Abstract

Background: Polycystic ovarian syndrome (PCOS) is a kind of common gynecological endocrine disorder. And the mutations of melatonin receptor (MTNR) genes are related to the occurrence of PCOS. But previous researches have shown opposite results. So, the object of our systematic review and meta-analysis is to investigate the relationship between MTNR 1A/B polymorphisms and PCOS.

Methods: PubMed, Embase, Ovid, the Cochrane Library, Web of Science and three Chinese databases (VIP, CNKI and Wanfang) were used to retrieve eligible articles published between January 1980 and February 2020. And we used the odds ratio (OR) and its 95% confidence interval (CI) to investigate the strength of the association by six genetic models, allelic, codominant (homozygous and heterozygous), dominant, recessive and superdominant models. Review Manager 5.3, IBM SPSS statistics 25 and Stata MP 16.0 software were used to do this meta-analysis.

Results: Our meta-analysis involved 2553 PCOS patients and 3152 controls, for two single nucleotide polymorphisms (rs10830963 C> G in MTNR1B and rs2119882 T> C in MTNR1A) and significant associations were found in some genetic models of these single nucleotide polymorphisms (SNPs). For rs10830963, strongly significant was found in the heterozygote model (GC vs. CC, P=0.02). Additionally, a slight trend was detected in the allelic (G vs. C), homozygote (GG vs. CC) and dominant (GG+GC vs. CC) model of rs10830963 (P=0.05). And after further sensitivity analysis, a study with high heterogeneity was removed. In the allelic (P=0.000), homozygote (P=0.001), dominant (P=0.000) and recessive (GG vs. GC+CC, P=0.001) model, strong associations between rs10830963 and PCOS were found. Moreover, for rs2119882, five genetic models, allelic (C vs. T, P=0.000), codominant (the homozygote (CC vs. TT, P=0.000) and heterozygote model (CT vs. TT, P=0.02), dominant (CC + CT vs. TT, P=0.03) and recessive model (CC vs. CT + TT, P=0.000) showed significant statistical associations with PCOS.

Conclusion: MTNR1B rs10830963 and MTNR1B rs2119882 polymorphisms are associated with PCOS risk. However, the above conclusions still require being confirmed by much larger multi-ethnic studies.

Background

Melatonin secreted by the pineal gland during the dark phase of the sleep/wake cycle, is a kind of hormone which periodically regulates several physiological functions [1], including glucose homeostasis [2] and insulin secretion [3]. When the melatonin secretion or the corresponding Melatonin Receptor (MTNR) is abnormal, the metabolism in humans may be seriously damaged [4]. And MTNR exists in ovarian granulosa cells membranes [5,6], therefore, melatonin as a pleiotropic molecule has a direct effect on ovarian function [7,8]. Low melatonin levels in follicular fluid affect the quality and number of oocytes, and ultimately affect the outcome of in vitro fertilization (IVF) [9]. Moreover, melatonin treatment can also be used as a combination therapy to help control the blood glucose level [2], slow the progress or improve type 2 diabetes mellitus (T2DM) [10], increase pregnancy rates and improve endocrine levels eventually [11].

Additionally, multiple studies reveal that melatonin secretion is increased in polycystic ovarian syndrome (PCOS) patients [12–14]. PCOS is a kind of common metabolic and endocrine disorder in reproductive women [15], of which global prevalence is approximately 6–10% [16,17]. It has a variety of heterogeneous clinical manifestations, and approximately 20–30% of patients with PCOS suffer from various complications [18], like metabolic syndrome [19] and insulin resistance (IR) [20], which makes PCOS hard to be explained by a single factor. PCOS is a highly clinical as well as genetic heterogeneity syndrome [21]. For example, oocytes of PCOS patients also have abnormal gene transcription and expression, which will affect individual reproductive capacity [22]. As metabolic disorders have become much more prevalent recently [23], more genome-wide association and cohort studies were conducted and more variant genes and novel single nucleotide polymorphisms (SNPs) are found in large Chinese PCOS population [24,25], which have been confirmed later by multi-ethnic studies [26,27], including thyroid associated protein gene [28], Fat Mass and Obesity (FTO) gene [29,30], Follicle-stimulating Hormone Receptor (FSHR) gene [31,32], DENN/MADD domain containing 1A gene [33], Vitamin D Receptor (VDR) gene [34–36] and so on.

Additionally, the SNPs of MTNR 1A/B gene (MTNR1A/B) are found to have associations with many kinds of metabolic disorders. For example, MTNR1B rs10830963 polymorphism is not only associated with fasting blood glucose levels, but also with IR and T2DM risk [37]. And MTNR1A rs2119882 is also associated with gestational diabetes mellitus and IR [38]. However, whether MTNR polymorphisms relate to another metabolic disorder, PCOS, is still inconclusive because previous genetic research has shown conflicting conclusions [39]. So, the object of our meta-analysis is to ascertain the association between MTNR1A/B polymorphisms and PCOS.

Methods

Our study was conducted with the requirements of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [40]. All data were available from currently published studies, so no informed consent and Ethics Committee approval were required.

Study protocol

Five English databases (PubMed, Embase, Ovid, the Cochrane Library and Web of Science) and three Chinese databases (VIP, CNKI and Wanfang) were searched in our study. And we used three subject heading terms, ‘Polycystic ovarian syndrome’, ‘melatonin’ and ‘melatonin receptor’, as well as the synonyms of these terms confirmed by Medical Subject Headings (MeSH) referred to in the Supplementary Material S1 (Search strategies) [41], where other free words were registered. The latest search results were updated on 14 February 2020. And there were no language restrictions in these search strategies. Finally, all references were exported to EndNote X9 software for further research.

Definitions and results

As the definition of PCOS used in the present study, all the eligible studies adopted the 2003 Rotterdam diagnostic inclusion criteria of PCOS [42]: (1) thin ovulation or anovulation. (2) Clinical manifestations of hyperandrogen or hyperandrogenemia. (3) Polycystic ovarian changes, that is, ≥12 follicles with a diameter of 2–9 millimeters on ovary, or ovarian volume > 10 ml. As long as two of the above criteria are met and other diseases are excluded, PCOS can be diagnosed. The results were the genotype distribution in MTNR gene and the odds ratio (OR) of PCOS.

Eligibility criteria

Included references needed to meet the following criteria:

  1. Assess the association between SNP in MTNR and PCOS risk,

  2. Contain particular data, such as the frequency of MTNR genotypes.

Excluded studies should meet the following criteria:

  1. Abstracts and reviews,

  2. Repeated dissertation,

  3. No research on genotype distribution,

  4. Non-human research.

Among them, Newcastle–Ottawa Scale (NOS), available from URL (http://www.ohri.ca/programs/clinical_epidemiology/oxford.htm) [43], was performed to evaluate the quality of all included studies.

