Effects of vitamin supplementation on related symptoms in women with endometriosis: a systematic review and meta-analysis

Endometriosis is a gynecological disease caused by the abnormal proliferation, infiltration, and transfer of endometrial stromal cells in the uterine cavity and outside of myometrium, and the mainly clinical symptoms are dysmenorrhea, infertility, and dyspareunia, which seriously affect women’s quality of life, mental health, and economic costs associated with treatment [ 1 ] . Currently, the incidence of endometriosis is very high. The incidence of endometriosis in women of childbearing age ranges from 6% to 10%, 20% to 50% in infertile women, and 30% to 80% in women with pelvic pain [ 2 ] . Existing studies have found that the pathogenesis of endometriosis may be related to immune response, inflammatory response, cell proliferation and apoptosis, angiogenesis, etc., but it is still unclear [ 3 , 4 ] . At present, endometriosis has three phenotypes: superficial pelvic endometriosis with mild pelvic pain, cystic ovarian endometriosis with severe pain, and deep invasive endometriosis with very severe pain [ 5 ] . Moreover, endometriosis can cause infertility; however, this is still controversial [ 6 ] . HIGHLIGHTS This study comprehensively evaluated the effects of vitamin supplementation on related symptoms in women with endometriosis. When taking vitamin E, vitamin D, or vitamin C combined with vitamin E to improve endometriosis-related symptoms, only vitamin E supplementation is beneficial to alleviate pelvic pain in women with endometriosis, and none of these vitamins can relieve endometriosis-related dysmenorrhea and dyspareunia. This study will provide a clinical reference for the treatment of endometriosis-related symptoms. This study comprehensively evaluated the effects of vitamin supplementation on related symptoms in women with endometriosis. When taking vitamin E, vitamin D, or vitamin C combined with vitamin E to improve endometriosis-related symptoms, only vitamin E supplementation is beneficial to alleviate pelvic pain in women with endometriosis, and none of these vitamins can relieve endometriosis-related dysmenorrhea and dyspareunia. This study will provide a clinical reference for the treatment of endometriosis-related symptoms. This study comprehensively evaluated the effects of vitamin supplementation on related symptoms in women with endometriosis. When taking vitamin E, vitamin D, or vitamin C combined with vitamin E to improve endometriosis-related symptoms, only vitamin E supplementation is beneficial to alleviate pelvic pain in women with endometriosis, and none of these vitamins can relieve endometriosis-related dysmenorrhea and dyspareunia. This study will provide a clinical reference for the treatment of endometriosis-related symptoms. At present, the therapeutics of endometriosis mainly include surgical treatment and conservative drug treatment. Laparoscopic surgery is often the first choice for cases unresponsive to medical treatment, but surgical treatment is difficult to completely remove ectopic lesions and prone to recurrence [ 7 ] . The recurrence rate of surgical treatment was 5% in 1 year, 5–14% in 2 years, and 40–50% in 5 years [ 8 ] . Conservative drug treatment is mainly to inhibit the production of ovarian estradiol, reduce the stimulation of growth and proliferation of endometrial tissues, and induce endometrial atrophy or decidualization [ 9 ] . The treatment drugs included non-steroidal anti-inflammatory drugs, androgens, progestins, oral contraceptives, and gonadotropin-releasing hormone agonists [ 10 ] . However, due to the limited efficacy and side effects of drugs, alternative or combination therapies are often used. In addition, new therapeutic drugs included gonadotropin-releasing hormone antagonists, aromatase inhibitors, selective progesterone and estrogen receptor modulators, anti-angiogenic drugs, and antioxidants were developed and widely used in clinical practice [ 11 ] . Previous studies have found that postoperative maintenance therapy with these drugs in patients with endometriosis could significantly reduce the recurrence and improve the symptoms [ 12 ] . More and more studies have shown that oxidative stress plays an important role in the occurrence and development of endometriosis [ 13 ] . Iron overload was found in different lesion sites, peritoneal fluid, peritoneum, and siderophages of patients with endometriosis. Excess iron caused massive production of reactive oxygen species (ROS) in cells, induced oxidative damage to cells, and produced ectopic endometrial cell adhesions [ 14 ] . Transplantation of macrophages, erythrocytes, and apoptotic endometrial tissue into the peritoneal cavity through retrograde menstruation was the inducer of oxidative stress; activated macrophages regulated the degradation of erythrocytes, which released pro-oxidants and pro-inflammatory factors such as heme and iron, and regulated the production of ROS [ 13 ] . To protect themselves from the harmful effects