BMC Endocrine Disorders

Open Access

Junde Zhao1† , Lingfen Dong2†, Zhiheng Lin1, Xiaohui Sui1, Ying Wang1, Lijuan Li3, Tingting Liu1*† and Jinxing Liu2*†

Background This study provides a systematic review and meta-analysis of randomized controlled trials, which examined the effect of the selenium supplementation on polycystic ovary syndrome (PCOS). Methods Confirmed studies related to selenium supplementation and PCOS were searched from the databases of EMBASE, PubMed and Web of Science. Data were reported as weighted mean difference (WMD) or standard mean difference (SMD) and associated 95% confidence intervals (CIs). Analysis was performed with Stata version 12.0. Results A total of 389 cases (selenium group n= 195, control group n= 194) were included in this studies. This meta-

analysis showed that selenium supplementation has a positive effect on TAC, and supplementation of selenium does not significantly improve the level of BMI, Weight, LDL, HDL, Triglycerides, Total Testosterone, HOMA-IR, NO, GSH, MDA and FPG.

Conclusion Although selenium can improve TAC in PCOS patients, it has no significant effect on BMI, Total Testosterone, et al. In terms of the results of this meta-analysis, it is not recommended for patients with PCOS to use selenium as a regular trace element supplement. Based on the improving effect of selenium on TAC, supplementation of selenium may have a positive effect on improving follicle quality for some PCOS patients who have poor follicle quality caused by oxidative stress or who want to undergo IVF. Keywords Selenium, Polycystic ovary syndrome, Meta-analysis

†Junde Zhao and Lingfen Dong contributed to the work equally and should be regarded as co-first authors.

†Jinxing Liu and Tingting Liu contributed to the work equally and should be regarded as co-corresponding authors.

*Correspondence: Tingting Liu [email protected] Jinxing Liu [email protected]

1. 1 Shandong University of Traditional Chinese Medicine, 16369 Jingshi Road, Lixia District, Jinan 250011, Shandong, China
2. 2 Shandong University of Traditional Chinese Medicine Affiliated Hospital, Jinan, China

3 Changchun University of Science and Technology, Jilin 130022, Changchun, China

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POLYCYSTIC OVARY SYNDROME (PCOS) is a common gynecological endocrine disease, which affects 5–20% women of reproductive age worldwide [1–3]. Its harm is not limited to infertility and abnormal menstruation [4–6], but also brings economic burden and longterm health risks to patients [7, 8]. Studies have shown that patients with PCOS often have insulin resistance and abnormal lipid metabolism [9–11]. In addition, patients with PCOS have oxidative stress [12–14]. Excessive oxidative stress and depletion of antioxidants may contribute to ovarian mesenchymal hyperplasia [15]. This affects the quality of oocytes in patients with PCOS, and ultimately leads to undesirable pregnancy [16, 17].

Selenium is an indispensable trace element for the human body and it has antioxidant and anti-inflammatory properties [18, 19]. Selenium operates as an integral part of selenoproteins assisting redox processes as an effective antioxidant [20]. Studies have shown that selenium supplementation has a positive effect on improving reproductive outcomes and inflammation biomarkers [21, 22]. It was proven that supplementing selenium increases the gene expression levels of certain enzymes and may improve lipid metabolism [23].

Many studies have confirmed that selenium supplementation has beneficial effects on patients with PCOS. It is necessary to accurately judge the effect of selenium on PCOS patients. Therefore, all relevant studies were selected and this meta-analysis was done to further confirm the effect of selenium on patients with PCOS.

Search strategy

A comprehensive literature search was carried out to identify all potentially relevant articles using the PubMed, EMBASE and Web of Science database from their inception to December 2022. All search methods were based on a systematic approach in line with the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P). And after "snowball search", all relevant literatures were included.

Searches for terms ("Selenium"[Mesh] OR "Selenium"[Text Word] OR “Selenium-80” OR “Selenium 80”) AND ("Polycystic Ovary Syndrome"[Mesh] OR "Polycystic Ovary Syndrome"[Text Word] OR (Ovary Syndrome, Polycystic) OR (Syndrome, Polycystic Ovary) OR “Stein-Leventhal Syndrome” OR “Stein Leventhal Syndrome” OR (Syndrome, Stein-Leventhal) OR “Sclerocystic Ovarian Degeneration” OR (Ovarian Degeneration, Sclerocystic) OR “Sclerocystic Ovary Syndrome” OR “Polycystic Ovarian Syndrome” OR (Ovarian Syndrome, Polycystic) OR “Polycystic Ovary Syndrome 1”

OR “Sclerocystic Ovaries” OR (Ovary, Sclerocystic) OR “Sclerocystic Ovary”) were performed. The GRADE approach was followed and uncertainty assessment performed for studies included in meta-analysis.

