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Aims: Vitamin D plays an important role in the regulation of ovulatory dysfunction. We aimed to study the effect of vitamin D on letrozole-induced PCOS in female rats., Material & Methods: 40 non-pregnant Wistar rats were divided into four groups: group I control (received 1 ml of 1% aqueous solution of (CMC)/d orally), group II letrozole-induced PCOS group (received letrozole 200 μg/d orally), group III vitamin D-treated group (received vitamin D 1000 IU/kg/d), group IV letrozole and vitamin D treated group (received letrozole and vitamin D as group II and group III for 90 days. BMI, ovarian weight, serum vitamin D, biochemical metabolic and oxidative stress markers were evaluated, ovarian tissues glutathione, malondialdehyde levels and caspase-3 activity were measured. Histopathological examination of the ovary and coronary artery were done., Key Findings: Letrozole-induced typical PCOS with significant decrease in vitamin D and coronary vasculopathy. Group II shows insignificant change in all parameters but there is significant increase in vitamin D and decrease in triglyceride and glutathione. In group VI all parameters were significantly improved but coronary vasculopathy was partly improved. Vitamin D was significantly negatively correlated with all parameters but significantly positively correlated with estradiol, insulin sensitivity, and HDL and insignificantly correlated with glutathione. Both Insulin resistance and testosterone were significantly positively correlated with all parameters but significantly negatively correlated with estradiol, insulin sensitivity, HDL and glutathione., Significance: These results holding the promise of beneficial impact of vitamin D administration to PCOS and its associated cardiovascular disorders., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Ghrelin and nesfatin-1 are enteroendocrine peptide hormones expressed in rat X/A-like and human P/D1cells of the gastric mucosa. Besides their effect on food intake, both peptides are also implicated in various other physiological systems. One of these is the reproductive system. This present review illustrates the distribution of ghrelin and nesfatin-1 along the hypothalamus-pituitary-gonadal (HPG) axis, their modulation by reproductive hormones, and effects on reproductive functions as well as highlighting gaps in current knowledge to foster further research.

Background: The polycystic ovary syndrome (PCOS) is the most common endocrine associated with insulin resistance, even in the absence of overweight. The global lipid profile of the follicular fluid in PCOS with normal weight as yet has not been investigated. The objection of this pilot study was to explore the changes of lipids in the follicular fluid of PCOS with normal weight., Methods: Follicular fluid samples were collected from patients who underwent IVF, including normal-weight women without PCOS (control group, n = 10) and normal-weight women with PCOS (PCOS group, n = 8). A lipidomic analysis was performed by high performance liquid chromatography/ mass spectrometry (HPLC-MS). Multidimensional statistical analysis was performed to disclose the global differences between the two groups. Further, differential lipid analysis between the two groups was performed by Fold Change Analysis (FC Analysis) and T-test to screen potential markers., Results: All 812 species of 32 subclasses of lipids were identified by lipidomics analysis. 108 kinds of lipids were considered as the potential candidate differential metabolites with the score of variable importance in the project (VIP) more than 1 by the orthogonal partial least squares discriminant analysis. 32 lipids were significantly different between the PCOS group and the control group simultaneously with FC > 1.5 or FC < 0.67, p-value < 0.05 and VIP value > 1. These differential species of lipid belong to lipid subclasses including triglycerides (TG), phosphatidylethanolamines (PE) and phosphatidylinositols (PI)., Conclusion: The identified differential lipids in the follicular fluid may be considered as candidate biomarkers as well as therapeutic targets of PCOS with normal-weight., (© 2021. The Author(s).)

Women with polycystic ovary syndrome (PCOS), commonly have profound skeletal muscle insulin resistance which can worsen other clinical features. The heterogeneity of the condition has made it challenging to identify the precise mechanisms that cause this insulin resistance. A possible explanation for the underlying insulin resistance may be the dysregulation of Transforming Growth Factor-beta (TGFβ) signalling. TGFβ signalling contributes to the remodelling of reproductive and hepatic tissues in women with PCOS. Given the systemic nature of TGFβ signalling and its role in skeletal muscle homeostasis, it may be possible that these adverse effects extend to other peripheral tissues. We aimed to determine if TGFβ1 could negatively regulate glucose uptake and insulin signalling in skeletal muscle of women with PCOS. We show that both myotubes from women with PCOS and healthy women displayed an increase in glucose uptake, independent of changes in insulin signalling, following short term (16 hr) TGFβ1 treatment. This increase occurred despite pro-fibrotic signalling increasing via SMAD3 and connective tissue growth factor in both groups following treatment with TGFβ1. Collectively, our findings show that short-term treatment with TGFβ1 does not appear to influence insulin signalling or promote insulin resistance in myotubes. These findings suggest that aberrant TGFβ signalling is unlikely to directly contribute to skeletal muscle insulin resistance in women with PCOS in the short term but does not rule out indirect or longer-term effects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 McIlvenna, Patten, McAinch, Rodgers, Stepto and Moreno-Asso.)

Purpose: Controversial results existed in amounts of studies investigating the authentic association of estrogen receptor genes (ESR1 and ESR2) polymorphisms with the occurrence and progression of polycystic ovary syndrome (PCOS). The inconsistency might result from different loci, sample sizes, and ethnicities. To find the potential correlations between ESR1/ESR2 polymorphisms and PCOS risk, we conducted the first systematic review and meta-analysis to comprehensively summarize current studies in a large combined population., Methods: Eligible studies were retrieved from PubMed, MEDLINE, EMBASE, Cochrane Library, CBM, CNKI, WANFANG, and VIP up to February 28, 2021. The quality of studies was assessed using the Newcastle-Ottawa Scale (NOS) scoring system. Odds ratios (ORs) and 95% confidence intervals (95%CIs) were calculated to synthesize data in five genetic models. Subgroup analyses were conducted by ethnicity. Heterogeneity and publication bias were also assessed. The protocol was registered in PROSPERO under the number CRD42021239200., Results: A total of 8 studies involving 1,522 PCOS patients and 4,198 controls were included. No evidence demonstrated the association of ESR1 rs2234693 (OR=1.07 95%CI 0.98-1.18), ESR1 rs9340799 (OR=0.99 95%CI 0.69-1.43), or ESR2 rs4986938 (OR=1.06 95%CI 0.81-1.38) polymorphisms and PCOS risk in five genetic models. According to stratified subgroup analyses, ethnicity was considered the major source of heterogeneity. No publication bias was found in eligible studies., Conclusion: The present meta-analysis found no significant associations between the variants of ESR1 rs2234693, ESR1 rs9340799, ESR2 rs4936938, and individual PCOS susceptibility, even if ethnicity was taken into account., Systematic Review Registration: The protocol was registered in PROSPERO (available from https://www.crd.york.ac.uk/PROSPERO) with the ID number CRD42021239200., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhou, Wen, Sheng, Yang, Shen, Chen, Kang and Xu.)

