Research Progress on the Relationship between Vitamin D and Female Reproduction

Xiaofei Xu1-4, Yongxiu Hao1-4 and Jie Qiao1-6 1Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, China 2National Clinical Research Center for Obstetrics and Gynecology, China 3Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, China 4Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, B China 5Beijing Advanced Innovation Center for Genomics, China 6Research Units of Comprehensive Diagnosis and Treatment of Oocyte Maturation Arrest

Vitamin D deficiency means a serum concentration of 25-(OH) D3 less than 20 ng/mL, and vitamin D insufficiency means a 25-(OH) D3 level between 21ng/mL and 29 ng/Ml [2]. The classical role of Vitamin D is maintaining the balance of calcium and phosphate homeostasis in intestines, bone, and the parathyroid glands. In recent years, Vitamin D receptor (VDR) expression has been confirmed in the other tissues besides the above classic target organs, such as immune cells, the pancreas, the cardiac system, the skeletal muscle. Moreover, VDR has been found in the female reproductive tract, such as ovary, uterus, fallopian tubes, placenta, etc. More recently there has been increasing interest in the role of vitamin D in reproductive function.
Vitamin D deficiency is common in both the developed and developing countries [2]. In the United States, 20%-90% of reproductive-aged women have vitamin D deficient despite prenatal vitamin intake [2]. Numerous studies have explored the influences of vitamin D deficiency in polycystic ovary syndrome (PCOS), in-vitro fertilization, pregnancy outcomes and so on.
However, the results and the effects of supplying vitamin D are still under debating. Therefore, we wrote this review to summarize the research progress about the potential role of vitamin D in female reproductive function and provide a perspective view for the following research.

Vitamin D and AMH
Anti-Mullerian hormone (AMH) is considered as an important marker of ovarian reserve used in clinical widely. One function of AMH is inhibiting recruitment of primordial follicles into folliculogenesis [3,4]. Epidemiology studies have shown an intricate correlation between vitamin D and AMH. One study enrolling thirtythree infertile women with normal ovarian reserve shown vitamin D altered AMH signaling and steroidogenesis in human cumulus GCs [5]. Another study recruiting 33 premenopausal women showed supplying vitamin D was able to reverse the seasonal decrease of AMH [6]. However, a retrospective cohort study reported that vitamin D levels were not associated with ovarian reserve in 457 infertile women (age: 21-50) with a high prevalence of diminished ovarian reserve [7]. And, a cross-sectional study in 73 healthy nonobese women of reproductive age without history of infertility did not find the correlation between vitamin D level and AMH too [8]. Moreover, a recent study demonstrated that patients with hereditary 1,25-(OH)2D-resistant rickets who had a nonfunctioning VDR appeared to have a normal reproductive history, suggesting that partial effects of vitamin D on the reproductive system might be not direct [9]. Summarizing the above results suggests that there needs more prospective study with a large group as well as participants with similar backgrounds to confirm the correlation between vitamin D and AMH.

Vitamin D and PCOS
Polycystic ovary syndrome (PCOS) is the common endocrine disorder in women of reproductive age, and its prevalence is about 6-10% in general population. Moreover, PCOS is the major cause of anovulatory infertility, and is associated with insulin resistance (IR), hyperinsulinemia, dyslipidemia, and central obesity [10][11][12][13].
It is estimated 67%-85% of women with PCOS have vitamin D deficiency [14]. And there are plenty of studies related to vitamin D and PCOS. Studies suggested that there was an association between vitamin D status and hormonal as well as metabolic dysfunctions in PCOS [14], and they found that the active VDR complex regulated genes important for glucose and lipid metabolism [15]. However, some other studies did not support the results [16][17][18][19][20][21]. One study reported that Tehran women with and without PCOS had the similar vitamin D levels. Moreover, some intervention trials had been carried out to explore the effect of vitamin D supplementation.

Vitamin D and In-vitro Fertilization
Whether vitamin D played a role in the process of in vitro fertilization are still elusive. Sebiha Ozkan et al. found that women with higher vitamin D level in serum and follicle fluid were more likely to achieve clinical pregnancy following in-vitro fertilizationembryo transfer (IVF-ET) [38]. A systematic review showed that there was a positive association between vitamin D status and assisted reproductive therapy (ART) outcomes and suggested vitamin D deficiency and insufficiency should be treated in women considering ARTs [39]. However, the majority of studies did not find a significant correlation between vitamin D level and IVF outcomes [40][41][42]. A meta-analysis concluded that there was not sufficient evidence supporting the necessary of vitamin D supplementation during IVF [43]. Thence, it still needs further analysis and exploration.

Vitamin D and Pregnancy Outcomes
Cumulative studies suggested that vitamin D deficiency related to adverse pregnancy outcomes, e.g. gestational diabetes (GDM), preeclampsia, pre-term birth and so on [44][45][46][47][48][49]. Recently, a systematic review indicated that pregnant women with low vitamin D level had an increased risk for GDM, and GDM could ameliorate after vitamin D supplementation [50]. A cohort study found that higher vitamin D (≥30 nmol/L) in early pregnancy was associated with lower blood glucose both in early and throughout pregnancy, but higher vitamin D in late pregnancy was associated with higher risk of large for gestational age(LGA)at birth [51]. Interestingly, a recent research found that high vitamin D at 15 ± 1 weeks' gestation was shown to be protective against the development of GDM and they also found that the correlation between vitamin D status and pregnancy complication might be was affected by fetal sex [52].
Mehri Jamilian et al. demonstrated that magnesium-zinc-calciumvitamin D co-supplementation to women with GDM might reduce biomarkers of inflammation and oxidative stress [53].
Sunni L Mumford and colleagues [54]  Urrutia-Pereira and Solé also reported low maternal vitamin D increased the risk for the later development of asthma and chronic obstructive pulmonary disease [61]. A post hoc analysis from RCT recommended regular exercise during pregnancy due to its positive influence on vitamin D level [62].

Authors' Contributions
Xiaofei Xu was responsible for the search and selection of articles, extraction of data, and writing and revision of the manuscript. Jie Qiao initiated the study, contributed to the study design, and revised the paper critically for important content.
Yongxiu Hao revised the paper critically. All the authors were involved in the final approval of the version to be published.