Study selection

All studies retrieved from all the databases were assessed and reviewed by the first and second authors (Shiqi Yi and Hao Shi) based on eligibility criteria. The data extraction results were agreed upon discussion with another first author (Jiawei Xu). Study and descriptors such as author, publication time, country, ethnicity, study period, study type, NOS scores, the number of participants and methods of study were extracted and recorded from the included studies.

The third and fourth authors (Wenbo Li and Qian Li) independently assessed the quality of eligible studies using NOS which consisted of three parts, namely selection, comparability and exposure, and their corresponding eight scoring items. Except for comparability which could score up to two stars, each item could only score up to one star. Possible maximum number of stars in each study was 9. When the score of eligible study in NOS was ≥7, the present study was regarded as high-quality research [44]. When scoring divergences occurred, the sixth investigator (Ying-pu Sun) was consulted.

Statistical analysis

Review Manager 5.3 software (available from the Cochrane Community, https://community.cochrane.org/help/tools-and-software/revman-5) was performed for data analysis [45]. Each study was evaluated by the Hardy–Weinberg equilibrium (H–W equilibrium, HWE) with a chi-square test (χ2 test) by IBM SPSS statistics 25 software [46]. Odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were utilized to test the association between each SNPs, rs2119882 and rs10830963 of MTNR1A/B and PCOS with six genetic models used to test the influence of genotype, that is, for rs10830963 (C> G): allelic (G vs. C), codominant (homozygote (GG vs. CC) and heterozygote (GC vs. CC) models), dominant (GG + GC vs. CC), recessive (GG vs. GC + CC) and superdominant (GG + CC vs. GC) models were calculated; and for rs2119882 (T> C): allelic (C vs. T), codominant (homozygote (CC vs. TT) and heterozygote (CT vs. TT) models), dominant (CC + CT vs. TT), recessive (CC vs. CT + TT) and superdominant (CC + TT vs. CT) models were calculated [47,48]. Our study used Cochrane Q-test for heterogeneity testing and the I2, a test statistic, for quantification [49]. In the Q-test, when P≥0.1 or I2 ≤ 50%, the fixed-effects model could be established to analyze. Otherwise, the random-effects model could be used. Next, a Z-test was performed to evaluate the statistical significance of combined ORs in quantitative synthesis. And all analysis will use 0.05 as significantly statistical level. Finally, by eliminating the heterogeneous merger studies one by one, the effect of a single heterogeneous study on the entire model was further discussed through a sensitivity analysis. And Stata MP 16.0 software was used to analyze the publication bias by Egger’s and Begg’s tests.

Results

Study selection

In total, 1028 references were identified after searching from databases (refer to Supplementary Material S1, Search strategies) and their recommended links. Then, all searched reference lists were imported into EndNote X9, which helps to remove duplicate studies. The majority of articles were excluded for unrelated titles and abstracts and other eight articles were excluded because of which studied populations were not PCOS patients, genotype data were not valid, or references were unrelated. Additionally, Song et al. (2015) study [50] was removed because it was a family-based transmission disequilibrium test without control group. Finally, five articles met the quality requirements of meta-analysis and the flow diagram of our study selection is shown in Figure 1.

Flow diagram of selection process on genetic studies of MTNR polymorphisms with PCOS

Figure 1
Flow diagram of selection process on genetic studies of MTNR polymorphisms with PCOS
Figure 1
Flow diagram of selection process on genetic studies of MTNR polymorphisms with PCOS

Study characteristics

The eligible references in the present study involved two genes and six polymorphisms, MTNR1B gene (rs10830963, rs10830962, rs4753426, rs1562444, rs12792653) and MTNR1A (rs2119882). Four references, including Xu et al. (2019) [51], Yang et al. (2016) [52], Li et al. (2010) [53] and Wang et al. (2010) [39], reported the associations between rs10830963 and PCOS, including 1145 patients and 1408 controls. And two references, Xu et al. (2019) [51] and Li et al. (2011) [54], reported rs2119882, including 1680 patients and 1472 controls. Other SNPs had not been included in subsequent analysis due to insufficient data. All included studies with an NOS score more than 7, indicated a good level of quality (Table 1). The majority populations of the eligible references were Chinese and the methods used to detect gene polymorphisms were polymerase chain reaction (PCR) and sequencing. The studies characteristics are described in Table 2. Allele frequencies and genotypes of each study, and the outcome of HWE was listed in Table 3.