Background: The present study was conducted to investigate the therapeutic effects of a potent polyphenol, fisetin, on the letrozole-induced rat model of polycystic ovary syndrome (PCOS)., Methodology: Twenty-four female Wistar rats (42 days old) were divided into four groups: control group (received carboxy methylcellulose (CMC 0.5 %)), PCOS group treated with letrozole (1 mg/kg), fisetin group received same dose of letrozole + fisetin (10 mg/kg), and metformin group received same dose of letrozole + metformin (300 mg/kg). At the end of the experiment, biochemical (glucose, lipid profile) and hormonal (insulin, testosterone, estradiol, and progesterone) parameters were analyzed. Histological examinations of ovaries were also conducted by hematoxylin and eosin (H&E) staining. Real-time polymerase chain reaction (PCR) and western blotting were carried out for cytochrome P450 17A1 (CYP17A1), sirtuin-1 (SIRT1), and 5' AMP-activated protein kinase (AMPK) gene expression in the ovaries. Furthermore, enzymatic activities of antioxidants including catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) in the ovaries were analyzed by colorimetric method., Results: Letrozole administration resulted in a remarkable abnormality in biochemical and hormonal parameters. Fisetin normalized levels of glucose, lipid profile, homeostatic model assessment for insulin resistance (HOMA-IR), testosterone, estradiol, and progesterone. Moreover, fisetin increased expression levels of SIRT1 and AMPK, and decreased expression level of CYP17A1 in the ovaries. Additionally, fisetin showed protective effect by enhancing antioxidant activities of CAT, SOD, and GPx depleted secondary to induction of PCOS. Fisetin effects were comparable to metformin, as the standard drug used for treatment of PCOS., Conclusion: Our results showed that, fisetin treatment caused significant alleviating effects by restoring PCOS-induced alterations in the key genes involved in energy homeostasis and antioxidant enzymes, suggesting that it may have a key role in combating with PCOS., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Polycystic ovary syndrome (PCOS) is a unification of endocrine and metabolic disorders and has become immensely prevalent among women of fertile age. The prime organ affected in PCOS is the ovary and its distressed functioning elicits disturbed reproductive outcomes. In the ovary, macroautophagy/autophagy performs a pivotal role in directing the chain of events starting from oocytes origin until its fertilization. Recent discoveries demonstrate a significant role of autophagy in the pathogenesis of PCOS. Defective autophagy in the follicular cells during different stages of follicles is observed in the PCOS ovary. Exploring different autophagy pathways provides a platform for predicting the possible cause of altered ovarian physiology in PCOS. In this review, we have emphasized autophagy's role in governing follicular development under normal circumstances and in PCOS, including significant abnormalities associated with PCOS such as anovulation, hyperandrogenemia, metabolic disturbances, and related abnormality. So far, few studies have linked autophagy and PCOS and propose its essential role in PCOS progression. However, detailed knowledge in this area is lacking. Here we have summarized the latest knowledge related to autophagy associated with PCOS. This review's main objective is to provide a background of autophagy in the ovary, its possible connection with PCOS and suggested a novel proposal for future studies to aid a better understanding of PCOS pathogenesis. Abbreviations : AE: androgen excess; AF: antral follicle; AKT/PKB: AKT serine/threonine kinase; AMH: anti-Mullerian hormone; AMPK: AMP-activated protein kinase; ATG: autophagy-related; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; BMP: bone morphogenetic protein; CASP3: caspase 3; CL: corpus luteum; CYP17A1/P450C17: cytochrome P450 family 17 subfamily A member 1; CYP19A1: cytochrome P450 family 19 subfamily A member 1; DHEA: dehydroepiandrosterone; EH: endometrial hyperplasia; FF: follicular fluid; FOXO: forkhead box O; FSH: follicle stimulating hormone; GC: granulosa cell; GDF: growth differentiation factor; HA: hyperandrogenemia; HMGB1: high mobility group box 1; IGF1: insulin like growth factor 1; INS: insulin; IR: insulin resistance; LHCGR/LHR: luteinizing hormone/choriogonadotropin receptor; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAPK/ERK: mitogen-activated protein kinase; MAPK8/JNK: mitogen-activated protein kinase 8; MTOR: mechanistic target of rapamycin kinase; MTORC: mechanistic target of rapamycin complex; NAFLD: nonalcoholic fatty liver disease; NFKB: nuclear factor kappa B; OLR1/LOX-1: oxidized low density lipoprotein receptor 1; oxLDL: oxidized low-density lipoproteins; PA: palmitic acid; PCOS: polycystic ovary syndrome; PF: primary follicle; PGC: primordial germ cell; PI3K: phosphoinositide 3-kinase; PMF: primordial follicle; ROS: reactive oxygen species; RP: resting pool; SIRT1: sirtuin 1; SQSTM1/p62: sequestosome 1; T2DM: type 2 diabetes mellitus; TC: theca cell; TUG1: taurine up-regulated 1.

Polycystic ovary syndrome (PCOS) resulting from abnormal glucose metabolism is a relatively common and complex endocrine disorder among women in their reproductive years, However, the pathogenesis of PCOS is still unclear. The purpose of this study is to investigate the macrophage migration inhibitory factor (MIF) involvement of the nuclear factor (NF)-κB in rats with PCOS. Results indicated that testosterone promoted the increase in the levels of MIF and luteinizing hormone (LH) but inhibited the increase in the level of follicular stimulating hormone (FSH). The MIF antibody could alleviate the process of PCOS to a certain extent. Testosterone promoted the expression of interleukin 1-beta (IL-1β), interleukin 6 (IL-6), Inducible nitric oxide synthase (iNOS), and tumor necrosis factor alpha (TNF-α); the MIF antibody could reverse this effect. Testosterone could inhibit the expression of NF-κB protein whereas MIF antibody could promote the expression in the ovarian cytoplasm. Testosterone promoted the expression of NF-κB protein in the nucleus, this effect also could be reversed by the MIF antibody. Hyperandrogenism activated the NF-κB pathway. After using the MIF antibody, this effect was reversed. This finding suggested that hyperandrogenism activated the NF-κB pathway through MIF. In short, increased MIF levels activated the NF-κB pathway in ovaries, leading to inflammation and the increase in the levels of relevant inflammatory indicators, which might be one of the important factors in the pathogenesis of PCOS., (Copyright © 2021 The First People¼s Hospital of Yunnan. Published by Elsevier Ltd.. All rights reserved.)

Reactive oxygen species (ROS), involved in the pathogenesis of the polycystic ovary syndrome (PCOS), play a key role in the onset of apoptosis in follicles and granulosa cells (GCs). We aimed to investigate the antioxidant effects of AST and metformin separately and in combination on GCs using a PCOS mouse model. Forty-eight prepubertal female BALB C mice aged 25-30 days and weighing 12-14 g were studied. The PCOS model was created by subcutaneous injection of the dehydroepiandrosterone (DHEA) hormone in 8 mice of BALB C for 20 consecutive days. Apoptosis and the amount of ROS were evaluated in GCs of the ovaries via flow cytometry. The activity of AKT protein was measured by western blot, and the viability of GCs was investigated using spectrophotometry. Ovarian tissue sections were prepared, stained with H&E, and the morphology of the sections was examined. Statistical analysis was performed by SPSS v22.0 software using one-way ANOVA. We found that AST administration leads to a significant reduction in oxidative stress (P<0.01) and consequently a significant decrease in the rate of apoptosis (P<0.01). While the expression of AKT in the AST group revealed a significant increase (P<0.05), it decreased in the metformin group. However, it was still significantly higher than the control and PCOS groups. Ovulation was confirmed in both metformin and AST groups. Further studies are warranted to prove the efficacy of AST and to introduce it as a complementary therapeutic agent in PCOS., (© 2021. Society for Reproductive Investigation.)

