DOI: https://doi.org/10.21203/rs.3.rs-933982/v1
Objective Systematic evaluation of the application of probiotics in the treatment of polycystic ovary syndrome (PCOS).
Methods Computer searches of PubMed, The Cochrane Library, Web of Science, Medline, Embase, Ovid, CNKI, Wan Fang Data, and VIP databases were conducted to retrieve RCT studies on probiotics for the treatment of patients with PCOS from the time of database creation to March 2021. Meta-analysis was performed by two researchers after screening, extracting, and evaluating the literature using revman 5.3 software.
Results A total of 13 studies were included, and the results of Meta-analysis showed that compared with the placebo group, probiotic supplementation increased sex hormone binding globulin (SHBG) and insulin sensitivity testing index (QUICKI) and decreased fasting insulin (INS), total testosterone (TT), insulin resistance index (HOMA-IR), fasting blood glucose (FPG), low-density lipoprotein (LDL-C), triglyceride (TG), and total cholesterol (TC) levels in PCOS patients (P<0.05); there was no significant effect on deoxyepiandrosterone sulfate (DHEAS), high-density lipoprotein (HDL-C), and hyper-sensitive c-reactive protein (HS-CRP) levels in PCOS patients (P>0.05).
Conclusions Probiotics may improve serum levels of endocrine and metabolism-related indicators in patients with PCOS, but further investigation and validation in large samples and high-quality RCT studies are needed.
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, with a prevalence of 6-10%, according to the Rotterdam criteria, the incidence of PCOS has reached 15%[1,2].Typical patients with polycystic ovary syndrome present with a range of metabolic abnormalities characterized by insulin resistance, lipid abnormalities, and increased inflammation[2,3], and elevated insulin resistance and inflammatory markers (e.g., c-reactive protein CRP) in women with PCOS are strongly associated with the development of metabolic syndrome, type 2 diabetes, and cardiovascular disease[4,6].Therefore, it is particularly important to improve endocrinology and metabolism in patients with PCOS.
In recent years, research on the etiology and treatment of PCOS has been constantly updated and developed at home and abroad. It has been shown that probiotic supplementation has an impact on the treatment of patients with PCOS, and that supplementation improves metabolic syndrome, insulin resistance and CRP in patients [7, 8],but the effect of probiotics on glycemic control and CRP levels in women with polycystic ovary syndrome is controversial [9, 10].Therefore,this study will systematically review the relevant domestic and international literature to evaluate the effects of probiotic supplementation on blood glucose, lipids, inflammation and hormone levels in patients with PCOS, and provide a scientific basis for future clinical treatment.
1.1Search Strategy
Computer searches of PubMed, The Cochrane Library, Web of Science, Medline, Embase, Ovid, CNKI, Wan Fang Data, VIP databases for "Polycystic Ovary Syndrome ", "PCOS", "polycystic ovarian syndrome", "Probiotics ", "Prebiotic", "synbiotic", "symbiotic The search of domestic and foreign databases was based on a combination of subject terms and free words such as "supplementation", "polycystic ovarian syndrome" and "probiotic". In addition, the references of the included literature were manually searched to obtain relevant literature.
1.2Inclusion and exclusion criteria of the literature
Inclusion criteria: (1) The type of literature was a randomized controlled trial (RCT) (2) The study population was PCOS patients who met the Rotterdam criteria [11] or the National Institutes of Health (NIH) criteria [12]. (3) The intervention was supplementation with probiotics, prebiotics or synthetics for the experimental group and placebo treatment for the control group.
Exclusion criteria: (1) duplicate publications (2) literature for which complete experimental data were not available (3) animal experiments, reviews, and other literature.
1.3Literature Extraction
The literature search, extraction and quality evaluation were performed by 2 researchers separately, and in case of disagreement, the decision was made after discussion or with the participation of a third researcher. Data extraction included: ①basic information: author, year of publication, country, etc., ②age, BMI, number of cases, probiotic supplementation dose and duration of study subjects, ③outcome indicators: endocrine indicators [fasting insulin (INS), insulin resistance index (HOMA-IR), insulin sensitivity testing index (QUICKI), total testosterone (TT), deoxyepiandrosterone sulfate ( DHEAS), sex hormone binding globulin (SHBG); metabolic indexes [fasting blood glucose (FPG), ultrasensitive c-reactive protein (hs-CRP), total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL-C), low-density lipoprotein (LDL-C).
1.4Quality evaluation
Independent evaluation by 2 investigators based on the Cochrane Collaboration Network's assessment tool and cross-checking of results, including randomization methods, allocation concealment, blinding, completeness of results, selective reporting, and other risks of bias.