Table 1
The NOS
StudySelectionComparabilityExposureTotal Score
Definition adequateRepresentativenessSelection of controlsDefinition of controlsAscertainmentSame methodNon-response rate
Xu et al. (2019) ★ ★  ★ ★★ ★ ★ ★ 
Yang et al. (2016) ★ ★  ★ ★★ ★ ★ ★ 
Song et al. ★ ★   ★★ ★ ★ ★ 
Li et al. (2011) ★ ★ ★ ★ ★ ★ ★ ★ 
Li et al. (2010) ★ ★ ★ ★ ★ ★ ★ ★ 
Wang et al. (2010) ★  ★ ★ ★★ ★ ★ ★ 
StudySelectionComparabilityExposureTotal Score
Definition adequateRepresentativenessSelection of controlsDefinition of controlsAscertainmentSame methodNon-response rate
Xu et al. (2019) ★ ★  ★ ★★ ★ ★ ★ 
Yang et al. (2016) ★ ★  ★ ★★ ★ ★ ★ 
Song et al. ★ ★   ★★ ★ ★ ★ 
Li et al. (2011) ★ ★ ★ ★ ★ ★ ★ ★ 
Li et al. (2010) ★ ★ ★ ★ ★ ★ ★ ★ 
Wang et al. (2010) ★  ★ ★ ★★ ★ ★ ★ 
Table 2
Characteristics of the eligible studies in the meta-analysis
StudyYearEthnicityPatientsMTNRStudy periodStydy typeNOSCase/controlGenotyping methods
Xu et al. 01/2019 Chinese PCOS MTNR1A, MTNR1B March 2013–May 2015 Case–control 191+168/215 PCR- sequencing 
Yang et al. 03/2016 Chinese PCOS MTNR1B January 2012–May 2013 Case–control 182/196 PCR- sequencing 
Song et al. 09/2015 Chinese, Han, Shandong PCOS MTNR1A, MTNR1B July 2007–April 2014 Family trios 263(789) PCR- sequencing 
Li et al. 04/2011 Chinese, Han, Shandong PCOS MTNR1A September 2006–February 2008 Case–control 481/522 PCR Tm-shift 
Li et al. 10/2010 Chinese, Han, Shandong PCOS MTNR1B February 2005–January 2007 Case–control 526/547 PCR Tm-shift 
Wang et al. 11/2010 Chinese PCOS MTNR1B Case–control 364/687 TaqMan-PCR 
StudyYearEthnicityPatientsMTNRStudy periodStydy typeNOSCase/controlGenotyping methods
Xu et al. 01/2019 Chinese PCOS MTNR1A, MTNR1B March 2013–May 2015 Case–control 191+168/215 PCR- sequencing 
Yang et al. 03/2016 Chinese PCOS MTNR1B January 2012–May 2013 Case–control 182/196 PCR- sequencing 
Song et al. 09/2015 Chinese, Han, Shandong PCOS MTNR1A, MTNR1B July 2007–April 2014 Family trios 263(789) PCR- sequencing 
Li et al. 04/2011 Chinese, Han, Shandong PCOS MTNR1A September 2006–February 2008 Case–control 481/522 PCR Tm-shift 
Li et al. 10/2010 Chinese, Han, Shandong PCOS MTNR1B February 2005–January 2007 Case–control 526/547 PCR Tm-shift 
Wang et al. 11/2010 Chinese PCOS MTNR1B Case–control 364/687 TaqMan-PCR 
Table 3
Genotype and allele frequency of rs10830963 and rs2119882 in PCOS patients and controls
rs10830963GroupGenotype (n)χ2P-valueAllele (n)χ2P-value
CCCGGGCG
Xu et al. (2019) PCOS 125 169 65 30.002 0.000 419 299 29.351 0.000 
 Control 114 91 10   319 111   
Yang et al. (2016) PCOS 50 89 43 6.426 0.040 189 175 5.934 0.015 
 Control 70 98 28   238 154   
Li et al. (2010) PCOS 143 258 125 15.352 0.000 544 508 13.207 0.000 
 Control 185 281 81   651 443   
Wang et al. (2010) PCOS 126 185 53 1.201 0.549 437 291 0.746 0.388 
 Control 229 340 118   798 576   
rs10830963GroupGenotype (n)χ2P-valueAllele (n)χ2P-value
CCCGGGCG
Xu et al. (2019) PCOS 125 169 65 30.002 0.000 419 299 29.351 0.000 
 Control 114 91 10   319 111   
Yang et al. (2016) PCOS 50 89 43 6.426 0.040 189 175 5.934 0.015 
 Control 70 98 28   238 154   
Li et al. (2010) PCOS 143 258 125 15.352 0.000 544 508 13.207 0.000 
 Control 185 281 81   651 443   
Wang et al. (2010) PCOS 126 185 53 1.201 0.549 437 291 0.746 0.388 
 Control 229 340 118   798 576   
rs2119882GroupGenotype (n)χ2P-valueAllele (n)χ2P-value
TTTCCCTC
Xu et al. (2019) PCOS 68 165 126 16.446 0.000 301 417 17.507 0.000 
 Control 69 97 49   235 195   
Li et al. (2011) PCOS 167 215 99 9.962 0.007 549 413 9.824 0.002 
 Control 215 236 71   666 376   
rs2119882GroupGenotype (n)χ2P-valueAllele (n)χ2P-value
TTTCCCTC
Xu et al. (2019) PCOS 68 165 126 16.446 0.000 301 417 17.507 0.000 
 Control 69 97 49   235 195   
Li et al. (2011) PCOS 167 215 99 9.962 0.007 549 413 9.824 0.002 
 Control 215 236 71   666 376   

Quantitative synthesis

The results of the association between the MTNR polymorphisms and the PCOS risk are shown in Table 4. The forest plots of each genetic model are described in Figures 2 and 3.

Forest plots of PCOS risk and the polymorphism of rs10830963 C>G in MTNR1B

Figure 2
Forest plots of PCOS risk and the polymorphism of rs10830963 C>G in MTNR1B

(A) G vs. C in allele. (B) GG vs. CC in homozygote. (C) GC vs. CC in heterozygote. (D) GG+GC vs. CC in dominant. (E) GG vs. GC+CC in recessive. (F) GG+CC vs. GC in superdominant.

Figure 2
Forest plots of PCOS risk and the polymorphism of rs10830963 C>G in MTNR1B

(A) G vs. C in allele. (B) GG vs. CC in homozygote. (C) GC vs. CC in heterozygote. (D) GG+GC vs. CC in dominant. (E) GG vs. GC+CC in recessive. (F) GG+CC vs. GC in superdominant.

Forest plots of PCOS risk and the polymorphism of rs2119882 T>C in MTNR1A

Figure 3
Forest plots of PCOS risk and the polymorphism of rs2119882 T>C in MTNR1A

(A) C vs. T in allele. (B) CC vs. TT in homozygote. (C) CT vs. TT in heterozygote. (D) CC+CT vs. TT in dominant. (E) CC vs. CT+TT in recessive. (F) CC+TT vs. CT in superdominant.

Figure 3
Forest plots of PCOS risk and the polymorphism of rs2119882 T>C in MTNR1A

(A) C vs. T in allele. (B) CC vs. TT in homozygote. (C) CT vs. TT in heterozygote. (D) CC+CT vs. TT in dominant. (E) CC vs. CT+TT in recessive. (F) CC+TT vs. CT in superdominant.

Table 4
Six genetic models of MTNR genes
AlleleHomozygoteHeterozygote
SNPnOR95% CIPI2OR95% CIPI2OR95% CIPI2
rs10830963 1.38 [1.00, 1.89] 0.05 88% 2.05 [0.99, 4.21] 0.05 89% 1.21 [1.03, 1.42] 0.02 44% 
rs2129882 1.44 [1.25, 1.67] 0.00 54% 2.07 [1.55, 2.76] 0.00 34% 1.32 [1.05, 1.65] 0.02 56% 
AlleleHomozygoteHeterozygote
SNPnOR95% CIPI2OR95% CIPI2OR95% CIPI2
rs10830963 1.38 [1.00, 1.89] 0.05 88% 2.05 [0.99, 4.21] 0.05 89% 1.21 [1.03, 1.42] 0.02 44% 
rs2129882 1.44 [1.25, 1.67] 0.00 54% 2.07 [1.55, 2.76] 0.00 34% 1.32 [1.05, 1.65] 0.02 56% 
DominantRecessiveSuperdominant
SNPnOR95% CIPI2OR95% CIPI2OR95% CIPI2
rs10830963 1.40 [1.00, 1.95] 0.05 78% 1.79 [0.98, 3.27] 0.06 87% 0.99 [0.85, 1.14] 0.87 0% 
rs2129882 1.59 [1.05, 2.41] 0.03 69% 1.72 [1.34, 2.22] 0.00 0% 1.00 [0.82, 1.22] 0.99 0% 
DominantRecessiveSuperdominant
SNPnOR95% CIPI2OR95% CIPI2OR95% CIPI2
rs10830963 1.40 [1.00, 1.95] 0.05 78% 1.79 [0.98, 3.27] 0.06 87% 0.99 [0.85, 1.14] 0.87 0% 
rs2129882 1.59 [1.05, 2.41] 0.03 69% 1.72 [1.34, 2.22] 0.00 0% 1.00 [0.82, 1.22] 0.99 0% 