of ROS, cells have evolved extensive antioxidant systems to inhibit ROS production and repair damaged cells [ 15 ] . Currently, antioxidants that have been developed include enzymatic antioxidants (catalase, superoxide dismutase, and glutathione peroxidase) and non-enzymatic antioxidants (vitamin E, vitamin C, taurine, and glutathione). Reducing oxidative stress may be a potential treatment option for endometriosis. Oxidative stress leads to an increase in ROS, increased phosphorylation and degradation of inhibitory subunit of NF-kappa B (IkB), resulting in nuclear translocation of nuclear factor kappa B (NF-κB), then activating the expression of downstream genes, which regulate cell survival, proliferation, differentiation, and migration of endometriosis. Supplementing with vitamin D, Omega-3, and vitamin C may inhibit the phosphorylation of IkB, preventing NF-κB nuclear translocation, reducing the level of oxidative stress, and improving endometriosis symptoms [ 16 ] . Previous studies have shown that adjunctive treatment of endometriosis with dietary supplements (alpha-lipoic acid, vitamin C, vitamin E, and vitamin D) could significantly reduce endometriosis-related pain [ 17 ] . A systematic review found that women with endometriosis had lower vitamin D levels than non-endometriosis women, which was inversely associated with endometriosis severity [ 18 ] . In addition, the levels of vitamin C, vitamin E, and glutathione were lower in patients with moderate to severe endometriosis than those with mild endometriosis [ 19 ] . After patients received vitamin C combined with vitamin E for 6 months, the levels of malondialdehyde (MDA) and lipid hydroperoxides in plasma and peritoneal fluid were significantly reduced and significantly improved the pelvic pain, dysmenorrhea, and dyspareunia [ 20 ] . Although antioxidants are beneficial in improving the symptoms of endometriosis, there are still differences in their results. Given the promising but variable effects of vitamin supplementation on endometriosis symptoms, this systematic review and meta-analysis aims to evaluate the efficacy of vitamins in alleviating these symptoms in women with endometriosis.

We searched the electronic databases including PubMed, Web of Science, Cochrane Library, EMBASE, China National Knowledge Infrastructure, and Wanfang Data without language restrictions, and all publications were deadline to 31 December 2022. The searching items included “endometriosis” and “vitamins” or “vitamin A” or “vitamin C” or “vitamin D” or “vitamin E,” and the types of studies were restricted to randomized controlled trials (RCTs). All included studies must meet the following criteria: (1) patients were diagnosed as endometriosis by laparoscopy, and currently experiencing dysmenorrhea, non-menstrual pelvic pain, and dyspareunia; (2) RCTs were conducted to assess the effects of vitamin supplementation on endometriosis-related symptoms; and (3) these studies were published literature and the full-text were available. The exclusion criteria were as follows: (1) patients had other complications, such as uterine fibroids, adenomyosis, and osteoporosis; (2) the types of studies were non-RCTs, protocol, or observational research; (3) the studies had insufficient data and the outcomes were not interesting. All relevant data were independently extracted by two investigators. The specific information included: authors’ names, publication time, study type, number of included patients and their baseline characteristics, types of vitamins, duration of medication, and outcomes. When the evaluations were inconsistent, the decisions were made by discussion or with the participation of a third researcher. The primary outcomes included the scores of dysmenorrhea, pelvic pain, and dyspareunia, and the second outcomes were the incidence of adverse reactions. The methodological quality of all included studies was assessed using the Cochrane risk of bias tool. In addition, all studies were scored by the Jadad scale, and the scores ranged from 0 to 7. When the evaluations were inconsistent, the decisions were made by discussion or with the participation of a third researcher. In addition, the studies included in the review were already conducted and published, and thus, ethical approval and informed consent were obtained by the original authors. All data were analyzed using RevMan 5.3 software, and standardized mean differences (SMDs) and 95% confidence intervals (CIs) were selected as combined statistics. The chi-squared test was used to assess heterogeneity between studies. If there was obvious heterogeneity ( I 2  > 50% or P < 0.05), the random-effects model was used for analysis. Otherwise, if there was no obvious heterogeneity ( I 2   0.05), the fixed-effects model was used. Sensitivity analysis was used to observe the impact of each study on the total effect size and then to judge the stability of the results. In addition, the funnel plot was used to evaluate the publication bias. P  < 0.05 was considered as significant difference.

