 784–804.
9.
Fabris A, Pacheco A, Cruz M, Puente JM, Fatemi H, Garcia-Velasco JA: Impact of circulating levels of total and bioavailable serum vitamin D on pregnancy rate in egg donation recipients. Fertil Steril 2014; 102: 1608–1612.
10.
Polyzos NP, Anckaert E, Guzman L, Schiettecatte J, Van Landuyt L, Camus M, Smitz J, Tournaye H: Vitamin D deficiency and pregnancy rates in women undergoing single embryo, blastocyst stage, transfer (SET) for IVF/ICSI. Hum Reprod 2014; 29: 2032–2040.
11.
Franasiak JM, Molinaro TA, Dubell EK, Scott KL, Ruiz AR, Forman EJ, Werner MD, Hong KH, Scott RT Jr: Vitamin D levels do not affect IVF outcomes following the transfer of euploid blastocysts. Am J Obstet Gynecol 2015; 212: 315.e311–e316.
12.
van de Vijver A, Drakopoulos P, Van Landuyt L, Vaiarelli A, Blockeel C, Santos-Ribeiro S, Tournaye H, Polyzos NP: Vitamin D deficiency and pregnancy rates following frozen-thawed embryo transfer: a prospective cohort study. Hum Reprod 2016; 31: 1749–1754.
13.
Voulgaris N, Papanastasiou L, Piaditis G, Angelousi A, Kaltsas G, Mastorakos G, Kassi E: Vitamin D and aspects of female fertility. Hormones (Athens) 2017; 16: 5–21.
14.
Anastasi E, Fuggetta E, De Vito C, Migliara G, Viggiani V, Manganaro L, Granato T, Benedetti Panici P, Angeloni A, Porpora MG: Low levels of 25-OH vitamin D in women with endometriosis and associated pelvic pain. Clin Chem Lab Med 2017; 55:e282–e284.
15.
Bacopoulou F, Kolias E, Efthymiou V, Antonopoulos CN, Charmandari E: Vitamin D predictors in polycystic ovary syndrome: a meta-analysis. Eur J Clin Invest 2017; 47: 746–755.
16.
Kibirige D, Mwebaze R: Vitamin B12 deficiency among patients with diabetes mellitus: is routine screening and supplementation justified? J Diabetes Metab Disord 2013; 12: 17.
17.
Smithells RW, Sheppard S, Wild J, Schorah CJ: Prevention of neural tube defect recurrences in Yorkshire: final report. Lancet 1989; 2: 498–499.
18.
Thaler CJ: Folate metabolism and human reproduction. Geburtshilfe Frauenheilkd 2014; 74: 845–851.
19.
Boxmeer JC, Macklon NS, Lindemans J, Beckers NG, Eijkemans MJ, Laven JS, Steegers EA, Steegers-Theunissen RP: IVF outcomes are associated with biomarkers of the homocysteine pathway in monofollicular fluid. Hum Reprod 2009; 24: 1059–1066.
20.
Chavarro JE, Rich-Edwards JW, Rosner BA, Willett WC: Use of multivitamins, intake of B vitamins, and risk of ovulatory infertility. Fertil Steril 2008; 89: 668–676.
21.
Ohrvik VE, Witthoft CM: Human folate bioavailability. Nutrients 2011; 3: 475–490.
22.
Ingrid Goh Y, Bollano E, Einarson TR, Koren G: Prenatal multivitamin supplementation and rates of congenital anomalies: a meta-analysis. J Obstet Gynaecol Can 2006; 28: 680–689.
23.
Zhao J, Huang X, Xu B, Yan Y, Zhang Q, Li Y: Whether vitamin D was associated with clinical outcome after IVF/ICSI: a systematic review and meta-analysis. Reprod Biol Endocrinol 2018; 16: 13.
24.
Rotterdam EA-SPCWG: Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004; 81: 19–25.
25.
Webb AR, Kline L, Holick MF: Influence of season and latitude on the cutaneous synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin. J Clin Endocrinol Metab 1988; 67: 373–378.
26.