Analysis of rs10830963 polymorphisms in MTNR1B

To study the relationship between rs10830963 (C>G) and PCOS risk, we included four case–control studies (Table 3) and analyzed them with six genetic models [55] (Table 4, Figure 2). Among them, in the heterozygote model, the variation was significantly associated with PCOS occurrence (OR: 1.21, 95% CI: 1.03–1.42, P=0.02, I2 = 44%). In the allelic, homozygote and dominant model, the variations were weakly associated to PCOS risk (OR: 1.38, 95% CI: 1.00–1.89, P=0.05, I2 = 88%; OR: 2.05, 95% CI: 0.99–4.21, P=0.05, I2 = 89%; OR: 1.40, 95% CI: 1.00–1.95, P=0.05, I2 = 78%). In the recessive model, this mutation had a weaker association (OR: 1.79, 95% CI: 0.98–3.27, P=0.06, I2 = 87%). And in last model, the superdominant model, no statistically significant association were found (OR: 0.99, 95% CI: 0.85–1.14, P=0.87, I2 = 0%). All studies were evenly distributed on both sides of the center line, and no obvious publication bias was found.

rs2119882 polymorphisms analysis in MTNR1A

To study the association between rs2119882 and PCOS risk, we included two case–control studies (Table 3) and used six genetic models for analysis (Table 4, Figure 3). In five genetic models, allelic, homozygote, heterozygote, dominant, recessive and superdominant, significant statistical associations were found (OR: 1.44, 95% CI: 1.25–1.67, P<0.001, I2 = 54%; OR: 2.07, 95% CI: 1.55–2.76, P<0.001, I2 = 34%; OR: 1.32, 95% CI: 1.05–1.65, P=0.02, I2 = 56%; OR: 1.59, 95% CI: 1.05–2.41, P=0.03, I2 = 69%; OR: 1.72, 95% CI: 1.34–2.22, P<0.001, I2 = 0%). However, in the superdominant model, no significant statistical association was found (OR: 1.00, 95% CI: 0.82–1.22, P=0.99, I2 = 0%). All models had low or moderate heterogeneity, so the fixed-effect models were used to analyze them.

Sensitivity analysis

For genetic models with high heterogeneity (I2 and P≤0.01), a sensitivity analysis was conducted by removing all the eligible references one by one in each model to assess the influence of each reference heterogeneity on the whole model analysis [56]. More details in forest plots and funnel plots are shown in Figure 4 and Table 5. After excluding the study of Wang et al. (2010) [39], the allelic, homozygote, dominant and recessive models in rs10830963 had significant statistical correlation with PCOS risk (OR: 1.58, 95% CI: 1.23–2.02, P=0.000, I2 = 70%; OR: 2.78, 95% CI: 1.51–5.10, P=0.001, I2 = 73%; OR: 1.58, 95% CI: 1.31–1.90, P=0.000, I2 = 50%; OR: 2.30, 95% CI: 1.40–3.77, P=0.001, I2 = 67%).

Forest plots and funnel plots of rs10830963 when Wang et al.’s study was removed

Figure 4
Forest plots and funnel plots of rs10830963 when Wang et al.’s study was removed

(A,E) G vs. C in allele. (B,F) GG vs. CC in homozygote. (C,G) GG+GC vs. CC in dominant. (D,H) GG vs. GC+CC in recessive.

Figure 4
Forest plots and funnel plots of rs10830963 when Wang et al.’s study was removed

(A,E) G vs. C in allele. (B,F) GG vs. CC in homozygote. (C,G) GG+GC vs. CC in dominant. (D,H) GG vs. GC+CC in recessive.

Table 5
Sensitivity analysis of rs10830963 C> G
ModelOR95% CIPI2
Allele 1.58 [1.34, 2.02] 0.000 70% 
Homozygote 2.78 [1.51, 5.10] 0.001 73% 
Dominant 1.58 [1.31, 1.90] 0.000 50% 
Recessive 2.30 [1.40, 3.77] 0.001 67% 
ModelOR95% CIPI2
Allele 1.58 [1.34, 2.02] 0.000 70% 
Homozygote 2.78 [1.51, 5.10] 0.001 73% 
Dominant 1.58 [1.31, 1.90] 0.000 50% 
Recessive 2.30 [1.40, 3.77] 0.001 67% 

Publication bias

Due to the limited number of available references [44], publication bias was investigated only for the relationship between rs10830963 and PCOS risk by Stata MP 16.0 software. The result of heterozygote model (GC vs. CC) is shown in Figure 5. In Egger’s test, P was 0.469, while similarly in Begg’s test P was 0.497. Because both the P-values were more than 0.1, so no publication bias was found. Relationship between rs10830963 and PCOS risk was relatively stable and convincing.

Egger’s test and Begg’s funnel plot of rs10830963 for heterozygote model

Figure 5
Egger’s test and Begg’s funnel plot of rs10830963 for heterozygote model

(A) Egger’s regression test. (B) Begg’s funnel plot.

Figure 5
Egger’s test and Begg’s funnel plot of rs10830963 for heterozygote model

(A) Egger’s regression test. (B) Begg’s funnel plot.

Discussion

As one among common endocrine disorders in gynecological reproduction, the PCOS pathogenesis is still unclear. Family studies revealed aggregation in PCOS [57], but no precise genetic mechanism can explain the etiology. Because these patients have hyperinsulinemia and IR, genes like MTNR1A/B related to insulin secretion possibly play a crucial role in PCOS progression. At the same time, recently several researches have been conducted or been registered [58] to determine the relationship between MTNR genes and PCOS susceptibility. But these researches have shown opposite results, so our study aims to further elaborate the relationship between MTNR1A/B gene and the risk of PCOS.

Melatonin works by activating two important G protein-coupled receptors, MT1 and MT2 [59]. By querying this National Center for Biotechnology Information (NCBI) database, it is known that the MTNR1A gene that encodes MT1 is located on the chromosome 4q35.2, and the MTNR1B gene of MT2 is located on chromosome 11q14.3. Rs10830963 is located in the intron region between the two exons encoding MTNR1B, while rs2119882 is located in the MTNR1A promoter region. Although these relative positions of SNPs in MTNR are different, the results for all genetic models in this two SNPs are still similar. However, the limitation of our study is that we only discussed from the perspective of MTNR gene while other SNPs are ignored. Because the pathogenesis of PCOS is complex and different genome-wide association studies (GWASs) conclusions are more heterogeneous [60], multiple SNPs mutations may affect metabolic and endocrine profiles in the same PCOS patient, such as insulin receptor gene (INSR) and luteinizing hormone/choriogonadotropin receptor (LHCGR) [61]. Therefore, further research is expected to combining multi-racial GWAS results of arrays by bioinformatics [62,63] and take other gene receptor into consideration to analysis-related molecular pathways [64].

