Successful embryo implantation requires two conditions: a well-developed embryo and a well-tolerated endometrium. Although assisted reproductive technology (ART) has been widely used in infertile couples, the failure of implantation resulted from poor endometrial receptivity is still an important factor which could not be underestimated [1]. There are different parameters to evaluate the endometrial receptivity such as endometrial morphology and endometrial blood supply, while endometrial thickness is most commonly used as compared to the other indexes. At present, there are various strategies to enhance endometrial thickness, such as surgical therapy (endometrial biopsy and curettage) [2], prolonged hormone therapy [3], intrauterine perfusion [4], vasoactive medicine therapy (low-dose aspirin and Sildenafil) [5, 6], and regenerative medicine (stem cell therapy) [7].

The above methods of improving endometrial receptivity are more or less invasive, difficult to perform, or expensive. In recent years, some investigators have proposed a simple, safe and economical strategy, namely taking a certain dose of Vit E in women of reproductive age to increase the thickness of endometrium [8, 9, 10, 11]. Vit E is an exogenous lipid-soluble molecule, acts as a peroxyl radical scavenger in vivo and is metabolized through the liver and kidney. Vit E is not only a kind of exogenous lipid soluble antioxidant molecule but also a direct scavenger of free radicals. According to research reports, Vit E may improve endometrial thickness by anti-oxidation and increase endometrial secretion activity [11]. As showed by some studies, Vit E can increase capillary blood flow in a wide variety of organs, thereby generating favorable endometrium [12]. On the contrary, Levent et al. pointed out that the methods such as taking vitamin E to increase endometrial thickness are inefficient or even useless [13]. Until now, whether vitamin E Supplementation can help increase endometrial thickness and even improve pregnancy outcomes remains controversial.

Infertility is mostly a result of complex interplay of various factors, such as uterine, fallopian tubes, ovarian and male. Increasing endometrial thickness itself will not enable an infertile woman to get pregnant, but still has a positive effect on pregnancy outcomes. Therefore, the objective of this systematic review was to investigate whether Vit E is beneficial to endometrial thickness and pregnancy outcomes, we reviewed the previous publications and analyzed the effects of Vit E on endometrial thickness and pregnancy outcomes.

This analysis mainly reports the effects of Vit E on the endometrium. As shown by the current meta-analysis, oral Vit E supplementation contributes to endometrial growth in women of reproductive age, especially for patients with thin endometrium. There was no significant difference between Vit E group and control group on ongoing pregnancy rate.

The successful implantation of an embryo requires the simultaneous development of the endometrium and the embryo [18]. Histologically, the endometrium consists of two layers of tissue: the basal layer and the functional layer [19]. Endometrial growth is a hormone-dependent process that requires proper blood supply to the uterus [20]. The high impedance of uterine arterial blood flow may promote the growth of epithelial cells, lead to a decrease in the expression of vascular endothelial growth factor (VEGF) in the endometrial vessels, and inhibit the formation of endometrial vessels, thus reducing the blood supply of the endometrium, which is not conducive to the formation of satisfactory endometrium for embryo implantation [21, 22].

The probable mechanism by which Vit E enhances endometrial thickness could be as following: Firstly, reactive oxygen species (Ros) can cause oxidative damage to cellular macromolecules (such as lipids, proteins and nucleic acids) in tissues [17]. Vit E scavenges Ros produced during oxidative stress and protects cell membrane from lipid peroxidation, thereby reducing the damage of Ros to endometrium at biochemical level [23]. Secondly, Vit E has an anticoagulant effect, which could increase the blood supply of follicles and granulosa cells, promote the production of estrogen, and thus produce favorable endometrium [8]. Thirdly, Vit E may improve vascular resistance, and the increase of endometrial glands, vascular development and VEGF protein expression in endometrium can be observed in patients who take Vit E [24], the increase of uterine blood supply provides sufficient nutrition for endometrial formation [14].

Previous findings toward Vit E have mainly focused on men’s semen quality, gestational diabetes and hypertension [25, 26, 27], while less attention has been given to the endometrial thickness. Our analysis showed that oral Vit E supplementation increased endometrial thickness in fertile women, especially for those who were suffered from the thin endometrium. Endometrial thickness may be critical to successful pregnancy. Some scholars suggest that the minimum intimal thickness should be 7 mm (preferably more than 9 mm) to achieve the highest pregnancy rate [28]. Although there are various schemes to improve endometrial thickness in patients with infertility due to endometrial causes, which are difficult to implement and have traumatic defects. Oral Vit E supplements provide an economical, convenient, and safe strategy for improving endometrial thickness. However, there was no significant difference between Vit E group and the control group on ongoing pregnancy rate in this analysis. Since less result was found to report the effect of Vit E on the pregnancy rate, live birth rate and miscarriage rate apart from endometrial thickness and ongoing pregnancy rate in these publications, we could not make an explicit conclusion of the effect of Vit E in the other pregnancy outcome. We expect that in the future multicenter randomized prospective study and a larger sample size would be performed in order to confirm the further outcome of the Vit E in pregnancy rate, live birth rate and miscarriage rate especially in the thin endometrium patients.

To the best of our knowledge, this meta-analysis is the first meta-analysis of the effects of oral Vit E supplementation on endometrial thickness and pregnancy outcome. However, there is still limitation, such as small amount of data, inclusion of only studies published in English journals, the failure to determine the effective duration and the most suitable population of Vit E to increase endometrial thickness. Limited by the quantity and quality of the included studies, these conclusions need to be verified by the further multicenter randomized prospective studies which require larger sample size. Prospective trials or randomized controlled trials could be designed to study the effects of different doses of vit E on endometrial thickness and pregnancy outcomes in infertile women.

In summary, current evidence suggests that oral Vit E supplementation may increases endometrial thickness. Further, due to few available studies, there is no clear evidence that oral Vit E supplementation is beneficial for pregnancy outcomes.

JW and DY made major contributions to data analysis, article conception and writing. JL and LC were responsible for data analysis. WQ and WM contributed to data collection and verification. XX contributed to the research and design, critical discussion and review of manuscripts.

Not applicable.

I would like to express my gratitude to all those who helped me during the writing of this manuscript. Thanks to all the peer reviewers for their opinions and suggestions.

This research received no external funding.

The authors declare no conflict of interest.