Polycystic ovary syndrome (PCOS) in an intricate disorder characterized by reproductive and metabolic abnormalities that may affect bone quality and strength along with the lifespan. The present study analysed the impact of postnatal androgenization (of a single dose of testosterone propionate 1.25 mg subcutaneously at day 5 of life) on bone development and markers of bone metabolism in adult female Wistar rats. Compared with healthy controls, the results of measurements of micro-computed tomography (microCT) of the distal femur of androgenized rats indicated an increased cortical bone volume voxel bone volume to total volume (VOX BV/TV) and higher trabecular number (Tb.n) with reduced trabecular separation (Tb.sp). A large magnitude effect size was observed in the levels of circulating bone formation Procollagen I N-terminal propeptide (P1NP) at day 60 of life; reabsorption cross-linked C-telopeptide of type I collagen (CTX) markers were similar between the androgenized and control rats at days 60 and 110 of life. The analysis of gene expression in bone indicated elements for an increased bone mass such as the reduction of the Dickkopf-1 factor ( Dkk1 ) a negative regulator of osteoblast differentiation (bone formation) and the reduction of Interleukin 1-b (Il1b), an activator of osteoclast differentiation (bone reabsorption). Results from this study highlight the possible role of the developmental programming on bone microarchitecture with reference to young women with PCOS., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Thieme. All rights reserved.)

Polycystic ovary syndrome (PCOS) is the most common endocrinopathies affecting the early reproductive age in women, whose pathophysiology perplexes many researchers till today. This syndrome is classically categorized by hyperandrogenism and/or hyperandrogenemia, menstrual and ovulatory dysfunction, bulky multi follicular ovaries on Ultrasonography (USG), and metabolic abnormalities such as hyperinsulinemia, dyslipidemia, obesity. The etiopathogenesis of PCOS is not fully elucidated, but it seems that the hypothalamus-pituitary-ovarian axis, ovarian, and/or adrenal androgen secretion may contribute to developing the syndrome. Infertility and poor reproductive health in women's lives are highly associated with elevated levels of androgens. Studies with ovarian theca cells taken from PCOS women have demonstrated increased androgen production due to augmented ovarian steroidogenesis attributed to mainly altered expression of critical enzymes (Cytochrome P450 enzymes: CYP17, CYP21, CYP19, CYP11A) in the steroid hormone biosynthesis pathway. Despite the heterogeneity of PCOS, candidate gene studies are the widely used technique to delineate the genetic variants and analyze for the correlation of androgen biosynthesis pathway and those affecting the secretion or action of insulin with PCOS etiology. Linkage and association studies have predicted the relationship between genetic variants and PCOS risk among families or populations. Several genes have been proposed as playing a role in the etiopathogenesis of PCOS, and the presence of mutations and/or polymorphisms has been discovered, which suggests that PCOS has a vital heritable component. The following review summarizes the influence of polymorphisms in crucial genes of the steroidogenesis pathway leading to intraovarian hyperandrogenism which can result in PCOS., (© 2021. The Author(s).)

Background: Polycystic ovary syndrome (PCOS), as the most common endocrine disorder in reproductive-aged women, is characterized by oxidative stress and ovarian tissue inflammation. Green tea extract (GTE) potentially possesses therapeutic effects for PCOS because of the antioxidant and anti-inflammatory compounds. This systematic review evaluates the potential roles of GTE on metabolic variables, hormone levels, and ovarian function in PCOS., Methods: A systematic review was conducted of published studies reporting the effects of GTE on PCOS. Several major databases, including PubMed, SCOPUS, and Google Scholar, were searched up from inception to April 2021. Clinical trials and animal studies that assessed the effects of GTE on PCOS were eligible for inclusion., Results: Of 314 articles found in the search, four human studies and four animal studies were included. All studies in humans showed the effects of GTE on weight loss. GTE's effect on decreasing testosterone levels in humans and LH levels in animals were also reported. In addition, increases in FSH and progesterone levels in animal models were observed. Although GTE improved fasting blood sugar and insulin levels, the effect of GTE on inflammatory parameters, such as TNF-alpha and IL-6 and antioxidant status, was limited to animal studies., Conclusion: Therefore, this review suggests that GTE could be considered a potential agent to attenuate PCOS complications mainly due to its effect on weight loss and glycemic levels. However, more studies are needed to formulate conclusions about the effects and mechanisms of GTE in PCOS., (© 2021. The Author(s).)

Aims: Polycystic ovarian syndrome (PCOS) is a reproductive, endocrine and metabolic disorder. Less is known about the mechanism of its effect on uterine function and therapeutic potential of melatonin. Our aim was to evaluate uterine dysfunction(s) in letrozole induced PCOS and its possible rectification by melatonin., Main Methods: Adult female golden hamsters were divided into groups of Control (C), Melatonin (M; 1 mg/kg b.w.), Letrozole (L; 3 mg/kg b.w.) and combination of Letrozole+Melatonin (L + M; 3 mg/kg b.w. + 1 mg/kg b.w.) which were treated for 40 days. Analysis of serum testosterone/estradiol/progesterone/leptin/insulin, uterine histomorphometry, immunohistochemistry for proliferation cell nuclear antigen (PCNA), homeostatic assessment model of insulin resistance (HOMA-IR), western blotting for PCNA, androgen receptor (AR), insulin receptor (InsR), glucose tansporter-4 (GLUT-4), nuclear factor-kappa B (NFκB), cyclooxygenase-2 (COX-2) and biochemical analysis of superoxide dismutase (SOD)/catalase/lipid peroxidation (LPO) were done., Key Findings: Serum testosterone, leptin and insulin increased while uterine InsR/GLUT-4 expression decreased in L group indicating metabolic abnormalities. Endometrial hyperplasia, increased expression of PCNA and AR indicated abnormal proliferation in L compared to C. Increased uterine oxidative load (SOD/catalase/LPO) and inflammatory markers NFκB/COX-2 expression in L was responsible for high tissue oxidative stress and inflammation. M administration normalized all the above parameters suggesting its ameliorative effect in L + M group., Significance: We report PCOS induced uterine dysfunction in Mesocricetus auratus for the first time. M administration restores uterine functions modulating cellular dynamicity, metabolic status, decreased oxidative and inflammatory load in PCOS hamsters. Therefore, we suggest the therapeutic potential of M against PCOS led uterine abnormalities to restore female fertility., (Copyright © 2021. Published by Elsevier Inc.)

In rats with polycystic ovary syndrome (PCOS) induced by injection of estradiol valerate (EV), unilateral or bilateral section of the vagus nerve restores ovulatory function in 75% of animals, suggesting that the vagus nerve participates in the development of PCOS. Since the vagus nerve is a mixed nerve through which mainly cholinergic-type information passes, the objective of the present study was to analyze whether acetylcholine (ACh) is involved in the development of PCOS. Ten-day-old rats were injected with 2.0 mg EV, and at 60 days of age, they were microinjected on the day of diestrus in the bursa of the left or right ovary with 100 or 700 mg/kg of ovarian weight atropine, a blocker of muscarinic receptors, and sacrificed for histopathological examination after the surgery. Animals with PCOS microinjected with 100 mg of atropine showed a lack of ovulation, lower serum concentrations of progesterone and testosterone, and cysts. Histology of the ovaries of animals microinjected with 700 mg of atropine showed corpus luteum and follicles at different stages of development, which was accompanied by a lower concentration of progesterone and testosterone. These results allow us to suggest that in animals with PCOS, ACh, which passes through parasympathetic innervation, is an important component in the persistence and development of the pathophysiology.