In our meta-analysis, we find that in the heterozygote model, MTNR1B rs10830963 polymorphism is significantly associated with the PCOS occurrence. Through the sensitivity analysis, after excluding Wang et al. study [39], multiple model analyses showed that rs10830963 also has a significant correlation (the allelic, homozygote, dominant and recessive models). This may be due to the large heterogeneity of the present study. First, the study was conducted 10 years ago and its population was not in H–W equilibrium, possibly due to the bias in collecting participants in a limited geographical region. Second, the article does not report the period for recruiting the participants. Therefore, the study cannot rule out the effect of selection bias on the population. Finally, the SNPs are in a strong linkage disequilibrium and there may be a certain association between linkage markers. In addition, due to the large heterogeneity in different ethnicity, our study still needs large sample, multi-center and multi-ethnic studies to confirm.

Moreover, obese women in PCOS patients can be complicated with T2DM [65]. At the same time, their IR level is higher than normal, which can effectively predict impaired glucose tolerance and the occurrence of metabolic syndrome [66]. MTNR is also a candidate gene for IR and gestational diabetes mellitus [38]. So, further studies can take the clinical heterogeneity of PCOS into consideration and divide patients into different groups, such as obese and non-obese groups by body mass index [67], in following subgroup and phenotype analysis of SNPs.

As a result of weak endocrine regulation of melatonin through mutation receptor, to some extent, our meta-analysis supports the feasibility and acceptability of appropriate melatonin supplementation for PCOS [68,69]. At the same time, some studies have suggested that inositol can also be used to an novel and additional treatment of PCOS to improve symptoms [70–72], because as an insulin sensitizer it can decrease the levels of androgen, improve glucose metabolism [73], and restore spontaneous ovulation [74,75]. But due to the limited study of melatonin and inositol combination therapy [76,77], the clinical outcomes of IVF are still uncertain [78,79]. Therefore, the follow-up systematic review and meta-analysis is recommended to further confirm the combination therapy effect of melatonin and other drugs for PCOS.

Conclusion

The SNPs rs10830963 and rs2119882 of MTNR1B and MTNR1A, are associated with a much higher PCOS risk in Chinese population. And above conclusions still require confirmation by future study including much larger multi-ethnic studies and other SNPs instead of the above conclusions.

Data Availability

The analytical data are all included in the published articles and the final supplementary materials.

Competing Interests

The authors declare that there are no competing interests associated with the manuscript.

Funding

This work was supported by the National Key R&D Program of China [grant number 2019YFA0110900 (to Ying-pu Sun and Jiawei Xu), 2019YFA0802200 (to Jiawei Xu)]; the Scientific and Technological Innovation Talent Project of Universities of Henan Province [grant number 20HASTIT045 (to Jiawei Xu)].

Author Contribution

Shiqi Yi and Jiawei Xu designed the present study. Shiqi Yi and Hao Shi conducted literature searches, statistical analysis, and charting. Jiawei Xu provided guidance on the genetics section of this article. Wenbo Li and Qian Li finished quality evaluations. Shiqi Yi wrote the draft and completed the present paper with the assistance of Ying-pu Sun. All authors agree with the conclusions of our study. Data sorting: Shiqi Yi, Hao Shi, Wenbo Li and Qian Li. Methods: Shiqi Yi and Jiawei Xu. Writing-draft: Shiqi Yi; Writing-reviewing and modifying: Ying-pu Sun.

Acknowledgements

We thank all participants for their contributions to this meta-analysis.