1.5Statistical Analysis
Mate analysis was performed using RevMan 5.3 software, and quantitative information was expressed as weighted mean difference (WMD) or standardized mean difference (SMD), and categorical information was expressed as dominance ratio (OR) or relative risk ratio (RR). Interval estimation was performed at 95% CI, and differences were considered statistically significant at P<O.05. Heterogeneity tests were determined using I2 and P values; if I2<50% or P>0.05, this indicated less heterogeneity and a fixed-effects model was used, and conversely, a random-effects model was used. If there was significant clinical heterogeneity, subgroup analysis and sensitivity analysis were required. Estimation of the presence of publication bias using funnel plots.
2.1Literature search results
Initially, 588 articles were retrieved, and a total of 13 RCT articles were screened for inclusion in the study, including a total of 862 patients, and all 13 articles were in English. The literature screening process and results are shown in Figure 1.
2.2Basic characteristics of the included literature and the results of the risk of bias evaluation
The basic characteristics of the included literature are shown in Table 1, and the results of the risk of bias evaluation are shown in Figure 2.
Table 1 General information of the included literature
Inclusion in the literature |
Number of cases Age (T/C) (T/C,age) |
BMI Intervention time (T/C,kg/m2)
|
Interventions
T C |
Ahmadi 2017[14] |
30/30 25.2±5.4/ 24.8±5.1 |
25.3±4.2 / 12weeks 26.4±4.3 |
Probiotic capsules containing Lactobacillus acidophilus, Placebo Lactobacillus casei, Bifidobacterium bifidum (2×109CFU/g)
|
Ghanei 2018[15] |
30/30 30.06±1.06/ 28.96±0.98 |
26.84±0.53/ 12weeks 25.97±0.42 |
Probiotic capsule (100mg) containing Lactobacillus acidophilus, Placebo Lactobacillus plantarum fermentum, Lactobacillus griseus (1×109CFU/g)
|
Jamilian 2018[16] |
30/30 26.0±5.3/ 25.6±3.8 |
24.6±3.3/ 12weeks 24.0±3.0 |
Probiotic capsules contain Lactobacillus acidophilus, Placebo Lactobacillus royi, Lactobacillus fermentum, Bifidobacterium bifidum (2×109CFU/g) + 200mcg selenium
|
Karamali 2018[17] |
30/30 27.2±4.6/ 27.7±4.7 |
23.7±3.6/ 12weeks 23.6±3.5 |
Probiotic capsules containing Lactobacillus acidophilus, Lactobacillus Placebo casei, Bifidobacterium bifidum (2×109 CFU/g)
|
Karimi 2018[18] |
50/49 28.1±5.5/ 29.0±5.1 |
32.89±6.11/ 12weeks 32.0±4.23 |
Probiotic capsule (500mg) containing Lactobacillus acidophilus (3×109CFU/g) Lactobacillus casei (3×109CFU/g), Placebo Lactobacillus bulgaricus (5×108CFU/g) Lactobacillus rhamnosus (7×109CFU/g), Bifidobacterium longum (7×109CFU/g) |
Nasri 2018[19]
Samimi 2019[10]
Shabani 2018[20]
Shoaei 2015[9]
Ostadmohammadi 2019[21]
Gholizadeh Shamasbi2019[22]
Sima Darvishi 2021[23]
Karimi 2020[24]
|
30/30 25.7±5.5/ 25.9±5.2
30/30 27.0±5.6/ 27.3±6.1
30/30 27.7±6.9/ 26.8±5.1
32/33 26.5±0.1/ 25.72±0.1
30/30 24.4±4.7/ 25.4±5.1
31/31 28±6.3/ 26±6.2
34/34 30.4±5.82/ 28.6±4.82
44/44 28.1±5.5/ 29±5.1 |
27.4±4.0/ 12weeks 27.2±5.3
27.3±3.8/ 12weeks 27.5±5.3
24.8±5.0/ 12weeks 25.5±3.9
26.06±0.1/ 8weeks 25.8±0.1
24.3±4.2/ 12weeks 25.1±4.9
25±4.4/ 3Months 27±5.6
29.43±5.69/ 8weeks 28.47±3.55
32.89±6.11/ 12weeks 32±4.23 |
Bifidobacterium shortum (2×109CFU/g), Streptococcus thermophilus (3×108CFU/g) + Probiotic inulin
Combination capsules contain Lactobacillus acidophilus, Placebo Lactobacillus casei, and Bifidobacterium bifidum (2×109CFU/g) + 800mg inulin
The capsules contain Lactobacillus acidophilus, Placebo Lactobacillus casei Bifidobacterium bifidum (2×109CFU/g) + 800mg inulin
