Effect of acupuncture and metformin on insulin sensitivity in women with polycystic ovary syndrome and insulin resistance: a three-armed randomized controlled trial.

STUDY QUESTION: Does acupuncture improve insulin sensitivity more effectively than metformin or sham acupuncture in women with polycystic ovary syndrome (PCOS) and insulin resistance (IR)? SUMMARY ANSWER: Among women with PCOS and IR, acupuncture was not more effective than metformin or sham acupuncture in improving insulin sensitivity. WHAT IS KNOWN ALREADY: Uncontrolled trials have shown that acupuncture improved insulin sensitivity with fewer side effects compared with metformin in women with PCOS and IR. However, data from randomized trials between acupuncture and metformin or sham acupuncture are lacking. STUDY DESIGN, SIZE, DURATION: This was a three-armed randomized controlled trial enrolling a total of 342 women with PCOS and IR from three hospitals between November 2015 and February 2018, with a 3-month follow-up until October 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women aged from 18 to 40 years with PCOS and homeostasis model assessment of insulin resistance (HOMA-IR) ≥2.14 were randomly assigned (n = 114 per group) to receive true acupuncture plus placebo (true acupuncture), metformin plus sham acupuncture (metformin, 0.5 g three times daily) or sham acupuncture plus placebo (sham acupuncture) for 4 months, with an additional 3-month follow-up. True or sham acupuncture was given three times per week, and 0.5 g metformin or placebo was given three times daily. The primary outcome was change in HOMA-IR from baseline to 4 months after baseline visit. Secondary outcomes included changes in the glucose AUC during an oral glucose tolerance test, BMI and side effects at 4 months after baseline visit. MAIN RESULTS AND THE ROLE OF CHANCE: After 4 months of treatment, the changes of HOMA-IR were -0.5 (decreased 14.7%) in the true acupuncture group, -1.0 (decreased 25.0%) in the metformin group and -0.3 (decreased 8.6%) in the sham acupuncture group, when compared with baseline. True acupuncture is not as effective as metformin in improving HOMA-IR at 4 months after baseline visit (difference, 0.6; 95% CI, 0.1-1.1). No significant difference was found in change in HOMA-IR between true and sham acupuncture groups at 4 months after baseline visit (difference, -0.2; 95% CI, -0.7 to 0.3). During the 4 months of treatment, gastrointestinal side effects were more frequent in the metformin group, including diarrhea, nausea, loss of appetite, fatigue, vomiting and stomach discomfort (31.6%, 13.2%, 11.4%, 8.8%, 14.0% and 8.8%, respectively). Bruising was more common in the true acupuncture group (14.9%). LIMITATIONS, REASONS FOR CAUTION: This study might have underestimated the sample size in the true acupuncture group with 4 months of treatment to enable detection of statistically significant changes in HOMA-IR with fixed acupuncture (i.e. a non-personalized protocol). Participants who withdrew because of pregnancy did not have further blood tests and this can introduce bias. WIDER IMPLICATIONS OF THE FINDINGS: True acupuncture did not improve insulin sensitivity as effectively as metformin in women with PCOS and IR, but it is better than metformin in improving glucose metabolism (which might reduce the risk of type 2 diabetes) and has less side effects. Metformin had a higher incidence of gastrointestinal adverse effects than acupuncture groups, and thus acupuncture might be a non-pharmacological treatment with low risk for women with PCOS. Further studies are needed to evaluate the effect of acupuncture combined with metformin on insulin sensitivity in these women. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grants 2017A020213004 and 2014A020221060 from the Science and Technology Planning Project of Guangdong Province. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov number: NCT02491333. TRIAL REGISTRATION DATE: 8 July 2015. DATE OF FIRST PATIENT'S ENROLLMENT: 11 November 2015.

The Prevalence and Factors Associated With Anxiety-Like and Depression-Like Behaviors in Women With Polycystic Ovary Syndrome.

Increasing evidence shows that polycystic ovary syndrome (PCOS) patients are particularly vulnerable to anxiety/depression-like behaviors. This study sought to determine the prevalence of anxiety/depression-like behaviors among women with PCOS and to identify factors associated with these behaviors. This study was a secondary analysis of three studies performed on Chinese women who were aged 18 to 40 and diagnosed with PCOS according to the modified Rotterdam criteria. We obtained 802 useable responses for the self-rating anxiety scale and 798 responses for the self-rating depression scale. The prevalence of anxiety-like and depression-like behaviors among women with PCOS was 26.1% (209/802) and 52.0% (415/798), respectively. Anxiety-like behaviors were associated with age, body image-related factors (including body mass index and waist-to-hip ratio), and hyperandrogenism-related factors (including free androgen index and hirsutism). Depression-like behaviors were associated with age, body image-related factors, hyperandrogenism-related factors, and metabolic factors (including fasting insulin, fasting plasma glucose, and homeostatic model assessment of insulin resistance). Body image-related factors and hyperandrogenism-related factors were related to both anxiety-like behaviors and depression-like behaviors in both infertile and fertile PCOS patients.