Background: Obesity is associated with the development of polycystic ovary syndrome (PCOS) and contributes substantially to metabolic abnormalities in women with PCOS. The study aimed to describe and compare the practices of physicians in the diagnosis, evaluation, and treatment of obesity in patients with PCOS., Methods: Reproductive endocrinologists (Repro-Endo) and obstetrician-gynecologists (non-reproductive medicine specialty, OB-Gyn) in China participated in a survey, and their responses were analyzed using χ 2 tests, Fisher exact tests, and multivariable logistic regression analysis., Results: The study analyzed 1318 survey responses (85.8% OB-Gyn; 97.3% women). Body mass index was the most common diagnostic criterion for obesity; only 1.3% of participants measured waist circumference to identify abdominal obesity. More Repro-Endo participants (25% of all participants) enquired about the psychological problems of patients with obesity than OB-Gyn participants, and 42.5% of participants reported ordering both a lipid profile and oral glucose tolerance test (OGTT) for patients with obesity and PCOS. Multivariable analysis, that included physician's specialty, age, hospital grade, and number of patients with PCOS seen annually, revealed that OB-Gyn participants were less likely to order OGTT (OR, 0.3; 95% CI, 0.2-0.4) and lipid profile (OR, 0.2; 95% CI, 0.1-0.3) than Repro-Endo participants. The most common treatments for patients with PCOS were lifestyle modification (> 95%) and metformin (> 80%). More Repro-Endo participants prescribed metformin at a dose of 1.5 g/day compared with OB-Gyn (47.6% vs. 26.3%), and more OB-Gyn participants reported being unclear about the appropriate dosage of metformin for patients with obesity and PCOS (8.9% vs. 1.6%)., Conclusion: Our survey identified knowledge gaps in metabolic screening for patients with obesity and PCOS and a disparity in the evaluation and treatment of obesity in PCOS among different specialties. Similarly, it highlights the need to improve obesity management education for physicians caring for women with PCOS., (© 2021. The Author(s).)

Objective: To evaluate the association between neck circumference (NC) and hyperuricemia in women with polycystic ovary syndrome (PCOS)., Methods: This is a cross-sectional study that recruited 601 women with PCOS from January 2018 to January 2021. PCOS was diagnosed according to the Rotterdam definition. Hyperuricemia was defined as serum uric acid level of at least 357 μmol/L., Results: PCOS females with hyperuricemia had significantly greater values of NC, body mass index (BMI), waist circumference (WC) and hip circumference (HC). NC was positively associated with serum uric acid levels, with a standardized regression coefficient of 0.34 after adjusting for confounding factors. Furthermore, logistic regression analysis showed that NC was significantly associated with an increased risk of hyperuricemia, with an adjusted odds ratio of 1.36. The associations between NC and serum uric acid levels were more considerable in those with medium/high BMI (BMI ≥ 21.63 kg/m 2 ), all ranges of WC or medium/high HC (HC ≥ 90 cm). The optimal cut-off point of NC in predicting hyperuricemia was 32.0 cm (Youden index = 0.48), with the sensitivity and negative predictive value of 84.81% and 92.08%, respectively., Conclusions: NC was positively correlated with serum uric acid levels and the prevalence of hyperuricemia in women with PCOS. Therefore, we suggest NC as a simple, novel, and reliable anthropometric measure to be used in the routine clinical assessment of women with PCOS to screen those at high risk of hyperuricemia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yang, Liu, Jin, Yu, Ding and Mu.)

Polycystic ovarian syndrome (PCOS) is the primary cause of female infertility affecting several women worldwide. Changes in hormonal functions such as hyperandrogenism are considered a significant factor in developing PCOS in women. In addition, many molecular pathways are involved in the pathogenesis of PCOS in women. To have better insights about PCOS, it is data from clinical studies carried on women suffering from PCOS should be collected. However, this approach has several implications, including ethical considerations, cost involved and availability of subject. Moreover, during the early drug development process, it is always advisable to use non-human models mimicking human physiology as they are less expensive, readily available, have a shorter gestation period and less risk involved. Many animal models have been reported that resemble the PCOS pathways in human subjects. However, the models developed on rats and mice are more preferred over other rodent/non-rodent models due to their closer resemblance with human PCOS development mechanism. The most extensively reported PCOS models for rats and mice include those induced by using testosterone, letrozole and estradiol valerate. As the pathophysiology of PCOS is complex, none of the explored models completely surrogates the PCOS related conditions occurring in women. Hence, there is a need to develop an animal model that can resemble the pathophysiology of PCOS in women. The review focuses on various animal models explored to understand the pathophysiology of PCOS. The article also highlights some environmental and food-related models that have been used to induce PCOS., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Polycystic ovary syndrome (PCOS) is a multifaced reproductive endocrinopathy affecting 6-20% of women of childbearing age. It was previously shown that women with PCOS have an increased risk of cardiovascular (CV) diseases. The aim of this study was to evaluate the cardiodynamic parameters of isolated rats' hearts, blood pressure levels, and histomorphological changes in the heart tissue following the androgen-induced PCOS model in rats and the role of oxidative stress in the development of these CV properties of PCOS. 21-day-old female rats ( n = 12) were divided into control and PCOS groups. PCOS was induced by administration of testosterone enanthate (1 mg/kg BW, daily) during 35 days. During the autoregulation protocol (40-120 mmHg) on the Langendorff apparatus, ex vivo cardiodynamic parameters of retrogradely perfused hearts showed enhanced contractile function and increased lusitropic effects in the left ventricle (LV) in PCOS rats. Systolic and diastolic pressures in LV were elevated at all perfusion pressure values. Systemic arterial systolic blood pressure showed borderline elevation, while mean arterial blood pressure was significantly higher in PCOS rats. Histological evaluation of heart tissue depicted hypertrophic (8.3%) alterations in LV cardiomyocytes and increase (7.3%) in LV wall thickness. Oxidative stress parameters were altered in systemic circulation, coronary venous effluent (CVE), and heart tissue. Levels of superoxide dismutase and reduced glutathione were decreased in blood and heart tissue, while catalase activity was not altered. Degree of lipid peroxidation was increased in circulation as well as heart tissue. Increased levels of O 2 - in CVE indicated the cardiotoxic effects in the rat PCOS model. The mentioned alterations of oxidative stress parameters in the blood, CVE, and heart could be recommended as potential contributors underlying the development of CV risk in PCOS women., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2021 Jovana Joksimovic Jovic et al.)

We examined the vasoactive effect of estradiol in a rat model of early PCOS and the influence of vitamin D deficiency (VDD). We created a model of chronic hyperandrogenism and VDD in adolescent female Wistar rats (N = 46) with four experimental groups: vitamin D supplemented (T-D+), VDD (T-D-), hyperandrogenic and vitamin D supplemented (T+D+), and hyperandrogenic and VDD (T+D-). T+ groups received an 8-week-long transdermal Androgel treatment, D-animals were on vitamin D-reduced diet and D+ rats were supplemented orally with vitamin D3. Estrogen-induced vasorelaxation of thoracic aorta segments were measured with a wire myograph system with or without the inhibition of endothelial nitric oxide synthase (eNOS) or cyclooxygenase-2 (COX-2). The distribution of estrogen receptor (ER), eNOS and COX-2 in the aortic wall was assessed by immunohistochemistry. VDD aortas showed significantly lower estradiol-induced relaxation independently of androgenic status that was further decreased by COX-2 inhibition. COX-2 inhibition failed to alter vessel function in D+ rats. Inhibition of eNOS abolished the estradiol-induced relaxation in all groups. Changes in vascular function in VDD were accompanied by significantly decreased ER and eNOS staining. Short-term chronic hyperandrogenism failed to, but VDD induced vascular dysfunction, compromised estrogen-dependent vasodilatation and changes in ER and eNOS immunostaining.