Abbreviations

     
  • CI

    confidence interval

  •  
  • H–W equilibrium/HWE

    Hardy–Weinberg equilibrium

  •  
  • GWAS

    genome-wide association study

  •  
  • IR

    insulin resistance

  •  
  • IVF

    in vitro fertilization

  •  
  • MTNR

    melatonin receptor

  •  
  • NOS

    Newcastle–Ottawa Scale

  •  
  • OR

    odds ratio

  •  
  • PCOS

    polycystic ovarian syndrome

  •  
  • SNP

    single nucleotide polymorphism

  •  
  • T2DM

    type 2 diabetes mellitus

References

References
1.
Dubocovich
M.L.
,
Delagrange
P.
,
Krause
D.N.
,
Sugden
D.
,
Cardinali
D.P.
and
Olcese
J.
(
2010
)
International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, classification, and pharmacology of G protein-coupled melatonin receptors
.
Pharmacol. Rev.
62
,
343
380
[PubMed]
2.
Doosti-Irani
A.
,
Ostadmohammadi
V.
,
Mirhosseini
N.
et al.
(
2018
)
The effects of melatonin supplementation on glycemic control: a systematic review and meta-analysis of randomized controlled trials
.
Horm. Metab. Res.
50
,
783
790
[PubMed]
3.
Shabani
A.
,
Foroozanfard
F.
,
Kavossian
E.
et al.
(
2019
)
Effects of melatonin administration on mental health parameters, metabolic and genetic profiles in women with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial
.
J. Affect. Disord.
250
,
51
56
[PubMed]
4.
Lyssenko
V.
,
Nagorny
C.L.F.
,
Erdos
M.R.
et al.
(
2009
)
Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion
.
Nat. Genet.
41
,
82
88
[PubMed]
5.
Woo
M.M.
,
Tai
C.J.
,
Kang
S.K.
,
Nathwani
P.S.
,
Pang
S.F.
and
Leung
P.C.
(
2001
)
Direct action of melatonin in human granulosa-luteal cells
.
J. Clin. Endocrinol. Metab.
86
,
4789
4797
[PubMed]
6.
Yie
S.M.
,
Niles
L.P.
and
Younglai
E.V.
(
1995
)
Melatonin receptors on human granulosa cell membranes
.
J. Clin. Endocrinol. Metab.
80
,
1747
1749
[PubMed]
7.
Li
Y.
,
Fang
L.
,
Yu
Y.
et al.
(
2019
)
Higher melatonin in the follicle fluid and MT2 expression in the granulosa cells contribute to the OHSS occurrence
.
Reprod. Biol. Endocrinol.
17
,
37
[PubMed]
8.
Scarinci
E.
,
Tropea
A.
,
Notaristefano
G.
et al.
(
2019
)
“Hormone of darkness” and human reproductive process: direct regulatory role of melatonin in human corpus luteum
.
J. Endocrinol. Invest.
42
,
1191
1197
[PubMed]
9.
Tong
J.
,
Sheng
S.
,
Sun
Y.
et al.
(
2017
)
Melatonin levels in follicular fluid as markers for IVF outcomes and predicting ovarian reserve
.
Reproduction
153
,
443
451
[PubMed]
10.
Dantas-Ferreira
R.F.
,
Raingard
H.
,
Dumont
S.
et al.
(
2018
)
Melatonin potentiates the effects of metformin on glucose metabolism and food intake in high-fat-fed rats
.
Endocrinol. Diabetes Metab.
1
,
e00039
[PubMed]
11.
Mokhtari
F.
,
Akbari Asbagh
F.
,
Azmoodeh
O.
,
Bakhtiyari
M.
and
Almasi-Hashiani
A.
(
2019
)
Effects of melatonin administration on chemical pregnancy rates of polycystic ovary syndrome patients undergoing intrauterine insemination: a randomized clinical trial
.
Int. J. Fertil. Steril.
13
,
225
229
[PubMed]
12.
Tarquini
R.
,
Bruni
V.
,
Perfetto
F.
,
Bigozzi
L.
,
Tapparini
L.
and
Tarquini
B.
(
1996
)
Hypermelatoninemia in women with polycystic ovarian syndrome
.
Eur. J. Contracept. Reprod. Health Care
1
,
349
350
[PubMed]
13.
Luboshitzky
R.
,
Qupti
G.
,
Ishay
A.
,
Shen-Orr
Z.
,
Futerman
B.
and
Linn
S.
(
2001
)
Increased 6-sulfatoxymelatonin excretion in women with polycystic ovary syndrome
.
Fertil. Steril.
76
,
506
510
[PubMed]
14.
Luboshitzky
R.
,
Herer
P.
and
Shen-Orr
Z.
(
2004
)
Urinary 6-sulfatoxymelatonin excretion in hyperandrogenic women: the effect of cyproterone acetate-ethinyl estradiol treatment
.
Exp. Clin. Endocrinol. Diab.
112
,
102
107
[PubMed]
15.
Goodman
N.F.
,
Cobin
R.H.
,
Futterweit
W.
et al.
(
2015
)
American association of clinical endocrinologists, American college of 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
.
Endocr. Pract.
21
,
1291
1300
[PubMed]
16.
Bozdag
G.
,
Mumusoglu
S.
,
Zengin
D.
,
Karabulut
E.
and
Yildiz
B.O.
(
2016
)
The prevalence and phenotypic features of polycystic ovary syndrome: a systematic review and meta-analysis
.
Hum. Reprod.
31
,
2841
2855
[PubMed]
17.
Wolf
W.M.
,
Wattick
R.A.
,
Kinkade
O.N.
and
Olfert
M.D.
(
2018
)
Geographical prevalence of polycystic ovary syndrome as determined by region and race/ethnicity
.
Int. J. Environ. Res. Public Health
15
,
2589
18.
Li
R.
,
Zhang
Q.
,
Yang
D.
et al.
(
2013
)
Prevalence of polycystic ovary syndrome in women in China: a large community-based study
.
Hum. Reprod.
28
,
2562
2569
[PubMed]
19.
Otaghi
M.
,
Azami
M.
,
Khorshidi
A.
,
Borji
M.
and
Tardeh
Z.
(
2019
)
The association between metabolic syndrome and polycystic ovary syndrome: a systematic review and meta-analysis
.
Diabetes Metab. Syndr.
13
,
1481
1489
20.
Yilmaz
B.
,
Vellanki
P.
,
Ata
B.
and
Yildiz
B.O.
(
2018
)
Diabetes mellitus and insulin resistance in mothers, fathers, sisters, and brothers of women with polycystic ovary syndrome: a systematic review and meta-analysis
.
Fertil. Steril.
110
,
523.e14
533.e14
21.
Chen
Z.-J.
,
Zhao
H.
,
He
L.
et al.
(
2011
)
Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3
.
Nat. Genet.
43
,
55
59
[PubMed]
22.
Wood
J.R.
,
Dumesic
D.A.
,
Abbott
D.H.
and
Strauss
J.F.
(
2007
)
Molecular abnormalities in oocytes from women with polycystic ovary syndrome revealed by microarray analysis
.
J. Clin. Endocrinol. Metab.
92
,
705
713
[PubMed]
23.
Aguilar
M.
,
Bhuket
T.
,
Torres
S.
,
Liu
B.
and
Wong
R.J.
(
2015
)
Prevalence of the metabolic syndrome in the United States, 2003-2012
.
JAMA
313
,
1973
1974
[PubMed]
24.
Shi
Y.
,
Zhao
H.
,
Shi
Y.
et al.
(
2012
)
Genome-wide association study identifies eight new risk loci for polycystic ovary syndrome
.
Nat. Genet.
44
,
1020
1025
[PubMed]
25.
Chen
Z.J.
,
Zhao
H.
,
He
L.
et al.
(
2011
)
Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3
.
Nat. Genet.
43
,
55
59
[PubMed]
26.
Brower
M.A.
,
Jones
M.R.
,
Rotter
J.I.
et al.
(
2015
)