Polycystic ovary syndrome is an independent risk factor for hypertensive disorders of pregnancy: A systematic review, meta-analysis, and meta-regression.

PURPOSE: The risk of hypertensive disorders of pregnancy (HDP) in women with polycystic ovary syndrome (PCOS) is inconsistent in some studies. The aim of this meta-analysis was to examine the evidence regarding the strength of the association between PCOS and HDP. METHODS: PubMed, Web of Science, Embase, and the Cochrane Library were systematically searched to identify observational studies investigating HDP in patients with PCOS. The primary outcome was the pooled odds ratio (OR) of HDP, including pregnancy-induced hypertension (PIH) and pre-eclampsia (PE), in women with PCOS compared with the non-PCOS population. RESULTS: A total of 30 studies were eligible for meta-analysis. PCOS was associated with a higher risk of HDP (OR 2.02, 95CI% 1.83-2.22), including PIH (OR 1.94, 95CI% 1.70-2.21), and PE (OR 2.07, 95CI% 1.91-2.24). The association remained significant after adjusting for age, body mass index (BMI), and nulliparity (HDP: OR 1.48, 95CI% 1.48-1.60; PIH: OR 1.42, 95%CI 1.29-1.57; PE: OR 2.07, and 95%CI 1.91-2.24). The increased risk of HDP for the PCOS group remained significant in subgroups of BMI, Age, singleton pregnancy, multiple pregnancy, gestational diabetes mellitus (GDM), hyperandrogenism, and nulliparity, while the finding was not observed in subgroups of nonhyperandrogenic and non-GDM. In the meta-regression, BMI contributed significantly to the heterogeneity in the prevalence of HDP. CONCLUSIONS: PCOS is independently associated with a significantly increased risk of HDP. To prevent HDP during pregnancy, our findings highlight the importance of establishing supervision guidelines for PCOS patients, especially in the population with hyperandrogenism and GDM.

Chemerin isoform analysis in human biofluids using an LC/MRM-MS-based targeted proteomics approach with stable isotope-labeled standard.

Targeted proteomics has advantages over earlier conventional technologies for protein detection. We developed and validated an LC/MRM-MS-based targeted proteomic method combined with immunoaffinity precipitation for the enrichment and detection of low abundance chemerin isoforms in human biofluids. After tryptic digestion, each chemerin isoform was characterized by isoform-specific peptides, and the absolute quantification was achieved by using stable isotope-labeled peptides as internal standards. In serum, follicular fluid and synovial fluid, a total of 6 chemerin isoforms were identified and quantified, among which a novel natural isoform 153Q was discovered for the first time. The relative content of the six chemerin isoforms in human serum was 157S ≫ 156F ≫ 158K > 154F ≥ 155A > 153Q in the ratio of 25:17:5:2.5:2.2:1, respectively. The absolute contents were in the range of 88-3.5 ng/mL. This distribution remained consistent among the 3 biofluids analyzed. Total chemerin were found to be increased in both polycystic ovary syndrome (serum and follicular fluid) and rheumatoid arthritis (serum) patients. However, chemerin isoform analysis revealed that only 156F & 157S were increased in the former, while 155A, 156F & 157S were increased in the latter. This demonstrates the potential of this method in detailed characterization of changes in chemerin isoforms that may be of clinical relevance.

Effects of Bushen Huoxue method for female with decreased ovarian reserve: A protocol for systematic review and meta-analysis.

BACKGROUND: Decreased ovarian reserve (DOR) is a common reproductive barrier in female. Bushen Huoxue (BSHX) method of TCM is widely applied to treat DOR clinically. The purpose of this study is to provide a systemic and comprehensive evaluation of BSHX in the treatment of DOR. METHODS: We have registered this protocol with OSF registry and the DOI is 10.17605/OSF.IO/QNUE2. We will search 4 English databases (PubMed, EMBASE, MEDLINE, Cochrane Library) and four Chinese databases (China national knowledge infrastructure database, Wanfang database, VIP and Superstar database) from their inception to August 10, 2020. Two authors will search and extract independently all related studies. RevMan 5.3 software will be applied to synthesize data. RESULTS: The results of this study will be published in a scientific journal after peer-review. CONCLUSION: This systematic review will provide reliable evidences for clinicians, and help them make decisions in DOR management.

MiRNAs expression profiling of rat ovaries displaying PCOS with insulin resistance.