Context: Premature adrenarche (PA) may increase the risk for polycystic ovary syndrome (PCOS)., Objective: To study features of PCOS in young adult women with a history of PA., Methods: Thirty PA and 42 control females were followed from prepuberty to young adulthood (median age 18.1 years). The main outcome measures were ovarian function, the use of contraceptives, and clinical and biochemical indicators of hyperandrogenism., Results: We found no differences in the use of hormonal contraceptives (50 vs 50%, PA vs controls, respectively; P > .999), indication for using contraceptives (P = .193), or in the history of oligo- (17 vs 26%, P = .392) and amenorrhea (0 vs 0%, P > .999). Among women not using hormonal contraceptives, those with a history of PA had a higher prevalence of hirsutism (27 vs 0%, P = .023) but not acne (87 vs 67%, P = .252). Steroid profiles were broadly comparable between the groups, but PA women had lower sex hormone-binding globulin (SHBG) concentrations (30.1 vs 62.4 nmol/L, P < .001) resulting in higher free androgen index (3.94 vs 2.14, P < .001). The difference in SHBG levels persisted through body mass index adjustment. SHBG correlated negatively with the homeostasis model assessment for insulin resistance (r -0.498, P = .003). Anti-Müllerian hormone concentrations were comparable between the groups (39.3 vs 32.1 pmol/L, P = .619)., Conclusion: PA was not associated with evident ovarian dysfunction in young adult women. However, women with a history of PA had decreased SHBG levels and thus, increased bioavailability of circulating androgens., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

The beneficial effects of metformin, especially its capacity to ameliorate insulin resistance (IR) in polycystic ovary syndrome (PCOS), explains why it is widely prescribed. However, its effect on the offspring of patients with PCOS remains uncertain. This study investigated the impact of metformin treatment on the first- and second-generation female offspring born to letrozole-induced PCOS-IR rats. Forty-five female Wistar rats were implanted with continuous-release letrozole pellets or placebo and treated with metformin or vehicle control. Rats exposed to letrozole showed PCOS-like reproductive, endocrine, and metabolic phenotypes in contrast to the controls. Metformin significantly decreased the risk of body weight gain and increased INSR expression in F1 female offspring in PCOS-IR rats, contributing to the improvement in obesity, hyperinsulinemia, and IR. Decreased FSHR expression and increased LHCGR expression were observed in F1 female rats of the PCOS-IR and PCOS-IR+Metformin groups, suggesting that FSHR and LHCGR dysfunction might promote the development of PCOS. Nevertheless, we found no significant differences in INSR , FSHR , and LHCGR expression or other PCOS phenotypes in F2 female offspring of PCOS-IR rats. These findings indicated widespread reproductive, endocrine, and metabolic changes in the PCOS-IR rat model, but the PCOS phenotypes could not be stably inherited by the next generations. Metformin might have contributed to the improvement in obesity, hyperinsulinemia, and IR in F1 female offspring. The results of this study could be used as a theoretical basis in support of using metformin in the treatment of PCOS-IR patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Xie, Xiao and Li.)

Polycystic ovary syndrome (PCOS) is a neuroendocrine heterogeneous disease that frequently occurs in women of reproductive age, causing serious damage to the fertility, quality of life, and physical and mental health of patients. The current studies have proved that satisfactory endometrial receptivity is one of the conditions that must be met during the process of spermatovum position, adhesion and invasion, as well as the subsequent blastocyst division and embryo development. Women with PCOS may suffer a series of pathological processes such as changes in the expression levels of hormones and related receptors, imbalances in the proportion of miscellaneous cytokines, insulin resistance, low-grade chronic inflammation and endometrial morphological changes, which will damage endometrial receptivity from various aspects and obstruct fertilized egg nidation and embryonic development, thus causing adverse reproductive health events including infertility and abortion. This article reviews the research progress about characteristics and related influencing factors of endometrial receptivity in PCOS patients., (© 2021. The Author(s).)

Since the lack of certainty in identifying polycystic ovary syndrome (PCOS) demonstrates confusion regarding the disorder's pathophysiology and its therapeutic approaches, systematic screening of women under diagnostic guidelines of the NIH reported that about 4-10 percent of reproductive women aged 20-44 years suffer from PCOS. Not all females with PCOS-defining biochemical and clinical characteristics and about 22% of PCOS women have no symptoms. PCOS is a heterogeneous phenotypic and clinical condition, combined with metabolic implications. The root cause of PCOS is the major issue of IR or irregular androgen secretion and constant effort is being made in identifying the dynamic pathogenic network underlying the syndrome. Regardless of PCOS initiating cause, IR therapy and hyperinsulinemia can restore metabolic and hormonal homeostasis, and minimize ovarian dysfunction. Thus, the impact of insulin on ovaries in hyperinsulinemic individuals can account for many of the PCOS characteristics and is important for developing treatment strategies. Therefore, our primary aim is to investigate the proper understanding of endocrine disruption during PCOS and secondary to the therapeutic potential of inositol in reestablishing the equilibrium of ovarian dysfunction, anovulation, and eventually infertility.

microRNA (miRs or miRNAs) is a type of non-coding RNA which plays the role of a regulator in gene expression. A number of miRNAs has been found by the researchers for its critical role in the pathogenesis of polycystic ovary syndrome (PCOS). But there is a no clear information available about the biological role played by miR-21 in PCOS prognosis. So, the aim of the current study is to determine the role played by miR-21 in the progression of PCOS. In order to achieve this aim, the researcher examined miR-21 expression levels in ovarian tissue samples collected from PCOS patients as well as their KGN cells (human granulosa-like tumor cell line). The study results inferred downregulation in the expression levels of miR-21 in ovarian tissues of PCOS patients and KGN cells, when compared with unaffected ovarian tissues and IOSE80 (human ovarian surface epithelial cell line). With the overexpression of miR-21, the proliferation of KGN cells was prevented and apoptosis was induced among these cells. The authors used StarBase analysis for predicting the direct binding target of miR-21. As per the assay results attained from luciferase reporter assay and western blot analysis, it was found that SNHG7 acted as a target gene for miR-21 while the latter downregulated the former. To conclude, the current study revealed the contribution of miR-21/SNHG7 axis in the regulation of Granulosa Cell (GC) proliferation and apoptosis. It further suggested a new molecular mechanism for GC dysregulation while the finding presents a new promising target for PCOS treatment procedure., (Copyright © 2021. Published by Elsevier B.V.)