Further investigation in europeans of susceptibility variants for polycystic ovary syndrome discovered in genome-wide association studies of Chinese individuals
.
J. Clin. Endocrinol. Metab.
100
,
E182
E186
[PubMed]
27.
Louwers
Y.V.
,
Stolk
L.
,
Uitterlinden
A.G.
and
Laven
J.S.
(
2013
)
Cross-ethnic meta-analysis of genetic variants for polycystic ovary syndrome
.
J. Clin. Endocrinol. Metab.
98
,
E2006
E2012
[PubMed]
28.
Goodarzi
M.O.
,
Jones
M.R.
,
Li
X.
et al.
(
2012
)
Replication of association of DENND1A and THADA variants with polycystic ovary syndrome in European cohorts
.
J. Med. Genet.
49
,
90
95
[PubMed]
29.
Liu
A.L.
,
Xie
H.J.
,
Xie
H.Y.
et al.
(
2017
)
Association between fat mass and obesity associated (FTO) gene rs9939609 A/T polymorphism and polycystic ovary syndrome: a systematic review and meta-analysis
.
BMC Med. Genet.
18
,
89
[PubMed]
30.
Wojciechowski
P.
,
Lipowska
A.
,
Rys
P.
et al.
(
2012
)
Impact of FTO genotypes on BMI and weight in polycystic ovary syndrome: a systematic review and meta-analysis
.
Diabetologia
55
,
2636
2645
[PubMed]
31.
Laven
J.S.E.
(
2019
)
Follicle stimulating hormone receptor (FSHR) polymorphisms and polycystic ovary syndrome (PCOS)
.
Front. Endocrinol. (Lausanne)
10
,
23
[PubMed]
32.
Mutharasan
P.
,
Galdones
E.
,
Peñalver Bernabé
B.
et al.
(
2013
)
Evidence for chromosome 2p16.3 polycystic ovary syndrome susceptibility locus in affected women of European ancestry
.
J. Clin. Endocrinol. Metab.
98
,
E185
E190
[PubMed]
33.
Welt
C.K.
,
Styrkarsdottir
U.
,
Ehrmann
D.A.
et al.
(
2012
)
Variants in DENND1A are associated with polycystic ovary syndrome in women of European ancestry
.
J. Clin. Endocrinol. Metab.
97
,
E1342
E1347
[PubMed]
34.
Siddamalla
S.
,
Reddy
T.V.
,
Govatati
S.
et al.
(
2018
)
Vitamin D receptor gene polymorphisms and risk of polycystic ovary syndrome in South Indian women
.
Gynecol. Endocrinol.
34
,
161
165
[PubMed]
35.
Shi
X.Y.
,
Huang
A.P.
,
Xie
D.W.
and
Yu
X.L.
(
2019
)
Association of vitamin D receptor gene variants with polycystic ovary syndrome: a meta-analysis
.
BMC Med. Genet.
20
,
32
[PubMed]
36.
Deswal
R.
,
Nanda
S.
and
Dang
A.S.
(
2017
)
Unveiling the association between vitamin D receptor and poly cystic ovary syndrome - a systematic review and meta-analysis
.
Int. J. Vitam. Nutr. Res.
87
,
207
218
[PubMed]
37.
de Luis Román
D.A.
,
Primo
D.
,
Aller
R.
and
Izaola
O.
(
2019
)
Association of the rs10830963 polymorphism in MTNR1B with fasting glucose, serum adipokine levels and components of metabolic syndrome in adult obese subjects
.
Nutr. Hosp.
36
,
60
65
[PubMed]
38.
Li
C.
,
Qiao
B.
,
Zhan
Y.
et al.
(
2013
)
Association between genetic variations in MTNR1A and MTNR1B genes and gestational diabetes mellitus in Han Chinese women
.
Gynecol. Obstet. Invest.
76
,
221
227
[PubMed]
39.
Wang
L.
,
Wang
Y.
,
Zhang
X.
et al.
(
2010
)
Common genetic variation in MTNR1B is associated with serum testosterone, glucose tolerance, and insulin secretion in polycystic ovary syndrome patients
.
Fertil. Steril.
94
,
2486.e24892
2489.e24892
40.
Moher
D.
,
Liberati
A.
,
Tetzlaff
J.
,
Altman
D.G.
and
PRISMA.Group
(
2009
)
Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement
.
PLoS Med.
6
,
e1000097
[PubMed]
41.
Wu
Y.T.
,
Li
X.
,
Liu
Z.L.
et al.
(
2017
)
Hepatitis B virus reactivation and antiviral prophylaxis during lung cancer chemotherapy: A systematic review and meta-analysis
.
PLoS ONE
12
,
e0179680
[PubMed]
42.
Rotterdam EA-SPcwg
(
2004
)
Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS)
.
Hum. Reprod.
19
,
41
47
[PubMed]
43.
Stang
A.
(
2010
)
Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses
.
Eur. J. Epidemiol.
25
,
603
605
[PubMed]
44.
Wu
H.
,
Yu
K.
and
Yang
Z.
(
2015
)
Associations between TNF-α and interleukin gene polymorphisms with polycystic ovary syndrome risk: a systematic review and meta-analysis
.
J. Assist. Reprod. Genet.
32
,
625
634
[PubMed]
45.
Chandler
J.
and
Hopewell
S.
(
2013
)
Cochrane methods–twenty years experience in developing systematic review methods
.
Syst. Rev.
2
,
76
[PubMed]
46.
Yan
A.
,
Cai
G.
,
Fu
N.
et al.
(
2016
)
Relevance study on cerebral infarction and resistin gene polymorphism in Chinese Han population
.
Aging Dis.
7
,
593
603
[PubMed]
47.
Minelli
C.
,
Thompson
J.R.
,
Abrams
K.R.
,
Thakkinstian
A.
and
Attia
J.
(
2005
)
The choice of a genetic model in the meta-analysis of molecular association studies
.
Int. J. Epidemiol.
34
,
1319
1328
[PubMed]
48.
Lewis
C.M.
and
Knight
J.
(
2012
)
Introduction to genetic association studies
.
Cold Spring Harb. Protoc.
2012
,
297
306
[PubMed]
49.
Huedo-Medina
T.B.
,
Sanchez-Meca
J.
,
Marin-Martinez
F.
and
Botella
J.
(
2006
)
Assessing heterogeneity in meta-analysis: Q statistic or I2 index?
Psychol. Methods
11
,
193
206
[PubMed]
50.
Song
X.
,
Sun
X.
,
Ma
G.
et al.
(
2015
)
Family association study between melatonin receptor gene polymorphisms and polycystic ovary syndrome in Han Chinese
.
Eur. J. Obstet. Gynecol. Reprod. Biol.
195
,
108
112
[PubMed]
51.
Xu
X.H.
,
Kou
L.C.
,
Wang
H.M.
,
Bo
C.M.
and
Song
X.C.
(
2019
)
Genetic polymorphisms of melatonin receptors 1A and 1B may result in disordered lipid metabolism in obese patients with polycystic ovary syndrome
.
Mol. Med. Rep.
19
,
2220
2230
[PubMed]
52.
Yang
J.F.
,
Yang
H.M.
and
C
Z.J.
(
2016
)
Association of rs10830963 SNPs in the melatonin receptor (MTNR IB) gene with polycystic ovary syndrome
.
J. Pract. Gynecol. Endocrinol.
3
,
145
148
53.
Li
C.
,
Shi
Y.H.
,
You
L.
,
Wang
L.C.
and
Chen
Z.J.
(
2011
)
Association of rs10830963 and rs10830962 SNPs in the melatonin receptor (MTNR1B) gene among Han Chinese women with polycystic ovary syndrome
.
Mol. Hum. Reprod.
17
,
193
198
[PubMed]
54.
Li
C.
,
Shi
Y.
,
You
L.
,
Wang
L.
and
Chen
Z.-J.
(
2011
)
Melatonin receptor 1A gene polymorphism associated with polycystic ovary syndrome
.
Gynecol. Obstet. Invest.
72
,
130
134
[PubMed]
55.
Thakkinstian
A.
,
McElduff