Rice SA, Carpenter M, Fityan A, Vearncombe LM, Ardern-Jones M, Jackson AA, Cooper C, Baird J, Healy E: Limited exposure to ambient ultraviolet radiation and 25-hydroxyvitamin D levels: a systematic review. Br J Dermatol 2015; 172: 652–661.
27.
Diffey BL: Modelling vitamin D status due to oral intake and sun exposure in an adult British population. Br J Nutr 2013; 110: 569–577.
28.
Presse N, Perreault S, Kergoat MJ: Vitamin B12 deficiency induced by the use of gastric acid inhibitors: calcium supplements as a potential effect modifier. J Nutr Health Aging 2016; 20: 569–573.
29.
Eloranta JJ, Zair ZM, Hiller C, Hausler S, Stieger B, Kullak-Ublick GA: Vitamin D3 and its nuclear receptor increase the expression and activity of the human proton-coupled folate transporter. Mol Pharmacol 2009; 76: 1062–1071.
30.
Skowronska P, Pastuszek E, Kuczynski W, Jaszczol M, Kuc P, Jakiel G, Woclawek-Potocka I, Lukaszuk K: The role of vitamin D in reproductive dysfunction in women – a systematic review. Ann Agric Environ Med 2016; 23: 671–676.
31.
Ding C, Gao D, Wilding J, Trayhurn P, Bing C: Vitamin D signalling in adipose tissue. Br J Nutr 2012; 108: 1915–1923.
32.
Piantanida E, Gallo D, Veronesi G, Dozio E, Trotti E, Lai A, Ippolito S, Sabatino J, Tanda ML, Toniolo A, Ferrario M, Bartalena L: Cardiometabolic healthy and unhealthy obesity: does vitamin D play a role? Endocr Connect 2017; 6: 943–951.
33.
Koszowska AU, Nowak J, Dittfeld A, Bronczyk-Puzon A, Kulpok A, Zubelewicz-Szkodzinska B: Obesity, adipose tissue function and the role of vitamin D. Cent Eur J Immunol 2014; 39: 260–264.
34.
He C, Lin Z, Robb SW, Ezeamama AE: Serum vitamin D levels and polycystic ovary syndrome: a systematic review and meta-analysis. Nutrients 2015; 7: 4555–4577.
35.
Vimaleswaran KS, Berry DJ, Lu C, Tikkanen E, Pilz S, Hiraki LT, Cooper JD, Dastani Z, Li R, Houston DK, Wood AR, Michaelsson K, Vandenput L, Zgaga L, Yerges-Armstrong LM, McCarthy MI, Dupuis J, Kaakinen M, Kleber ME, Jameson K, Arden N, Raitakari O, Viikari J, Lohman KK, Ferrucci L, Melhus H, Ingelsson E, Byberg L, Lind L, Lorentzon M, Salomaa V, Campbell H, Dunlop M, Mitchell BD, Herzig KH, Pouta A, Hartikainen AL; Genetic Investigation of Anthropometric Traits-GIANT Consortium, Streeten EA, Theodoratou E, Jula A, Wareham NJ, Ohlsson C, Frayling TM, Kritchevsky SB, Spector TD, Richards JB, Lehtimaki T, Ouwehand WH, Kraft P, Cooper C, Marz W, Power C, Loos RJ, Wang TJ, Jarvelin MR, Whittaker JC, Hingorani AD, Hypponen E: Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts. PLoS Med 2013; 10:e1001383.
36.
Mahmoudi T, Gourabi H, Ashrafi M, Yazdi RS, Ezabadi Z: Calciotropic hormones, insulin resistance, and the polycystic ovary syndrome. Fertil Steril 2010; 93: 1208–1214.
37.
Hastbacka J, Pettila V: Prevalence and predictive value of ionized hypocalcemia among critically ill patients. Acta Anaesthesiol Scand 2003; 47: 1264–1269.
38.
Lindner G, Felber R, Schwarz C, Marti G, Leichtle AB, Fiedler GM, Zimmermann H, Arampatzis S, Exadaktylos AK: Hypercalcemia in the ED: prevalence, etiology, and outcome. Am J Emerg Med 2013; 31: 657–660.
39.
Borel P, Caillaud D, Cano NJ: Vitamin D bioavailability: state of the art. Crit Rev Food Sci Nutr 2015; 55: 1193–1205.
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