Objective: To study the association between hyperandrogenism (HA) and adverse pregnancy outcomes in patients with different polycystic ovary syndrome phenotypes undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI)., Methods: We reviewed all eligible articles published up to October 2020 after searching in PubMed, Embase, Cochrane Library, Web of Science, Wanfang Data, and CNKI databases. The primary outcomes were the clinical pregnancy rate (CPR), miscarriage rate (MR), and live birth rate (LBR), whereas the secondary outcomes were the number of retrieved oocytes and endometrial thickness. Risk ratios (RRs) or mean differences with 95% confidence intervals (CIs) were calculated to estimate the HA impact on IVF/ICSI outcomes in patients with polycystic ovary syndrome (PCOS) phenotypes., Results: Of the 789 trials identified, nine retrospective studies involving 3037 patients with PCOS were included. Compared to the PCOS group with normal androgen levels, the PCOS group with HA exhibited increased MR (RR: 1.56, 95% CI: 1.13, 2.16); the CPR (RR: 0.88, 95% CI: 0.77, 1.01) and LBR (RR: 0.79, 95% CI: 0.55, 1.11) were not significantly different between these groups. Subgroup analysis revealed that the CPR was lower in the polycystic ovarian (PCO)-morphology + HA + oligo-anovulation (AO) group than in the PCO + AO group (RR: 0.81, 95% CI: 0.67, 0.99). Among Asians, the PCOS/HA group had increased MR (RR: 1.56, 95% CI: 1.06, 2.31) and showed thinner endometrial thickness. However, among Caucasians, no differences were observed between the two groups., Conclusions: HA may have adverse effects on clinical pregnancy and miscarriage outcomes in different PCOS phenotypes, particularly among Asians.

Although polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility worldwide, the aetiology of the disorder remains poorly defined. Animal-based evidence highlights the brain as a prime suspect in both the development and maintenance of PCOS. Prenatally androgenised (PNA) models of PCOS exhibit excessive GABAergic wiring associated with PCOS-like reproductive deficits in adulthood, with aberrant brain wiring detected as early as postnatal day (P) 25, prior to disease onset, in the PNA mouse. The mechanisms underlying this aberrant brain wiring remain unknown. Microglia, the immune cells of the brain, are regulators of neuronal wiring across development, mediating both the formation and removal of neuronal inputs. Here, we tested the hypothesis that microglia play a role in the excessive GABAergic wiring that leads to PCOS-like features in the PNA brain. Using specific immunolabelling, microglia number and morphology associated with activation states were analysed in PNA and vehicle-treated controls across developmental timepoints, including embryonic day 17.5, P0, P25 and P60 (n = 7-14 per group), and in two regions of the hypothalamus implicated in fertility regulation. At P0, fewer amoeboid microglia were observed in the rostral preoptic area (rPOA) of PNA mice. However, the greatest changes were observed at P25, with PNA mice exhibiting fewer total microglia, and specifically fewer "sculpting" microglia, in the rPOA. Based on these findings, we assessed microglia-mediated refinement of GABAergic synaptic terminals at two developmental stages of peak synaptic refinement: P7 and P15 (n = 7 per group). PNA mice showed a reduction in the uptake of GABAergic synaptic material at P15. These findings reveal time-specific changes in the microglia population and refinement of GABAergic inputs in a mouse model of PCOS driven by prenatal androgen excess and suggest a role for microglia in shaping the atypical brain wiring associated with the development of PCOS features., (© 2021 British Society for Neuroendocrinology.)

Polycystic Ovary Syndrome (PCOS), a major endocrine disorder, affects the reproductive function of a woman, along with an association with metabolic conditions like insulin resistance and inflammation. The inflammatory nature of PCOS is much debated over, owing to numerous cases of elevation in cytokine levels. Studies have shown the beneficiary effect of Gamma-Linolenic acid (GLA) in reducing inflammation related to many conditions such as atopic dermatitis, rheumatoid arthritis, arterial disease, obesity, and even PCOS. The study aims at assessing the expression of inflammatory cytokines in the ovary and Peri-ovarian adipose tissue (POAT) of the Dehydroepiandrosterone (DHEA) induced PCOS rat model. Further, this study also evaluates the effect of γ-linolenic Acid (GLA) on these cytokines in POAT. Female Wistar rats were subcutaneously injected with 60 mg/kg DHEA daily for 28 days. These PCOS-induced rats were then orally administered with 50 mg/kg GLA for 14 days. The gene expression of cytokines was assessed by Real Time-PCR. The study showed an increase in the expression of cytokines in the ovary and POAT of the DHEA group. This suggests the role of ovarian adipose in adding to the pro-inflammatory state of PCOS. Moreover, the administration of GLA to the PCOS-induced rats resulted in a reduction of cytokine expression from the POAT, indicating that the compound was successful in reducing the associated inflammation. The study throws light on the possibility of using GLA as a supplementary or naturalistic alternative in ameliorating ovarian adipose-associated inflammation that accompanies PCOS., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: Adult women with polycystic ovary syndrome (PCOS) and obesity have an 8-fold increased risk of developing type 2 diabetes (T2D). Our goal was to determine the incidence and risk factors for T2D in adolescents with PCOS and obesity., Research Design and Methods: Retrospective chart review of girls aged 11-21 years with confirmed PCOS (oligomenorrhea and hyperandrogenism) diagnosis between July 2013 and Aug 2018 and at least one follow-up visit and BMI >85%ile. T2D incidence, defined with an HbA1c ≥6.5%, was calculated. A nested case-control study with 1:3 matching by race, ethnicity, and BMI was performed to determine predictors of T2D diagnosis., Results: Four hundred ninety-three patients with PCOS (age 15.6 ± 1.9 years, BMI 36.2 ± 6.3 kg/m 2 ) were identified with a follow-up of 1018 person-years. Twenty-three developed T2D (incidence 22.6/1000 person-years) with diagnosis a median of 1.8 years (2 months-5.5 years) after PCOS diagnosis. T2D risk was higher in girls with a prediabetes HbA1c (5.7%-6.4%) (HR 14.6 [4.8-44.5]) and among Hispanic girls with an elevated HbA1c and alanine aminotransferase (HR 19.0 [3.7-97.2]) at the time of PCOS diagnosis. In the 1:3 matched cohort, T2D risk was 18.7 times higher (OR 18.66 [2.27-153.24]) for every 0.1% increase in HbA1c at the time of PCOS diagnoses., Conclusions: Girls with PCOS and obesity have an 18-fold increase in T2D incidence compared to published rates in non-PCOS youth. Hispanic girls with elevated HbA1c and ALT are at particular risk. Due to the morbidity associated with youth onset T2D, these findings argue for better screening and prevention approaches in this population., (© 2021 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

In this prospective study, seventy-six patients (PCOS group; n = 36, multifollicular ovary group; n = 40) were evaluated by 2-D and 3-D ultrasonography. VOCAL programme, echogenicity, number of follicles and blood flow parameters were evaluated. The patients with PCOS had a higher total ovarian volume, mean stromal volume and stromal echogenicity (18.6 ± 4.75 to 10.2 ± 3.4 p  < .01; 12.23 ± 2.53 to 5.02 ± 2.44 p  = .02; score 1:28 to 10 p  < .01, respectively). There was no statistically significant difference in terms of mean RI and PI values between the groups ( p  > .05). 3 D power Doppler parameters included VI, FI, and VFI values of the patients with PCOS were higher when compared to those of the patients with multifollicular ovary (3.82 ± 2.65 to 1.78 ± 1.2, p  < .01; 50.76 ± 4.45 to 40.6 ± 3.64, p  = .03; and 2.34 ± 1.02 to 1.12 ± 0.65, p  = .02, respectively). Our results revealed that total ovarian volume, stromal volume and echogenicity; VFI, VI, and FI could be useful for differential diagnosis in women with PCOS and multifollicular ovaries.Impact statement What is already known on this subject? Ultrasonography is considered the new diagnostic tool for PCOS. Enlarged ovaries with multiple small follicles peripherally located around increased ovarian stroma with increased stromal echogenicity are the sonographic features of polycystic ovaries. What do the results of this study add? 3-D Doppler ultrasonography may be more specific in the determination of multifollicular and polycystic ovaries when compared to RI and PI in 2-D Doppler ultrasonography. Moreover, 3-D power Doppler ultrasonography could be useful for differential diagnosis in women with PCOS and multifollicular ovaries. What are the implications of these findings for clinical practice and/or further research? In clinical practice, the differentiation of multifollicular ovaries and polycystic ovaries (PCO) is difficult with the use of 2-D sonography alone. Therefore, 3-D ultrasound and power Doppler may also be used in addition to 2-D ultrasound for the differentiation of multifollicular ovaries and PCO.