Selection criteria

Two reviewers performed the literature search, evaluated potentially eligible studies for inclusion, and extracted the data independently. When required, disagreements were resolved by consultation with a third reviewer. Authors of the original studies were contacted for additional data, if necessary.

The main selection criteria are as follows:

1. (a) Randomized controlled clinical trials, case–control studies. Patients took selenium or selenium combined with probiotics in the selenium group. Patients took placebo in the control group.
2. (b) Study population: patients with PCOS and obesity. PCOS was diagnosed on the basis of the revised Rotterdam 2003 criteria [24]. The presence of 2 out of 3 criteria (oligo or/and anovulation, clinical or/and biochemical signs of hyperandro-genism, and polycystic ovary) was recommended as diagnostic of PCOS.
3. (c) Aged 20–40 years
4. (d) Studies that reporting weighted mean difference (WMD) or Standard mean difference (SMD) with corresponding 95% confidence intervals (95% CIs) or providing other ways to calculate or obtain these values.

Data extraction

Two researchers extracted data from the eligible studies independently, and resolved the divergence through discussion. The information collected included author, the year of publication, age of patient, sample size, treatment method, WMD (95% CI) or SMD (95% CI), and controlled variables for matching or used in some multivariable models. The data were entered into the Review Manager software (RevMan 5.3). The quality of selected studies was evaluated by Cochrane score according to the quality standards of the Cochrane scale. The disagreement was resolved through discussion between the two reviewers. If necessary, the disagreement was resolved by consultation with the third reviewer.

Data analysis

According to each study, 13 variables were extracted as mean± standard deviation (SD). In this study, data were analyzed by Stata (version 12.0). P-values were two-sided, and P < 0.05 was considered the limit of

statistical significance. In addition, the heterogeneity of these seven studies was assessed. In this meta-analysis, I2 was used to assess the heterogeneity between these included studies, and I2≥ 50 was set as significant heterogeneity. The random effects model was used for

calculation. The WMD or SMD for continuous variables were used to explain outcomes with the 95% CI. For some data with significant heterogeneity, in-depth research was also conducted on subgroup (or regression) analysis and sensitivity analysis.

Fig. 1 Flow Diagram of Study Selection

Table 1The characteristics of studies included in this meta-analysis

2baseline (kg/m) Weight at study baseline

N(s)N(c)Age(s)Age(c)BMI(s)BMI(c)W(s)W(c)

(kg)

intervention BMI at study

Study identifierYrSampleAge(yr)InterventionDuration of

Placebo group received the placebo 8 weeks24.73.525.34.3not availablenot available±±

enriched yeast tablet or placebo 12 weeks27.44.528.393.770.213.872.613.7±±±±

ments or placebo 8 weeks25.03.725.24.166.710.067.111.0±±±±

tablet or placebo 12 weeks28.35.229.55.471.914.374.614.2±±±±

placebo 12 weeks24.63.324.03.063.99.363.47.7±±±

as zinc and copper or placebo per day 8 weeks26.54.127.32.669.810.770.77.1±±±±

8 weeks27.23.128.62.574.58.076.86.5±±±

Mehri Jamilian, et al. [28]2015353525.45.125.74.8receive 200 µg per day selenium supple-±±

et al. [27] 2016262729.234.928.906.1received 200 µg selenium as a selenium-±±

nium yeast-free other supplements such

selenium yeast (Nature Made, California,

Shahrzad Zadeh Modarres, et al. [29]2017202031.14.731.43.6receive either 200-μg selenium as sele-±±

USA) or placebo (Barij Essence, Kashan,

selenium as a selenium-enriched yeast

selenium tablet as selenium yeast and

M. Razavi, et al. [26]2015323225.14.525.44.9Selenium group received 200 μg daily±±

Mehri Jamilian, et al. [25]2018303026.05.325.63.8intake 8109 CFU/day probiotic plus±±×

200 μg/day selenium supplements or

Zahra Heidar, et al. [30]2019181832.14.732.63.5intake either 200 μg/day selenium as±

Batool Hossein Rashidi, et al. [312019343229.45.328.65.5receive either a daily dose of 200 μg±±

Iran)

Fatemeh Mohammad Hosseinzadeh,

Literature search and study characteristics

Figure 1 summarizes the research selection process. A total of 1098 unique references were retrieved through literature search, of which 708 were considered duplicate and irrelevant, following title and abstract screening, 17 were considered duplicate. 13 of these articles were excluded due to inappropriate article type. Of the remaining eight articles, one was excluded because of improper administration of medicine. Finally, in total, seven studies eligible for data extraction were included in the meta-analysis.