The flow diagram of the search process is shown in Fig. 1 , and we found 929 relevant articles. After weeding out duplicates, reviews, meta-analyses, observational trials, and clinical guidelines, 53 articles remained and were assessed for eligibility. Forty-four full-text articles were excluded for the following reasons: study protocol, non-RCTs, and lack of available data. Finally, nine studies [ 21 – 29 ] involving 562 patients were included in this meta-analysis. The characteristics of all included studies were presented in Table 1 . Among the studies, four studies were double-blind RCTs, one study was single-blind, and the other four studies did not mention the method of blind. Among all included studies, 245 patients received different dosages of vitamin C, vitamin D, and vitamin E, and the other 317 patients received placebo treatment. Ninety-one patients received drospirenone ethinylestradiol tablets combined with vitamin E in three studies. The mean ages of all included patients ranged from 20.1 to 38.03. The duration of patients receiving vitamin treatment ranged from 8 weeks to 12 months. In addition, all included studies had a Jadad score: six studies were scored 4 or higher and the other three studies were lower than 4. The methodological quality of all included studies was assessed, and the results indicated that only two studies with incomplete outcome data were high risk, while the others were low risk and unclear risk (Fig. 2 ). Figure 1. Flow diagram for selected studies in this meta-analysis. Table 1 The characteristics of included studies in this meta-analysis Study Study design Blind Sample sizes Age (years) Regimens and dosage Duration Outcomes Jadad score V P V P Almassinokiani 2016 RCTs Double 19 20 30.84 ± 5.79 28.95 ± 4.71 Vitamin D 50 000 IU/week 12 weeks Pelvic pain, dysmenorrhea 4 Amini 2021 RCTs Double 30 30 35.7 ± 5.71 38.03 ± 6.47 Vitamin C 1000 mg/day, vitamin E 800 IU/day 8 weeks Pelvic pain, dysmenorrhea 6 Dyspareunia, MDA Hu 2015 RCTs None 26 25 32.45 ± 6.18 34.62 + 5.47 Vitamin E 100 mg/day 6 months Pelvic pain, dysmenorrhea 3 Dyspareunia, side effects Mehdizadehkashi 2021 RCTs Double 30 30 34.8 ± 7.1 35.6 ± 7.0 Vitamin D 50 000 IU each 2 weeks 12 weeks Dysmenorrhea, dyspareunia, MDA 6 Mier-Cabrera 2008 RCTs Double 16 18 32.7 ± 2.36 32.8 ± 2.49 Vitamin C 343 mg and vitamin E 84 mg each day 6 months MDA 4 Nodler 2020 RCTs Single 27 22 20.0 ± 2.7 20.1 ± 3.5 Vitamin D 2000 IU/day 6 months Pelvic pain, dyspareunia 5 Sesti 2007 RCTs None 35 110 29.0 ± 3.9 31.0 ± 4.9 Vitamins 12 months Pelvic pain, dysmenorrhea 5 Dyspareunia Wang 2017 RCTs None 32 32 37.9 ± 3.5 35.0 ± 3.3 Vitamin E 100 mg/day 6 months Pelvic pain, dysmenorrhea 3 Dyspareunia, side effects Xiao 2018 RCTs None 30 30 35.12 ± 3.26 38.02 ± 4.01 Vitamin E 100 mg/day 6 months Pelvic pain, dysmenorrhea 3 Dyspareunia, side effects RCTs, randomized controlled trials; V, vitamins; P, placebo; MDA, malondialdehyde. Figure 2. Risk of bias summary. Red (−), high risk of bias; green (+), low risk of bias; yellow (?), unclear risk of bias. Flow diagram for selected studies in this meta-analysis. The characteristics of included studies in this meta-analysis RCTs, randomized controlled