Research Question: What is the effect of weight loss through different interventions (three-component lifestyle intervention with short message service [SMS+] versus three-component lifestyle intervention without SMS [SMS-] versus care as usual [CAU]) on polycystic ovary syndrome (PCOS) characteristics (ovulatory dysfunction, hyperandrogenism, polycystic ovarian morphology [PCOM]) and phenotype distribution?, Design: Analysis of secondary outcome measures of a randomized controlled trial. Women diagnosed with PCOS (n = 183), who wished to become pregnant, with a body mass index above 25 kg/m², were assigned to a 1-year three-component (cognitive behavioural therapy, diet, exercise) lifestyle intervention group, with or without SMS, or to CAU (advice to lose weight)., Results: The prevalence of biochemical hyperandrogenism was 30.9% less in the SMS- group compared with CAU after 1 year (P = 0.027). Within-group analyses revealed significant improvements in ovulatory dysfunction (SMS+: -39.8%, P = 0.001; SMS-: -30.5%, P = 0.001; CAU: -32.1%, P < 0.001), biochemical hyperandrogenism (SMS-: -27.8%, P = 0.007) and PCOM (SMS-: -14.0%, P = 0.034). Weight loss had a significantly favourable effect on the chance of having ovulatory dysfunction (estimate 0.157 SE 0.030, P < 0.001) and hyperandrogenism (estimate 0.097 SE 0.027, P < 0.001)., Conclusions: All groups demonstrated improvements in PCOS characteristics, although these were more profound within the lifestyle intervention groups. Weight loss per se led to an amelioration of diagnostic characteristics and in the phenotype of PCOS. A three-component lifestyle intervention aimed at a 5-10% weight loss should be recommended for all women with PCOS before they become pregnant., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: TMPO-AS1 is a recently characterized oncogenic lncRNA in ovarian cancer. Its role in other ovary diseases is unknown. This study explored its role in polycystic ovary syndrome (PCOS)., Methods: Follicular fluid was extracted from both PCOS patients and controls. The levels of TMPO-AS1 and mature and premature miR-335-5p were analyzed by RT-qPCR. The role of TMPO-AS1 in regulating miR-355-5p maturation in granulosa-like tumor (KGN) cells was analyzed by overexpression experiments. The interaction between TMPO-AS1 and premature miR-335-5p was analyzed by RNA pull-down assay. The subcellular location of TMPO-AS1 in KGN cells was analyzed by nuclear fractionation assay. The role of TMPO-AS1 and miR-335-5p in KGN cell proliferation was analyzed by BrdU assay., Results: TMPO-AS1 was increased in PCOS, while mature miR-355-5p was decreased in PCOS. TMPO-AS1 overexpression decreased mature miR-355-5p level but increased premature miR-355-5p. TMPO-AS1 was localized in both nucleus and cytoplasm. TMPO-AS1 directly interacted with premature miR-355-5p in KGN cells. TMPO-AS1 increased KGN cell proliferation while miR-355-5p decreased cell proliferation. The co-transfection assay showed that TMPO-AS1 reduced the suppressive effects of miR-355-5p on cell proliferation., Conclusions: TMPO-AS1 might suppress miR-335-5p maturation to participate in PCOS., (© 2021. The Author(s).)

Oxidative stress has been recognized as one of the causal mediators of female infertility by affecting the oocyte quality and early embryo development. Improving oxidative stress is essential for reproductive health. Melatonin, a self-secreted antioxidant, has a wide range of effects by improving mitochondrial function and reducing the damage of reactive oxygen species (ROS). This minireview illustrates the applications of melatonin in reproduction from four aspects: physiological ovarian aging, vitrification freezing, in vitro maturation (IVM), and oxidative stress homeostasis imbalance associated with polycystic ovary syndrome (PCOS), emphasising the role of melatonin in improving the quality of oocytes in assisted reproduction and other adverse conditions., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2021 Yonghui Jiang et al.)

Background: Polycystic ovary syndrome (PCOS) affects up to 18% of reproductive-age females. The prevalence of obesity in PCOS patients reaches up to 80%, which is 2-fold higher than the general population., Objective: The present study aimed to compare the effectiveness of 55 pharmacological interventions across 17 different outcomes in overweight/obese PCOS patients with hyperandrogenism manifestations for both short- and long-term follow-ups. A comprehensive literature search was performed on PubMed, Scopus, Embase, Science Direct, Web of Science, and Cochrane CENTRAL for randomized controlled trials comparing any conventional pharmacological intervention as a monotherapy or a combination in overweight/obese patients with polycystic ovary syndrome and hyperandrogenism manifestations. Extracted data included three main parameters; I. Anthropometric parameters (BMI, Waist and Hip circumferences, and Waist/HIP ratio), II. Hormonal parameters (FSH, LH, FSG, SHBG, Estradiol, Total Testosterone, Free testosterone, DHEAS, Androstenedione), and III. Metabolic parameters (Total Cholesterol, LDL-C, HDL-C, Triglycerides, Fasting glucose, Fasting glucose, HOMA-IR). Critical appraisal and risk of bias assessments were performed using the modified Jadad scale, and the overall quality of this network meta-analysis was evaluated according to the CINeMA framework. We performed both a pairwise meta-analysis and a network meta-analysis to evaluate the effect sizes with 95% CI, and we calculated the surface under the cumulative ranking curve (SUCRA) for each intervention., Results: Our final search on May 15th 2021 retrieved 23,305 unique citations from searching six electronic databases. Eventually, 101 RCTs of 108 reports with a total of 8,765 patients were included in our systematic review and multi-treatments meta-analysis. 55 different interventions were included: 22 monotherapies, and 33 combinations. The two-dimensional cluster ranking of the average SUCRA values for metabolic and hormonal parameters with significant estimates revealed flutamide (77.5%, 70%; respectively) as the highest and rosiglitazone (38.2%, 26.3%; respectively) as the lowest, in terms of the overall efficacy in reducing weight and hyperandrogenism. However, cyproterone-acetate+ethinylestradiol exhibited a higher ranking in improving hormonal parameters (71.1%), but even a lower-ranking regarding metabolic parameters (34.5%)., Conclusions and Relevance: Current evidence demonstrated the superiority of flutamide in improving both metabolic and hormonal parameters, and the higher efficacy of cyproterone-acetate+ethinylestradiol only in improving hormonal parameters. Nearly all interventions were comparable in female hormones, FGS, HDL, glucose, and insulin levels improvements., Competing Interests: The authors have declared that no competing interests exist.