P.
,
D’Este
C.
,
Duffy
D.
and
Attia
J.
(
2005
)
A method for meta-analysis of molecular association studies
.
Stat. Med.
24
,
1291
1306
[PubMed]
56.
Champagne
N.
,
Eadie
L.
,
Regan
L.
and
Wilson
P.
(
2019
)
The effectiveness of ultrasound in the detection of fractures in adults with suspected upper or lower limb injury: a systematic review and subgroup meta-analysis
.
BMC Emerg. Med.
19
,
17
[PubMed]
57.
Song
X.
,
Sun
X.
,
Ma
G.
et al.
(
2015
)
Family association study between melatonin receptor gene polymorphisms and polycystic ovary syndrome in Han Chinese
.
Eur. J. Obstet. Gynecol. Reprod. Biol.
195
,
108
112
[PubMed]
58.
Iwata
M.
,
Carvalho
K.
,
Maciel
G.
,
Neto
J.
,
Baracat
E.
and
Maria
J.
(
2016
)
MTNR1B melatonin receptor gene polymorphisms and carbohydrate metabolism in young women with polycystic ovary syndrome
.
Gynecol. Endocrinol.
32
,
84
59.
Jockers
R.
,
Delagrange
P.
,
Dubocovich
M.L.
et al.
(
2016
)
Update on melatonin receptors: IUPHAR Review 20
.
Br. J. Pharmacol.
173
,
2702
2725
[PubMed]
60.
Sun
Y.
,
Yuan
Y.
,
Yang
H.
et al.
(
2016
)
Association between common genetic variants and polycystic ovary syndrome risk in a Chinese Han population
.
J. Clin. Res. Pediatr. Endocrinol.
8
,
405
410
[PubMed]
61.
Cui
L.
,
Li
G.
,
Zhong
W.
et al.
(
2015
)
Polycystic ovary syndrome susceptibility single nucleotide polymorphisms in women with a single PCOS clinical feature
.
Hum. Reprod.
30
,
732
736
[PubMed]
62.
Lee
H.
,
Oh
J.Y.
,
Sung
Y.A.
and
Chung
H.W.
(
2016
)
A genetic risk score is associated with polycystic ovary syndrome-related traits
.
Hum. Reprod.
31
,
209
215
[PubMed]
63.
Shen
H.
,
Liang
Z.
,
Zheng
S.
and
Li
X.
(
2017
)
Pathway and network-based analysis of genome-wide association studies and RT-PCR validation in polycystic ovary syndrome
.
Int. J. Mol. Med.
40
,
1385
1396
[PubMed]
64.
Vitale
S.G.
,
Lagana
A.S.
,
Nigro
A.
et al.
(
2016
)
Peroxisome proliferator-activated receptor modulation during metabolic diseases and cancers: master and minions
.
PPAR Res.
2016
,
6517313
[PubMed]
65.
Kakoly
N.S.
,
Khomami
M.B.
,
Joham
A.E.
et al.
(
2018
)
Ethnicity, obesity and the prevalence of impaired glucose tolerance and type 2 diabetes in PCOS: a systematic review and meta-regression
.
Hum. Reprod. Update
24
,
455
467
[PubMed]
66.
Liang
S.J.
,
Liou
T.H.
,
Lin
H.W.
,
Hsu
C.S.
,
Tzeng
C.R.
and
Hsu
M.I.
(
2012
)
Obesity is the predominant predictor of impaired glucose tolerance and metabolic disturbance in polycystic ovary syndrome
.
Acta Obstet. Gynecol. Scand.
91
,
1167
1172
[PubMed]
67.
Jones
M.R.
,
Brower
M.A.
,
Xu
N.
et al.
(
2015
)
Systems genetics reveals the functional context of PCOS loci and identifies genetic and molecular mechanisms of disease heterogeneity
.
PLoS Genet.
11
,
e1005455
[PubMed]
68.
Mokhtari
F.
,
Akbari Asbagh
F.
,
Azmoodeh
O.
,
Bakhtiyari
M.
and
Almasi-Hashiani
A.
(
2019
)
Effects of melatonin administration on chemical pregnancy rates of polycystic ovary syndrome patients undergoing intrauterine insemination: a randomized clinical trial
.
Int. J. Fertil. Steril.
13
,
225
229
[PubMed]
69.
Hu
K.L.
,
Ye
X.
,
Wang
S.
and
Zhang
D.
(
2020
)
Melatonin application in assisted reproductive technology: a systematic review and meta-analysis of randomized trials
.
Front. Endocrinol. (Lausanne)
11
,
160
[PubMed]
70.
Lagana
A.S.
,
Rossetti
P.
,
Sapia
F.
et al.
(
2017
)
Evidence-based and patient-oriented inositol treatment in polycystic ovary syndrome: changing the perspective of the disease
.
Int. J. Endocrinol. Metab.
15
,
e43695
[PubMed]
71.
Facchinetti
F.
,
Appetecchia
M.
,
Aragona
C.
et al.
(
2020
)
Experts’ opinion on inositols in treating polycystic ovary syndrome and non-insulin dependent diabetes mellitus: a further help for human reproduction and beyond
.
Expert Opin. Drug Metab. Toxicol.
16
,
255
274
[PubMed]
72.
Paul
C.
,
Lagana
A.S.
,
Maniglio
P.
,
Triolo
O.
and
Brady
D.M.
(
2016
)
Inositol’s and other nutraceuticals’ synergistic actions counteract insulin resistance in polycystic ovarian syndrome and metabolic syndrome: state-of-the-art and future perspectives
.
Gynecol. Endocrinol.
32
,
431
438
[PubMed]
73.
Unfer
V.
,
Facchinetti
F.
,
Orru
B.
,
Giordani
B.
and
Nestler
J.
(
2017
)
Myo-inositol effects in women with PCOS: a meta-analysis of randomized controlled trials
.
Endocr. Connect.
6
,
647
658
[PubMed]
74.
Papaleo
E.
,
Unfer
V.
,
Baillargeon
J.P.
et al.
(
2007
)
Myo-inositol in patients with polycystic ovary syndrome: a novel method for ovulation induction
.
Gynecol. Endocrinol.
23
,
700
703
[PubMed]
75.
Lagana
A.S.
,
Garzon
S.
,
Casarin
J.
,
Franchi
M.
and
Ghezzi
F.
(
2018
)
Inositol in polycystic ovary syndrome: restoring fertility through a pathophysiology-based approach
.
Trends Endocrinol. Metab.
29
,
768
780
[PubMed]
76.
Pacchiarotti
A.
,
Carlomagno
G.
,
Antonini
G.
and
Pacchiarotti
A.
(
2016
)
Effect of myo-inositol and melatonin versus myo-inositol, in a randomized controlled trial, for improving in vitro fertilization of patients with polycystic ovarian syndrome
.
Gynecol. Endocrinol.
32
,
69
73
[PubMed]
77.
Unfer
V.
,
Raffone
E.
,
Rizzo
P.
and
Buffo
S.
(
2011
)
Effect of a supplementation with myo-inositol plus melatonin on oocyte quality in women who failed to conceive in previous in vitro fertilization cycles for poor oocyte quality: a prospective, longitudinal, cohort study
.
Gynecol. Endocrinol.
27
,
857
861
[PubMed]
78.
Banaszewska
B.
,
Pawelczyk
L.
and
Spaczynski
R.
(
2019
)
Current and future aspects of several adjunctive treatment strategies in polycystic ovary syndrome
.
Reprod. Biol.
19
,
309
315
[PubMed]
79.
Showell
M.G.
,
Mackenzie-Proctor
R.
,
Jordan
V.
,
Hodgson
R.
and
Farquhar
C.
(
2018
)
Inositol for subfertile women with polycystic ovary syndrome
.
Cochrane Database Syst. Rev.
12
,
CD012378
[PubMed]

Author notes

*

These authors contributed equally to this work.

This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).