PURPOSE: The present study established microRNA (miRNA) expression profiles for rat ovaries displaying polycystic ovary syndrome (PCOS) with insulin resistance and explored the underlying biological functions of differentially expressed miRNAs. METHODS: A PCOS with insulin resistance rat model was created by administering letrozole and a high-fat diet. Total RNA was extracted from the ovaries of PCOS with insulin resistance rats and normal rats. Three ovaries from each group were used to identify differentially expressed miRNAs by deep sequencing. A hierarchical clustering heatmap and volcano plot were used to display the pattern of differentially expressed miRNAs. Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted to explore the potential target genes of the differentially expressed miRNAs and identify their putative biological function. Nine of the differentially expressed miRNAs were selected for validation by Real-time Quantitative PCR (qRT-PCR). RESULTS: A total of 58 differentially expressed miRNAs were identified in the rat ovaries exhibiting PCOS with insulin resistance compared with control ovaries, including 23 miRNAs that were upregulated and 35 miRNAs that were downregulated. GO and KEGG pathway analyses revealed that the predicted target genes were related to metabolic processes, cellular processes, and metabolic pathways. Furthermore, qRT-PCR confirmed that miR-3585-5p and miR-30-5p were significantly upregulated and miR-146-5p was downregulated in the ovaries of PCOS with insulin resistance rats compared with the controls. CONCLUSION: These results indicate that differentially expressed miRNAs in rat ovaries may be involved in the pathophysiology of insulin resistance in PCOS. Our study may be beneficial in establishing miRNAs as novel diagnostic and therapeutic biomarkers for insulin resistance in PCOS.

Circular RNA expression profiling of granulosa cells in women of reproductive age with polycystic ovary syndrome.

PURPOSE: This study aimed to explore the expression profiles of circRNA in granulosa cells of women of reproductive age with polycystic ovary syndrome (PCOS). METHODS: Total RNA was isolated from granulosa cells of 15 women with PCOS and 15 body mass index- and age-matched healthy women (control). RNA sequencing was conducted on ribosomal-depleted RNA for circRNA expression profiling. The differential expression of circRNA between women with PCOS and controls was compared and visualized using hierarchical clustering heat maps and Volcano plots. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed to determine the role of the differential expression of circRNAs. The expression rates of circRNAs were confirmed using quantitative real-time PCR (qRT-PCR) using divergent primers. RESULTS: A total of 4258 and 7395 candidate circRNAs were predicted in PCOS and controls, respectively, based on the RNA-sequencing data. Differences were noted in the expression patterns of circRNA between the two groups. Analysis of the expression profiles revealed that four circRNAs were upregulated, whereas 23 were downregulated in the women with PCOS. GO analysis suggested that the 27 differentially expressed circRNAs were mainly distributed in biological process pathways, particularly in pathways involving inflammation, proliferation, and the vascular endothelial growth factor-related signaling pathway. Six circRNAs were identified in PCOS-affected women using divergent primers. qRT-PCR confirmed that hsa_circ_0001577 was significantly upregulated and hsa_circ_0020093 was downregulated in the women with PCOS. CONCLUSIONS: Several circRNAs were differentially expressed in women of reproductive age with PCOS, suggesting the involvement of these circRNAs in the development of PCOS and the potential clinical implications of their use as PCOS biomarkers.

Alterations of Sphingolipid Metabolism in Different Types of Polycystic Ovary Syndrome.

The roles of sphingolipids in polycystic ovary syndrome (PCOS) are still unknown. This study aimed to investigate the sphingolipid characteristics for different types of PCOS using liquid chromatography-mass spectrometry (LC-MS). A total of 107 women with PCOS and 37 healthy women as normal controls were studied. PCOS patients were further classified into non-obesity with insulin resistance (IR) (NOIR), obesity with IR (OIR), and non-obesity and non-IR (NIR) subgroups. A total of 87 serum sphingolipids, including 9 sphingosines, 3 sphinganines, 1 sphingosine-1-phosphate (S1P), 19 ceramides (Cers), 1 ceramide-1-phosphate, 44 sphingomyelins (SMs), 4 hexosylceramides, and 6 lactosylceramides (LacCers) were analyzed using an improved sphingolipidomic approach based on LC-MS. Notable elevations in the levels of S1P, Cer, and SM were observed in PCOS patients when compared with healthy women, and SM species with long saturated acyl chains showed potential as novel biomarkers of PCOS. In addition, the level of LacCer was only elevated in NIR, and there was almost no change in NOIR and OIR. This study is the first to report the comprehensive sphingolipidomic profiling of different subgroups of PCOS with or without IR or obesity and suggests that serum sphingolipids might be useful as diagnostic biomarkers for different types of PCOS.