1. Table 1 summarizes the characteristics of these studies. After "snowball search", no other literature was included.

Risk of bias for all studies

For each randomized and prospective non-randomized clinical study which was selected, the risk of bias was

assessed according to the criteria described in the Cochrane Reviewers Handbook [32]. Figure 2 shows the summary of the risk of bias for each included study.

Effects on TAC

TAC was reported in two studies with 124 subjects, with 62 patients in the selenium group and 62 patients in control group. Compared with control group, the TAC level of selenium group increased significantly (WMD= 106.213 mmol/L, 95%CI 65.24 to 147.18, p≤ 0.001). No significance was considered for heterogeneity. (p= 0.857, I2= 0.0%) (Fig. 3).

Effects on SHBG

SHBG was reported in three studies with 179 subjects, with 90 patients in selenium group and 89 patients in control group. Compared with control group, the

Fig. 2 Summary of risk for each included study+ ,low risk of bias;?,unknown risk of bias;-,high risk of bias

1. Fig. 3 Forest plots of selenium supplementation on TAC in patients with PCOS

SHBG level of selenium group increased significantly (WMD= 9.747 nmol/L, 95%CI 0.32 to 19.18, p= 0.043). Heterogeneity was considered non-significant. (p= 0.952, I2= 0.0%) (Fig. 4). In the subgroup analysis, no significant effects were observed in the subgroup of trials using selenium combined with probiotics supplements (WMD= 9.100, 95%CI -1.168 to 19.368 to 0.71) and those administrated with selenium as a single supplement (WMD= 13.228, 95% CI -10.583 to 37.039) (Fig. 5).

Effects on BMI

BMI was reported in five studies with 270 subjects, with 135 patients in selenium group and 135 patients in control group. The current meta-analysis showed that no difference in BMI was witnessed between selenium group and control group (WMD= -0.503 kg/m2, 95% CI -1.32 to 0.31, p= 0.227). No significance was considered in heterogeneity (p= 0.681, I2= 0.0%) (Fig. 6).

Other outcomes

1. Table 2 shows a summary of the all the results of the meta-analysis, which includes the following: all outcomes: Total Testosterone, SHBG, HOMA-IR, BMI, Weight, NO, TAC, GSH, MDA, LDL, HDL, Triglycerides and FPG. Table 2 shows the results of publication bias.

Figure 7 shows Begg’s funnel plots estimating publication bias (Table 3).

Selenium has a significant effect of increasing TAC in patients with PCOS. The results of the study were not heterogeneous, which affirmed the antioxidant effect of selenium. There was oxidative stress in patients with polycystic ovary [9–11]. Fenkci et al. studied the TAC levels of PCOS patients and compared them with a control group matched with age, body mass index, and smoking status. They proved that TAC levels in PCOS patients were significantly reduced [33]. Oxidative stress is a state characterized by an imbalance between pro-oxidant molecules including reactive oxygen and nitrogen species, and antioxidant defenses [34]. The increased level of reactive oxygen species (ROS) deteriorates oocyte quality by inducing apoptosis [35–39]. In light of the important role that oxidative stress plays in the aetiology of oocyte function [40], it is possible that the antioxidant effects of selenium have a therapeutic role in the context of both in vitro fertilization outcomes and controlling the impact of PCSO on fertility.

SHBG can be improved with selenium, but this conclusion contradicts many studies. According to the subgroup

1. Fig. 6 Forest plots of selenium supplementation on BMI in patients with PCOS

1. Table 2 Summary of meta-analysis outcomes

Outcome No. of studies

No. of participants

Type of meta-analysis Effect estimate (95% CI)

P value I2 (%) Egger’s

test (P value)

Total Testosterone 3 179 WMD (fixed) -0.14,0.11 0.767 31.8 0.991 SHBG 3 179 WMD (fixed) 0.32,19.18 0.043 0.0 0.075 HOMA-IR 3 189 WMD (random) -1.12,0.37 0.326 53.3 0.687 BMI 5 270 WMD (fixed) -1.32,0.31 0.227 0.0 0.182 Weight 4 206 WMD (fixed) -3.25,1.54 0.485 0.0 0.588 NO 2 124 WMD (random) -8.78,5.31 0.630 69.9 \ TAC 2 124 WMD (fixed) 65.24,147.18 ≤ 0.001 0.0 \ GSH 2 124 WMD (random) -39.30,91.68 0.433 64.1 \ MDA 2 124 WMD (random) -1.16,0.43 0.373 54.3 \ LDL 2 136 SMD (fixed) -0.49,0.18 0.359 0.0 \ HDL 2 136 SMD (fixed) -0.48,0.19 0.405 0.0 \ Triglycerides 2 136 SMD (random) -0.84,0.62 0.769 78.6 \ FPG 2 123 SMD (random) -1.38,0.90 0.678 89.7 \