Probiotic capsules contain Lactobacillus acidophilus, Placebo Lactobacillus royale,Lactobacillus fermentum, Bifidobacterium bifidum (2×109CFU/g) + 200mcg selenium
Probiotic capsule (500mg) contains Lactobacillus casei (7×109CFU/g) Placebo Lactobacillus acidophilus (2×109CFU/g), Lactobacillus rhamnosus (1.5×109CFU/g), Lactobacillus bulgaricus (2×108CFU/g) Bifidobacterium shortum (2×1010CFU/g), Bifidobacterium longum (7×109CFU/g) Streptococcus thermophilus (1.5×109CFU/g)
Probiotic capsule contains Lactobacillus acidophilus, Placebo Lactobacillus royi, Lactobacillus fermentum Bifidobacterium bifidum (2×109CFU/g) + 50,000 units of vitamin d
The prebiotic group ingested 20 grams of resistant dextrin dissolved Placebo in a glass of water per day, and Placebo group ingested 20 grams of maltose dextrin dissolved in one cup of water per day
Combination capsule (500mg) contains Lactobacillus Placebo casei (3×109CFU/g), Lactobacillus rhamnosus (7×109CFU/g), Lactobacillus bulgaricus (5×108CFU/g), Lactobacillus acidophilus (3×1010CFU/g), Bifidobacterium longum (1×109CFU/g), strain ACS-071-V-Sch8b (2×1010CFU/g), Streptococcus thermophilus (3×108CFU/g) and inulin-type prebiotics
Lactobacillus acidophilus (3×1010CFU/g), Lactobacillus casei Placebo (3×109CFU/g), Lactobacillus bulgaricus (5×108CFU/g), Lactobacillus rhamnosus (500mg) (3×109CFU/g), Lactobacillus bulgaricus (5×108CFU/g), Lactobacillus rhamnosus (7×109CFU/g), Bifidobacterium longum (1×109CFU/g), Bifidobacterium shortum (2×1010CFU/g), Streptococcus thermophilus (3×108CFU/g) and prebiotic inulin |
2.3 Meta-analysis results
2.3.1 Effect of probiotic supplementation on endocrine indexes in PCOS patients The combined results showed that probiotic supplementation increased SHBG and QUICKI and decreased INS, TT, and HOMA-IR levels in PCOS patients compared with placebo (P<0.05); there was no significant effect on DHEAS levels in PCOS patients (P>0.05), as shown in Table 2.
Table 2 Meta-analysis of endocrine index results of pcos patients in the probiotic and placebo groups
Indicators |
Probiotic group Placebo group ,n ,n |
RMS estimation P SMD(95%CI)
|
Heterogeneity test P I2 |
QUICKI |
172 172
|
2.10(0.72~3.48) 0.003 |
0.00001 97% |
HOMA-IR |
206 206
|
-0.57(-0.98~-0.15) 0.007 |
0.0008 76% |
INS |
206 206
|
-0.52(-0.93~-0.12) 0.01 |
0.001 76% |
TT |
120 120 |
-0.24(-0.35~-0.13) 0.0001 |
0.001 81% |
DHEAS
SHBG |
91 91
120 120 |
0.02(-0.36~0.39) 0.93
0.51(0.03~0.99) 0.04 |
0.19 39%
0.02 70% |
2.3.2 Effect of probiotic supplementation on metabolic indexes in PCOS patients The combined results showed that probiotic supplementation reduced the levels of FPG, LDL-C, TG, and TC compared with placebo (P < 0.05); there was no significant effect on the levels of HDL-C and HS-CRP in PCOS patients (P > 0.05), as shown in Table 3.
Table 3 Meta-analysis of metabolic index results of pcos patients in the probiotic and placebo groups
Indicators |
Probiotic group Placebo group ,n ,n |
RMS estimation P SMD(95%CI)
|
Heterogeneity test P I2 |
TC |
199 199
|
-1.25(-2.22~-0.28) 0.01 |
0.00001 95% |
LDL-C |
199 199
|
1.12(0.04~-2.20) 0.04 |
0.00001 96% |
HDL-C |
199 199
|
0.48(-0.47~1.43) 0.32 |
0.00001 95% |
TG |
199 199 |
-0.86(-1.69~-0.02) 0.04 |
0.00001 93% |
FPG
HS-CRP |
203 203
213 214 |
-1.65(-2.80~-0.49) 0.005
-0.68(-1.61~0.26) 0.16 |
0.00001 96%
0.00001 95% |
2.3.3 Subgroup analysis
Subgroup analyses were performed on the type of intervention (probiotic and cobiotic groups) and duration of intervention (≥12 weeks and <12 weeks) of the included studies according to the heterogeneity present in the included literature, as shown in Table 4.