trials; V, vitamins; P, placebo; MDA, malondialdehyde. Risk of bias summary. Red (−), high risk of bias; green (+), low risk of bias; yellow (?), unclear risk of bias. Seven studies involving 468 patients evaluated the effects of vitamins on pelvic pain (Fig. 3 ). Subgroup analysis was used to assess this outcome because patients received different types of vitamins. Three studies evaluated the effect of vitamin E on pelvic pain, and the fixed-effects model was used because no heterogeneity was observed ( P = 0.78, I 2  = 0%). Compared with the placebo group, vitamin E could significantly alleviate the pelvic pain in patients with endometriosis ( P < 0.00001, SMD = −1.63, CI = −1.98 to −1.29). Two studies evaluated the effect of vitamin D on pelvic pain, and the fixed-effects model was used because no heterogeneity was observed ( P = 0.33, I 2  = 0%). However, vitamin D was not significantly different from placebo in improving pelvic pain ( P = 0.13, SMD = 0.32, CI = −0.10 to 0.75). In addition, two studies assessed the effect of vitamin C combined with vitamin E on pelvic pain. Significant heterogeneity was observed, and the random-effects model was used to analyze this outcome ( P = 0.0005, I 2  = 92%). Compared with the placebo group, there was no significant difference in improving pelvic pain in patients receiving vitamin C combined with vitamin E ( P = 0.10, SMD = −0.98, CI = −2.15 to 0.18). Figure 3. The effects of vitamin supplementation on the pelvic pain. The effects of vitamin supplementation on the pelvic pain. Seven studies involving 479 participants evaluated the effect of vitamins on dysmenorrhea in women with endometriosis, and subgroup analysis was used to assess this outcome based on different types of vitamins (Fig. 4 ). Among these included studies, three studies compared the effect of vitamin E and placebo on dysmenorrhea, and the fixed-effects model was used because there was no significant heterogeneity ( P = 0.95, I 2  = 0%). Compared with the placebo group, vitamin E did not significantly improve dysmenorrhea symptoms in women with endometriosis ( P = 0.14, SMD = −0.23, CI = −0.52 to 0.07). In addition, two studies compared the effect of vitamin D and placebo on dysmenorrhea, and the fixed-effects model was used ( P = 0.64, I 2  = 0%). There was no significant difference in alleviating endometriosis-related dysmenorrhea when patients were treated with vitamin D and placebo ( P = 0.56, SMD = −0.12, CI = −0.51 to 0.28). The other two studies compared vitamin C plus vitamin E and placebo on dysmenorrhea, and the random-effects model was used to analyze this outcome ( P = 0.03, I 2  = 80%). Moreover, vitamin C plus vitamin E could not remarkably alleviate the dysmenorrhea when compared with placebo ( P = 0.35, SMD = −0.34, CI = −1.06 to 0.37). Figure 4. The effects of vitamin supplementation on dysmenorrhea in women with endometriosis. The effects of vitamin supplementation on dysmenorrhea in women with endometriosis. Seven studies involving 469 patients evaluated the effect of vitamins on endometriosis-related dyspareunia, and subgroup analysis was used to assess this outcome based on different types of vitamins (Fig. 5 ). No significant heterogeneity was