Values are mean± SD; (s): selenium group (c): control group;

Fig. 7 Funnel plots of publication bias. a Publication bias on TAC. b Publication bias of SHBG. c Publication bias of BMI

analysis, it is clear that the overall results of the combined studies are meaningful, but two independent subgroup studies have shown that selenium supplementation alone has no effect on SHBG, and the combination of selenium and probiotics has no effect on SHBG. The reason may be that dividing the subgroups will reduce the sample size in each group. In addition, the 95% CI shows that selenium and probiotics (-1.17, 19.37) may have a more positive effect on SHBG than selenium alone (-10.58, 37.04). And it has been proven that probiotics have a significant improvement effect on SHBG [25, 41, 42]. Therefore, it is

inferred that this positive result should be caused by the addition of probiotics in subgroup 1. However, it is still not clear whether the combination of probiotics and selenium has a better effect than probiotics alone.

Some limitations should be considered when the results of this meta-analysis are examined. Significant heterogeneity was founded in eligible studies on HOMA-IR, NO, GSH, MDA, Triglycerides and FPG, which has a negative impact on the meaningful results of the current meta-analysis. And because these indicators involve a small number of studies, it is impossible

1. Table 3 GRADE approach

Study identifier Type of Study Factor of downgrade Factor of

escalation

Risk of bias inconsistency indirectness imprecision Publication bias

Level of evidence

Mehri Jamilian, et al. [25] RCT 0 -1 0 0 0 None Medium M. Razavi, et al. [26] RCT -1 0 0 -1 0 None Low Fatemeh Mohammad Hosseinzadeh, et al. [27]

RCT -1 0 0 0 0 None Medium

Mehri Jamilian, et al. [28] RCT -1 0 0 0 0 None Medium Shahrzad Zadeh Modarres, et al. [29]

RCT -1 0 0 0 0 None Medium

Zahra Heidar, et al. [30] RCT -1 0 0 -1 0 None Low Batool Hossein Rashidi, et al. [31]

RCT 0 0 0 -1 0 None Medium

1. 0 Values are mean “not lower the level”, -1 Values are mean “lower one level”

Fig. 8 Sensitivity analysis

to accurately determine the heterogeneity source. And, the protocol of this study has not been pre-registered in PROSPERO. In addition, publication bias may slightly bias our conclusions due to the insufficient number of included studies.

Despite these limitations, all existing studies on the treatment of PCOS with selenium are included, and the conclusions obtained are more valuable than a single study. And sensitivity analysis shows that the studies Mehri Jamilian, et al. [25–31] have significant sensitivity (Fig. 8) However, it is necessary to accurately determine the therapeutic effect of selenium on PCOS patients for the treatment of polycystic ovary. Therefore, more randomized controlled clinical trials of selenium in the treatment of PCOS are suggested to prove the effects of selenium on all aspects of PCOS patients.

Regardless of its positive effect on TAC, this meta-analysis shows that supplementation of selenium does not significantly improve the level of BMI, Weight, LDL, HDL, Triglycerides, Total Testosterone, HOMA-IR, NO, GSH, MDA and FPG. Therefore, in terms of the results of this meta-analysis, it is not recommended for patients with PCOS to use selenium as a regular trace element supplement. As for some PCOS patients who have poor follicle quality caused by oxidative stress or who want to undergo IVF, supplementation of selenium may have a positive effect on improving follicle quality.

Abbreviations CI Confidence interval PRISMA Preferred Reporting Items Systematic Reviews and Meta-Analyses WMD Weighted mean difference SMD Standard mean difference RCT Randomized controlled trial PubMed National Library of Medicine EMBASE Excerpta Medica Database PCOS Polycystic ovary syndrome LDL Low-density lipoprotein SHBG Sex hormone binding globulin BMI Body mass index HDL High-density lipoprotein HOMA-IR Homeostasis model of assessment-insulin resistance FPG Fasting plasma glucose NO Nitric oxide MDA Malondialdehyde TAC Total antioxidant capacity GSH Total glutathione

Acknowledgements None.

Authors’ contributions ZH L,LF D and XH S conceived and designed the study; ZH L, JD Z and Y W searched the related articles; ZH L,XH S,Y W and LJ L analyzed the data; ZH L,XH S, LF D and LJ L wrote the manuscript. TT L and JX L supervised the whole process. The author(s) read and approved the final manuscript.

Funding None.

Availability of data and materials All the data in this paper support the results of this study.