Table 4 Subgroup analysis of probiotic group versus placebo group for outcome indicators in pcos patients
Indicators |
Number of included literature |
Subgroup
|
95%CI I2 Overall I2 (%) (%) |
QUICKI |
Type of Intervention 4 1 Intervention time 4 1 |
Probiotic group Hapten group ≥12weeks <12weeks |
0.68~4.20 97 97 0.69~1.80 - 0.03~1.04 77 8.76~12.68 - |
HOMA-IR |
Type of Intervention 4 2 Intervention time 4 2 |
Probiotic group Hapten group ≥12weeks <12weeks |
-1.17~0.06 84 76 -1.03~-0.18 30 -0.75~-0.01 58 -1.99~0.13 88 |
INS |
Type of Intervention 4 2 Intervention time 4 2 |
Probiotic group Hapten group ≥12weeks <12weeks |
-1.11~0.09 84 76 -1.04~-0.08 44 -0.78~0.04 65 -1.81~0.16 87 |
TT |
Type of Intervention 3 1 Intervention time 4 - |
Probiotic group Hapten group ≥12weeks <12weeks |
-0.37~-0.15 86 81 -0.38~0.58 - -0.35~-0.13 81 - - |
SHBG
TC
LDL-C
TG
FPG |
Type of Intervention 3 1 Intervention time 4 - Type of Intervention 3 3 Intervention time 5 1 Type of Intervention 3 3 Intervention time 5 1 Type of Intervention 3 3 Intervention time 5 1 Type of Intervention 5 1 Intervention time 5 1 |
Probiotic group Hapten group ≥12weeks <12weeks Probiotic group Hapten group ≥12weeks <12weeks Probiotic group Hapten group ≥12weeks <12weeks Probiotic group Hapten group ≥12weeks <12weeks Probiotic group Hapten group ≥12weeks <12weeks |
-0.15~0.86 65 70 0.46~1.54 - 0.03~0.99 70 - - -5.23~-0.19 98 95 -0.42~0.11 0 -2.76~-0.35 96 -0.51~0.44 - 0.55~6.76 98 96 -0.38~0.16 0 0.19~2.93 96 -0.54~0.41 - -3.64~0.19 97 93 -0.34~0.19 0 -2.06~0.02 95 -0.62~0.33 - -3.35~-0.45 97 96 -1.14~-0.10 - -3.58~0.04 97 -3.10~-1.79 - |
2.3.4 Sensitivity analysis Meta-analysis results showed that the TT indicator after excluding Karamali 2018 literature was (SMD: -0.18; 95% CI: -0.30 to -0.07), the HOMA-IR indicator after excluding Shoaei 2015 literature was (SMD: -0.38; 95% CI: -0.67 to -0.09), the SHBG indicator after excluding SHBG index after exclusion of Ostadmohammadi 2019 literature was (SMD: 0.72; 95% CI: 0.41 to 1.04), and TC index after exclusion of Ostadmohammadi 2019 literature was (SMD: -0.30; 95% CI: -0.52 to -0.07). For details, see Table 5.
Table 5 Sensitivity analysis of the probiotic group versus the placebo group for outcome indicators in pcos patients
indicators
|
Before sensitivity analysis
Inclusion in theliterature SMD 95%CI |
|
After sensitivity analysis
SMD 95%CI Exclusion of literature |
|||
QUICKI
|
5 2.10 0.72~3.48 |
|
0.54 0.03~1.04 Shoaei 2015 |
|||
HOMA-IR |
6 -0.57 -0.98~-0.15
|
|
-0.38 -0.67~-0.09 Shoaei 2015 |
|||
INS |
6 -0.52 -0.93~-0.12
|
|
-0.35 -0.67~-0.04 Shoaei 2015 |
|||
TT
SHBG
TC
LDL-C
TG |
4 -0.24 -0.35~-0.13
4 0.51 0.03~0.99
6 -1.25 -2.22~-0.28
6 1.12 0.04~-2.20
6 0.86 -1.69~-0.02 |
|
-0.18 -0.30~-0.07 Karamali 2018
0.72 0.41~1.04 Ostadmohammadi 2019
-0.30 -0.52~-0.07 Ostadmohammadi 2019
-0.15 -0.36~0.07 Ostadmohammadi 2019
-0.22 -0.46~0.02 Ostadmohammadi 2019
|
2.3.5 Publication bias test
Due to the small number of studies included for individual outcome indicators, no publication bias test was performed in this study.