observed between these studies, and the fixed-effects model was used ( P = 0.84, I 2  = 0%; P = 0.17, I 2  = 48%; P = 0.34, I 2  = 0%). Compared with the placebo group, neither vitamin D nor vitamin E monotherapy or vitamin C in combination with vitamin E significantly improved symptoms of dyspareunia in women with endometriosis ( P = 0.72, SMD = 0.05, CI = −0.24 to 0.35; P = 0.10, SMD = −0.37, CI = −0.82 to 0.07; P = 0.70, SMD = 0.06, CI = −0.24 to 0.36; total P = 0.81, SMD = −0.02, CI = −0.22 to 0.17). Figure 5. The effects of vitamin supplementation on endometriosis-related dyspareunia. The effects of vitamin supplementation on endometriosis-related dyspareunia. One study compared the effect of vitamin D and placebo on the level of MDA, and two studies involving 94 patients assessed the effect of vitamin C plus vitamin E on the level of MDA (Fig. 6 ). Significant heterogeneity was observed among studies, and the random-effects model was used ( P = 0.02, I 2  = 80%; total P < 0.00001, I 2  = 92%). Compared with the placebo group, vitamin D monotherapy or vitamin C in combination with vitamin E could significantly reduce the level of MDA in the serum of women with endometriosis ( P = 0.03, SMD = 0.56, CI = 0.04 to 1.07; P = 0.03, SMD = −1.21, CI = −2.30 to −0.13; total P = 0.004, SMD = −0.62, CI = −1.88 to 0.63). Figure 6. The effects of vitamin supplementation on the level of MDA. The effects of vitamin supplementation on the level of MDA. Patients receiving vitamin E treatment for a long time will also affect their health to a certain extent, including fatigue, breast enlargement, diarrhea, angular stomatitis, cheilitis, chapped skin, blurred vision, headache, dizziness, vomiting, and nausea. In this study, three trials evaluated the events of side effects (including rash, nausea, and weight gain) after taking vitamin E in endometriosis patients (Fig. 7 ). No significant heterogeneity was observed between these studies, and the fixed-effects model was used ( P = 0.62, I 2  = 0%; P = 0.55, I 2  = 0%; P = 0.95, I 2  = 0%). Compared with the placebo group, there was no significant difference in the incidence of rash, nausea, and weight gain in patients with endometriosis who took vitamin E for a long time ( P = 0.71, SMD = 0.76, CI = 0.18 to 3.17; P = 0.75, SMD = 1.24, CI = 0.32 to 4.79; P = 0.35, SMD = 0.65, CI = 0.26 to 1.60). Figure 7. The summary of the occurrence of rash, nausea, and weight gain in this meta-analysis. The summary of the occurrence of rash, nausea, and weight gain in this meta-analysis. During data processing, sensitivity analysis was performed to evaluate the accuracy of the results. Fixed-effects and random-effects models were used to process data, respectively, and there was no significant difference in the heterogeneity and overall results. In addition, a funnel plot was used to evaluate publication bias, and it was found that the funnel plot was asymmetric and there was potential publication bias (Fig. 8 ). Moreover, Egger’s test results indicate significant publication bias existed ( P < 0.05). Figure 8. Funnel plot for evaluating the publication bias in this meta-analysis. Funnel plot for evaluating the publication bias in this meta-analysis.