Polycystic ovary syndrome (PCOS) is an endocrine metabolic syndrome with complex etiology and diverse clinical manifestations, and is one of the most common causes of endocrine disorders and infertility in women of reproductive age. The etiology of PCOS is unknown and may be related to genetics, lifestyle and other factors [25]. Studies have shown that intestinal flora is closely related to the level of endocrine metabolism in humans, and dysbiosis of intestinal flora can increase androgen levels, lead to insulin resistance, cause chronic inflammation, obesity, and other metabolic syndromes. Therefore, regulation of intestinal flora and supplementation of probiotics have certain adjuvant and therapeutic effects on PCOS disease [26-29]. In recent years, probiotics have received wide attention in regulating the balance of intestinal flora, controlling and managing blood glucose and lipid levels, and regulating inflammation and hormones. Foreign studies on RCTs of probiotics in PCOS patients have been increasing, but studies related to the effects of probiotics in PCOS patients are not the same. Therefore, this study will systematically evaluate the effects of probiotics on glucose, lipid, inflammation and hormone levels in patients with PCOS, and thus provide a relevant scientific basis for clinical treatment.
3.1 Effect of probiotics on endocrine indexes in PCOS patients
The results of this study showed that probiotic supplementation increased SHBG and QUICKI and decreased INS, TT, and HOMA-IR levels in PCOS patients, but had no significant effect on DHEAS levels in PCOS patients. Pathophysiological mechanisms suggest that PCOS patients are prone to glucose intolerance and impaired insulin sensitivity, and the intake of probiotics or synbiotics balances the intestinal microbial community and intestinal pH, improves the intestinal catabolism and metabolism of starch, and enhances intestinal digestion and absorption of nutrients [30], thus lowering blood glucose and reducing insulin resistance, however, the exact glucose-lowering effect of probiotics mechanism of the hypoglycemic effect of probiotics is still not fully understood [31]. Some studies have shown that probiotic supplementation significantly reduces blood glucose, insulin and insulin resistance levels in diabetic patients [32-34]. However, a meta-analysis by Javad Heshmati showed no effect of probiotic supplementation on insulin resistance levels in patients with PCOS [35]. This may be due to the different pathophysiological mechanisms in diabetic patients and PCOS patients; therefore, more studies are needed to demonstrate the effect of probiotics on insulin levels in PCOS. Cholesterol, a prerequisite for androgen production in PCOS patients, leads to increased androgen levels [22, 36], and probiotics lower cholesterol by reducing cholesterol production in the liver, which in turn reduces androgen production, such as testosterone, DHEAS, and SHBG levels [22, 37, 38]. Shamasbi SG et al. showed that intake of probiotics or cobiotics in PCOS patients had significantly lower serum testosterone, SHBG, and DHEAS [39]. However, the present study showed no effect of probiotics on DHEAS, which may be related to the short duration of intervention in the included articles or the small number of included literature; therefore, subsequent RCT clinical trials may further confirm the effect of probiotics on androgen levels by extending the duration of intervention.
3.2 Effect of probiotics on metabolic indexes of PCOS patients
The results of this study showed that probiotic supplementation reduced FPG, LDL-C, TG, and TC levels and had no significant effect on HDL-C and HS-CRP levels in patients with PCOS. CRP is an important inflammatory factor in diabetes and other metabolic diseases [40], and probiotics can exert anti-inflammatory and antioxidant effects by producing short-chain fatty acids in the gut [41], and prebiotics (e.g.,oligofructose ) act by reducing oxidative and inflammatory markers in the liver [42]. Some studies have demonstrated that probiotic supplementation reduces inflammatory factors and CRP levels [43], but the Meta-analysis by Reza Tabrizi et al. found that probiotic supplementation given with PCOS did not affect CRP levels [44], which is consistent with the results of the present study. Therefore, more RCT studies are still needed to confirm whether probiotics can reduce the inflammatory response in PCOS. The beneficial effect of probiotics or synbiotics on lipids may be due to blocked cholesterol absorption [45] and the inhibition of bile acid reabsorption in the lumen [46, 47], and the mechanism by which probiotics lower TG and elevate HDL-C levels is not clear. Previous studies have confirmed that probiotics can significantly reduce TC, TG and LDL-C values [48], and a meta-analysis showed no effect of probiotic supplementation on HDL-C [49], which is consistent with the results of the present study, but the results of Li et al [50] showed that probiotics can elevate HDL-C; therefore, this conclusion needs further validation.
3.3 Limitations of this study
①Most of the included studies were from Iran, and the generalizability of the results may be affected by factors such as ethnic differences and lifestyle, therefore, it is recommended that more countries conduct RCTs to confirm the results. ②The number of included literature is insufficient and the sample size is small, which may produce some heterogeneity in the results. ③The interventions in the included studies were slightly different, such as the dose and type of probiotic supplementation and the duration of intervention, and also the units of measurement for each outcome varied, which may be an important source of heterogeneity. ④ The outcome metrics of the included studies varied, and the small number of included literature for certain outcome metrics (e.g., DHEAS) may have influenced the results.
In conclusion, the preliminary evidence from this Meta-analysis suggests that probiotic supplementation can improve the levels of endocrine and metabolism-related indicators in PCOS patients, but due to various limitations of this study, more large-sample, high-quality randomized controlled trials are needed in the future to evaluate the efficacy of probiotic supplementation in PCOS patients.
Conflicts of Interest: The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Contributions: (I) Conception and design: Lian-Hua Xu; (II) Administrative support: Lian-Hua Xu; (III) Provision of study materials or patients: All authors; (IV) Collection and assembly of data: Lian-Hua Xu; (V) Data analysis and interpretation: Lian-Hua Xu; (VI) Manuscript writing: Lian-Hua Xu; (VII) Final approval of manuscript: All authors.
[1] Neil F Goodman M F, Rhoda H. Cobin M M, Walter Futterweit M F F, et al. American association of clinical endocrinologists, American college if endocrinology, and androgen excess and PCOS society disease state clinical review: guide to the best practices in the evaluation and treatment of polycystic ovary syndrome-part 1[J]. ENDOCRINE PRACTICE, 2015.
[2] Fauser B C, Tarlatzis B C, Rebar R W, et al. Consensus on women's health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group[J]. Fertil Steril, 2012,97(1):28-38.
[3] Pasquali R. Contemporary approaches to the management of polycystic ovary syndrome[J]. Ther Adv Endocrinol Metab, 2018,9(4):123-134.
[4] Keskin K R, Okyay A G, Hakverdi A U, et al. The effect of obesity on inflammatory markers in patients with PCOS: a BMI-matched case-control study[J]. Arch Gynecol Obstet, 2014,290(2):315-319.
[5] Saleem F, Rizvi S W. New Therapeutic Approaches in Obesity and Metabolic Syndrome Associated with Polycystic Ovary Syndrome[J]. Cureus, 2017,9(11):e1844.
[6] Boulman N, Levy Y, Leiba R, et al. Increased C-reactive protein levels in the polycystic ovary syndrome: a marker of cardiovascular disease[J]. J Clin Endocrinol Metab, 2004,89(5):2160-2165.
[7] Sun J, Buys N. Effects of probiotics consumption on lowering lipids and CVD risk factors: a systematic review and meta-analysis of randomized controlled trials[J]. Ann Med, 2015,47(6):430-440.
[8] Bollero P, Di Renzo L, Franco R, et al. Effects of new probiotic mouthwash in patients with diabetes mellitus and cardiovascular diseases[J]. Eur Rev Med Pharmacol Sci, 2017,21(24):5827-5836.
[9] Shoaei T, Heidari-Beni M, Tehrani H G, et al. Effects of Probiotic Supplementation on Pancreatic beta-cell Function and C-reactive Protein in Women with Polycystic Ovary Syndrome: A Randomized Double-blind Placebo-controlled Clinical Trial[J]. Int J Prev Med, 2015,6:27.
[10] Samimi M, Dadkhah A, Haddad K H, et al. The Effects of Synbiotic Supplementation on Metabolic Status in Women With Polycystic Ovary Syndrome: a Randomized Double-Blind Clinical Trial[J]. Probiotics Antimicrob Proteins, 2019,11(4):1355-1361.
[11] group R E A S. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS)[J]. Hum Reprod, 2004,19(1):41-47.
[12] Zawadri J. Diagnostic criteria for polycystic ovary syndrome : towards a rational approach[J]. Polycystic ovary syndrome. Current issues in endocrinology and metabolism, 1992.
[13] GREEN J P H S. Cochrane handbook for systematic Reviews 0f Interventions Version 5.1.0[J]. The cochmne collaboration, 2011.
[14] Ahmadi S, Jamilian M, Karamali M, et al. Probiotic supplementation and the effects on weight loss, glycaemia and lipid profiles in women with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial[J]. Hum Fertil (Camb), 2017,20(4):254-261.
[15] Ghanei N, Rezaei N, Amiri G A, et al. The probiotic supplementation reduced inflammation in polycystic ovary
syndrome: A randomized, double-blind, placebo-controlled trial[J]. 2018.