In this study, we found that vitamin E supplementation alleviated the pelvic pain in patients with endometriosis, but vitamin D monotherapy or vitamin C in combination with vitamin E could not reduce pelvic pain. Vitamin E and vitamin D monotherapy or vitamin C in combination with vitamin E did not improve dyspareunia and dysmenorrhea. In addition, vitamin D monotherapy or the combination of vitamin C and vitamin E remarkably reduced the level of MDA in serum of patients with endometriosis. Endometriosis is an estrogen-dependent gynecological disease that affects 10–15% of women of childbearing age, which is characterized by the abnormal growth of endometrial tissue outside the uterine cavity [ 30 ] . The clinical manifestations were mainly manifested as dysmenorrhea, chronic pelvic pain, abnormal menstruation, and infertility. Women with endometriosis suffer from dysmenorrhea and chronic pelvic pain, which affects work, leisure, social, and romantic relationships [ 31 ] . The pain associated with endometriosis can also affect psychological aspects, affect sleep quality, and cause anxiety and depression in women. Evidence studies suggested that these symptoms of the disease resulted from a localized inflammatory peritoneal response to ectopic endometrial implants, with circulatory bleeding [ 32 ] . Currently, the purpose of clinical treatment for endometriosis is to relieve pain and reduce the incidence of complications, and laparoscopic surgery is the preferred treatment method, but the recurrence rate of postoperative is up to 40% [ 33 ] . However, it is difficult to improve the fertility of patients with methods such as surgery and drugs for patients with fertility requirements. Currently, embryo, oocyte, and ovarian tissue transplantation are internationally recognized as a conservative treatment for infertility in patients with endometriosis [ 34 ] . At present, the first-line treatments for endometriosis include nonsteroidal antiinflammatory drugs (NSAIDs) and combined oral contraceptives (COCs) or progesterone, and the second-line treatments include GnRH agonists, which could reduce the levels of estrogen to postmenopausal concentrations [ 35 ] . The purpose of all hormone therapy was to reduce or suppress the levels of local or systemic estrogen. Clinically, the commonly used treatment drugs were COCs and progesterone, but the long-term use of these drugs might cause irregular bleeding, mastoid pain, psychological disturbances, weight gain, mood swings, and inconvenient androgenic side effects (acne, alopecia, lipid profile changes, and/or hirsutism) [ 36 ] . Additionally, the mechanisms of endometriosis were unclear, and alternative treatments such as acupuncture, herbal medicine, dietary changes, physical medications, and anti-inflammatory and antioxidant treatments emerged [ 37 ] . Abnormal endocrine microenvironment and multiple enzyme pathways leading to increased local estrogen synthesis are considered the main characteristics of endometriosis lesions. The main enzyme pathways involved in endometriosis, such as aromatase (CYP19A1), 17β-hydroxysteroid dehydrogenase types 1, 2, and 5, steroid sulfate esterase, and estrogen sulfotransferase (SULT1E1), may represent potential mechanisms of disease resistance and new therapeutic targets [ 38 ] . Previous studies have found that oxidative stress appeared to be involved in the pathological process of endometriosis [ 39 ] . During menstruation, continuous administration of estrogen, progesterone, and antioxidants could reduce menstrual retrograde and pelvic infections, and prevent new lesions [ 40 ] . In the peritoneal fluid of women with endometriosis, superoxide dismutase (SOD) activity and oxidized lipoproteins were increased, accompanied by a decrease in glutathione (GSH) and an increase in MDA levels, which activated the myeloperoxidase and generated oxygen-free radicals, covalently altered proteins and lipids. Hidrox is the aqueous extract of olive pulp and has the potential antioxidant activity. It could inhibit the imbalance of antioxidant activity in endometriosis rats, increase GSH levels, reduce the activities of SOD and MPO, and show a potential ameliorative effect on endometriotic implants and related pain-induced behaviors [ 41 ] . Vitamin C, vitamin E, and vitamin B may be involved in the pathogenesis of endometriosis through regulating oxidative stress and steroid hormone metabolism [ 19 ] . A previous study found that dose-dependent vitamin C supplementation could obviously decrease the volume and weight of