[16] Jamilian M, Mansury S, Bahmani F, et al. The effects of probiotic and selenium co-supplementation on parameters of mental health, hormonal profiles, and biomarkers of inflammation and oxidative stress in women with polycystic ovary syndrome[J]. J Ovarian Res, 2018,11(1):80.
[17] Karamali M, Eghbalpour S, Rajabi S, et al. Effects of Probiotic Supplementation on Hormonal Profiles, Biomarkers of Inflammation and Oxidative Stress in Women With Polycystic Ovary Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial[J]. Arch Iran Med, 2018,21(1):1-7.
[18] Karimi E, Moini A, Yaseri M, et al. Effects of synbiotic supplementation on metabolic parameters and apelin in women with polycystic ovary syndrome: a randomised double-blind placebo-controlled trial[J]. Br J Nutr, 2018,119(4):398-406.
[19] Nasri K, Jamilian M, Rahmani E, et al. The effects of synbiotic supplementation on hormonal status, biomarkers of inflammation and oxidative stress in subjects with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial[J]. BMC Endocr Disord, 2018,18(1):21.
[20] Shabani A, Noshadian M, Jamilian M, et al. The effects of a novel combination of selenium and probiotic on weight loss,
glycemic control and markers of cardio-metabolic risk in women with
polycystic ovary syndrome[J]. Journal of Functional Foods, 2018.
[21] Ostadmohammadi V, Jamilian M, Bahmani F, et al. Vitamin D and probiotic co-supplementation affects mental health, hormonal, inflammatory and oxidative stress parameters in women with polycystic ovary syndrome[J]. J Ovarian Res, 2019,12(1):5.
[22] Gholizadeh S S, Dehgan P, Mohammad-Alizadeh C S, et al. The effect of resistant dextrin as a prebiotic on metabolic parameters and androgen level in women with polycystic ovarian syndrome: a randomized, triple-blind, controlled, clinical trial[J]. Eur J Nutr, 2019,58(2):629-640.
[23] Darvishi S, Rafraf M, Asghari-Jafarabadi M, et al. Synbiotic Supplementation Improves Metabolic Factors and Obesity Values in Women with Polycystic Ovary Syndrome Independent of Affecting Apelin Levels: A Randomized Double-Blind Placebo - Controlled Clinical Trial[J]. Int J Fertil Steril, 2021,15(1):51-59.
[24] Karimi E, Moini A, Yaseri M, et al. Effects of synbiotic supplementation on metabolic parameters and apelin in women with polycystic ovary syndrome: a randomised double-blind placebo-controlled trial - Corrigendum[J]. Br J Nutr, 2020,124(4):479.
[25] Palomba S, Santagni S, Falbo A, et al. Complications and challenges associated with polycystic ovary syndrome: current perspectives[J]. Int J Womens Health, 2015,7:745-763.
[26] Di Gioia D, Aloisio I, Mazzola G, et al. Bifidobacteria: their impact on gut microbiota composition and their applications as probiotics in infants[J]. Appl Microbiol Biotechnol, 2014,98(2):563-577.
[27] Kadooka Y, Sato M, Ogawa A, et al. Effect of Lactobacillus gasseri SBT2055 in fermented milk on abdominal adiposity in adults in a randomised controlled trial[J]. Br J Nutr, 2013,110(9):1696-1703.
[28] Backhed F, Ding H, Wang T, et al. The gut microbiota as an environmental factor that regulates fat storage[J]. Proc Natl Acad Sci U S A, 2004,101(44):15718-15723.
[29] Zhang N, Li F, Li L, et al. Research progress on the mechanism of the role of intestinal flora dysbiosis in the development of polycystic ovary syndrome[J]. Shandong Medicine, 2018,58(3):96-98.
[30] Pan C, Zhao Y, Liao S F, et al. Effect of selenium-enriched probiotics on laying performance, egg quality, egg selenium content, and egg glutathione peroxidase activity[J]. J Agric Food Chem, 2011,59(21):11424-11431.
[31] Akbari V, Hendijani F. Effects of probiotic supplementation in patients with type 2 diabetes: systematic review and meta-analysis[J]. Nutr Rev, 2016,74(12):774-784.
[32] Sun J, Buys N J. Glucose- and glycaemic factor-lowering effects of probiotics on diabetes: a meta-analysis of randomised placebo-controlled trials[J]. Br J Nutr, 2016,115(7):1167-1177.
[33] Zhang Q, Wu Y, Fei X. Effect of probiotics on glucose metabolism in patients with type 2 diabetes mellitus: A meta-analysis of randomized controlled trials[J]. Medicina (Kaunas), 2016,52(1):28-34.
[34] Kasinska M A, Drzewoski J. Effectiveness of probiotics in type 2 diabetes: a meta-analysis[J]. Pol Arch Med Wewn, 2015,125(11):803-813.
[35] Heshmati J, Farsi F, Yosaee S, et al. The Effects of Probiotics or Synbiotics Supplementation in Women with Polycystic Ovarian Syndrome: a Systematic Review and Meta-Analysis of Randomized Clinical Trials[J]. Probiotics Antimicrob Proteins, 2019,11(4):1236-1247.
[36] Y K, L P, A H R, et al. The Role Of Intestinal Microbiota In The Health And A Short Review On The Probiotic And Prebiotic Supplements In Obesity Prevention[J]. European Journal of Surgical Oncology, 2014,174(1):2-5.
[37] Aliasgharzadeh A, Khalili M, Mirtaheri E, et al. A Combination of Prebiotic Inulin and Oligofructose Improve Some of Cardiovascular Disease Risk Factors in Women with Type 2 Diabetes: A Randomized Controlled Clinical Trial[J]. Adv Pharm Bull, 2015,5(4):507-514.
[38] Amiri M, Golsorkhtabaramiri M, Esmaeilzadeh S, et al. Effect of Metformin and Flutamide on Anthropometric Indices and Laboratory Tests in Obese/Overweight PCOS Women under Hypocaloric Diet[J]. J Reprod Infertil, 2014,15(4):205-213.
[39] Shamasbi S G, Ghanbari-Homayi S, Mirghafourvand M. The effect of probiotics, prebiotics, and synbiotics on hormonal and inflammatory indices in women with polycystic ovary syndrome: a systematic review and meta-analysis[J]. Eur J Nutr, 2020,59(2):433-450.
[40] Bansal D, Gudala K, Esam H P, et al. Microvascular Complications and Their Associated Risk Factors in Newly Diagnosed Type 2 Diabetes Mellitus Patients[J]. Int J Chronic Dis, 2014,2014:201423.
[41] Sadrzadeh-Yeganeh H, Elmadfa I, Djazayery A, et al. The effects of probiotic and conventional yoghurt on lipid profile in women[J]. Br J Nutr, 2010,103(12):1778-1783.
[42] Cani P D, Possemiers S, Van de Wiele T, et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability[J]. Gut, 2009,58(8):1091-1103.
[43] Mazidi M, Rezaie P, Ferns G A, et al. Impact of Probiotic Administration on Serum C-Reactive Protein Concentrations: Systematic Review and Meta-Analysis of Randomized Control Trials[J]. Nutrients, 2017,9(1).
[44] Tabrizi R, Ostadmohammadi V, Akbari M, et al. The Effects of Probiotic Supplementation on Clinical Symptom, Weight Loss, Glycemic Control, Lipid and Hormonal Profiles, Biomarkers of Inflammation, and Oxidative Stress in Women with Polycystic Ovary Syndrome: a Systematic Review and Meta-analysis of Randomized Controlled Trials[J]. Probiotics Antimicrob Proteins, 2019.
[45] Gilliland S E, Nelson C R, Maxwell C. Assimilation of cholesterol by Lactobacillus acidophilus[J]. Appl Environ Microbiol, 1985,49(2):377-381.
[46] Liong M T, Dunshea F R, Shah N P. Effects of a synbiotic containing Lactobacillus acidophilus ATCC 4962 on plasma lipid profiles and morphology of erythrocytes in hypercholesterolaemic pigs on high- and low-fat diets[J]. Br J Nutr, 2007,98(4):736-744.
[47] Kim G B, Yi S H, Lee B H. Purification and characterization of three different types of bile salt hydrolases from Bifidobacterium strains[J]. J Dairy Sci, 2004,87(2):258-266.
[48] He J, Zhang F, Han Y. Effect of probiotics on lipid profiles and blood pressure in patients with type 2 diabetes: A meta-analysis of RCTs[J]. Medicine (Baltimore), 2017,96(51):e9166.
[49] Cozzolino M, Vitagliano A, Pellegrini L, et al. Therapy with probiotics and synbiotics for polycystic ovarian syndrome: a systematic review and meta-analysis[J]. Eur J Nutr, 2020,59(7):2841-2856.
[50] Li C, Li X, Han H, et al. Effect of probiotics on metabolic profiles in type 2 diabetes mellitus: A meta-analysis of randomized, controlled trials[J]. Medicine (Baltimore), 2016,95(26):e4088.