cysts [ 42 ] . In addition, another study showed that oral contraceptives combined with vitamin E could increase the metabolic rate of oxygen-free radicals, restore the redox reaction to a balanced state, and significantly alleviate the pelvic pain. However, there was no significant difference in improving dyspareunia and dysmenorrhea when compared with oral contraceptive monotherapy [ 29 ] . A meta-analysis evaluated the association of vitamin D levels with the onset of endometriosis, and the results indicated that women with endometriosis had lower vitamin D levels, which were associated with endometriosis severity [ 43 ] . Our results indicated that vitamin E supplementation significantly alleviated the pelvic pain in patients with endometriosis, but no significant differences were observed in vitamin D monotherapy or vitamin C in combination with vitamin E groups. This was related to the fact that vitamin E could enhance the metabolism rate of oxygen-free radicals in the body and maintain a dynamic balance of redox reactions. Moreover, vitamin E and vitamin D monotherapy or vitamin C in combination with vitamin E did not significantly improve dyspareunia and dysmenorrhea. However, Amini and Sesti et al [ 22 , 27 ] confirmed that vitamin supplementation or the combination of vitamin C and vitamin E could significantly improve endometriosis-related dysmenorrhea and dyspareunia. These results were inconsistent with the present study, and we inferred that the reason might be related to the small sample sizes. Available evidence suggested that the levels of several antioxidant components were lower in serum and follicular fluid (FF) of patients with endometriosis, such as vitamin A, vitamin C, vitamin E, and SOD, whereas MDA levels were elevated, and the level of MDA in serum was higher than that in FF [ 44 ] . MDA is an oxygen-free radical lipid oxide that participates in mitochondrial oxidative stress response. The characteristic of endometriosis is an increase in MDA and resolution D1 levels, and the involvement of oxidative stress in the occurrence of endometriosis is manifested by an increase in MDA levels. Oral vitamin C formulation (1000 mg/day) for 2 months significantly increased vitamin C levels in serum and FF of patients with endometriosis, but it did not affect the levels of oxidative stress markers (ROS, total antioxidant capacity [TAC], SOD, and MDA) [ 45 ] . Subsequent studies found that a high-antioxidant diet for 3 months in patients with endometriosis remarkably increased the levels of vitamin A, vitamin C, vitamin E, and SOD activity and decreased the levels of MDA and lipid hydroperoxidase [ 46 ] . In this study, we included three studies to evaluate the effect of vitamin supplementation on the level of MDA, and the results indicated that vitamin supplementation in patients with endometriosis could significantly reduce MDA levels in serum. From these results, we inferred that vitamin supplementation could inhibit oxidative stress and improve the symptoms of endometriosis. In addition, there are some limitations that should be taken into consideration in this study. First, all included studies had small sample sizes, and some of the trials combined the use of estrogen, which might have affected the results. Second, heterogeneity was significant among included studies, so we performed subgroup and sensitivity analyses to explore its origin. Third, we were unable to assess the effects of vitamin supplementation on the levels of oxidative stress markers (ROS, TAC, SOD, and MDA) in serum of patients with endometriosis due to lack of data in some of the included studies.

In summary, our study revealed that vitamin E supplementation alleviated the pelvic pain in patients with endometriosis, but vitamin D monotherapy or vitamin C in combination with vitamin E could not reduce pelvic pain. Vitamin E and vitamin D monotherapy or vitamin C in combination with vitamin E did not improve dyspareunia and dysmenorrhea. In addition, vitamin D monotherapy or the combination of vitamin C and vitamin E remarkably reduced the level of MDA in serum of patients with endometriosis. Moreover, the safety of vitamin E was good. Therefore, vitamin E supplementation is beneficial to alleviate pelvic pain in patients with endometriosis, and this study will provide a clinical reference for the treatment of endometriosis-related symptoms. In addition, future large-sample clinical studies still need to explore the effects of vitamin supplementation on other endometriosis-related complications.