Aims: Accumulating evidence have shown the important roles of long noncoding RNA (lncRNA) in controlling different diseases. In the present study, we tried to explore the role which lncRNA MALAT1 plays in polycystic ovary syndrome (PCOS) with the involvement of microRNA-302d-3p (miR-302d-3p) and leukemia inhibitory factor (LIF)., Methods: A PCOS rat model was established and characterized, followed by treatment with si-MALAT1, oe-MALAT1, miR-302d-3p mimic, or miR-302d-3p inhibitor constructs. Serum hormonal levels were detected to evaluate endocrine conditions. The effect of MALAT1 and miR-302d-3p on activities of ovarian granulosa cells was assessed, as well as the involvement of LIF., Results: MALAT1 expression was shown to be downregulated in ovarian tissue of PCOS rats. Overexpression of MALAT1 in vitro promoted proliferation and inhibited apoptosis of ovarian granulosa cells. Overexpression of MALAT1 in vivo reduced the ovarian tissue injury and endocrine disorders accompanied with decreased level of FSH and elevated serum levels of E2, T, and LH in the PCOS rat. Overexpression of MALAT1 also promoted the expression of LIF, which could be reversed by overexpression of miR-302d-3p, indicating that MALAT1 up-regulated the expression of LIF via miR-302d-3p. Furthermore, overexpression of MALAT1 reduced endocrine disorders and ovarian tissue damage via the miR-302d-3p/LIF axis., Conclusion: Our study highlighted that MALAT1 plays a protective role in reducing ovarian tissue damage and endocrine disorder in PCOS by regulating the miR-302d-3p/LIF axis., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Polycystic ovary syndrome (PCOS) is a common endocrine disorder worldwide. We aimed to examine the associations of two mitochondrial DNA (mtDNA) biomarkers in the peripheral blood, mtDNA copy number (CN), and mtDNA 4977 deletion rate (DR), with PCOS in a clinical setting., Methods: We performed a study involving 263 women with PCOS and 326 age-matched controls between June 2015 and June 2019. The mtDNA CN and mtDNA 4977 DR were measured using multiplex probe-based qPCR. The associations of the mtDNA CN and mtDNA 4977 DR with the risk of PCOS were estimated using logistic regression., Results: Analysis of the associations between mtDNA biomarkers and PCOS indicate that the mtDNA CN ( P = 0.003) and mtDNA 4977 DR ( P < 0.001) in PCOS patients were significantly higher than those in the controls. After adjusting for the body mass index, luteinizing hormone/follicle-stimulating hormone ratio, and testosterone level, only higher mtDNA 4977 DR was associated with PCOS (odds ratio 1.053, 95% confidence interval 1.024 to 1.083; P < 0.001). The linear dose-response trends of the mtDNA 4977 DR were also supported by the quartile analysis., Conclusion: Multivariable models suggest that mtDNA 4977 DR levels are strongly associated with PCOS and represent an independent risk factor for PCOS. Further investigation of the utility of mtDNA as a biomarker for PCOS is warranted., Competing Interests: Author BH was employed by company Shanghai WeHealth BioMedical Technology Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ye, Hu, Shi, Guo, Xu and Li.)

Introduction: Both polycystic ovary syndrome (PCOS) and autoimmune thyroiditis (AT) are considered to be among the most common endocrinopathies in young women, and they are classified as diseases that affect many processes in the human body. Their role in the development of metabolic disorders and diseases of the cardiovascular system in adult women is also emphasized. However, there are no data available to assess such risk in the teenage girl population. The aim of the study was to assess the hormonal and metabolic profile of adolescent girls with PCOS, additionally diagnosed with AT, as well as to identify possible risk factors for the coexistence of AT and PCOS., Material and Methods: 80 euthyroidic PCOS patients were qualified for the study (chronological age 16.54 ± 1.00 years, BMI 24.60 ± 4.16 kg/m 2 ). Eighteen girls diagnosed with AT were included in the study group and 62 girls without AT-in the control group. Each patient had biochemical and hormonal tests performed. Additionally, to diagnose AT, the level of antibodies against thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-TG), as well as the image of the thyroid gland on ultrasound examination, were taken into account., Results: Estradiol concentration was significantly higher in the study than in the control group (203.00 ± 217.00 vs. 152.00 ± 78.50 pmol/L, p=0.02). Higher DHEAS concentrations were also observed in the AT group compared with the group without AT (391.28 ± 176.40 vs. 317.93 ± 114.27 µg/dl, p=0.04). Moreover, there was a positive correlation between AT and estradiol concentration (r y =0.27; p=0.04). It was also shown that there is a tendency toward statistical significance for the positive correlation between the positive anti-TPO titer and the glucose concentration at 120 min OGTT (r ƴ =0.26; p=0.07) and girls with PCOS and AT had higher glucose levels in 120 min OGTT (115.29±41.70 vs. 98.56±28.02 mg/dl, p=0.08)., Conclusion: The study results showed no difference in the metabolic profile between the groups. The high concentration of estradiol found in girls with PCOS and AT may indicate the role of this hormone in the development of the autoimmune process. However, the numbers are small, and more research is needed to confirm our findings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Skrzyńska, Zachurzok and Gawlik.)

Polycystic ovary syndrome is a common reproductive disorder in the female of reproductive age, which is characterized by hyperandrogenism, insulin resistance, cystic ovary and infertility. The level of pro-inflammatory adipokine, visfatin is elevated in PCOS conditions in human and animal. In this study, letrozole induced hyperandrogenised PCOS mice model have been used to unravel the effects of visfatin inhibition. The results showed that letrozole induced hyperandrogenisation significantly (p < 0.05) elevates ovarian visfatin concentration from 66.03 ± 1.77 to 112.08 ± 3.7 ng/ml, and visfatin expression to 2.5 fold (p < 0.05) compared to control. Visfatin inhibition in PCOS by FK866 has significantly (p < 0.05) suppressed the secretion of androgens, androstenedione (from 0.329 ± 0.07 to 0.097 ± 0.01 ng/ml) and testosterone levels (from 0.045 ± 0.003 to 0.014 ± 0.0009 ng/ml). Ovarian histology showed that visfatin inhibition suppressed cyst formation and promotes corpus luteum formation. Visfatin inhibition has suppressed apoptosis and increases the expression of BCL2 along with increase in the proliferation (GCNA expression elevated). Visfatin inhibition has increased ovarian glucose content (from 167.05 ± 8.5 to 210 ± 7 mg/dl), along with increase in ovarian GLUT8 expression. In vitro study has also supported the in vivo findings where FK866 treatment significantly (p < 0.05) suppressed testosterone (control-3.84 ± 0.44 ng/ml, 1 nM FK866-2.02 ± 0.048 ng/ml, 10 nM FK866-1.74 ± 0.20 ng/ml) and androstenedione (control-4.68 ± 0.91 ng/ml, 1 nM FK866-3.38 ± 0.27 ng/ml, 10 nM FK866-4.55 ± 0.83 ng/ml) production from PCOS ovary. In conclusion, this is first report, which showed that visfatin inhibition by FK866 in hyperandrogenised mice ameliorates pathogenesis of PCOS. Thus, it may be suggested that visfatin inhibition could have a therapeutic potential in PCOS management along with other intervention., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To examine whether subcutaneous (SC) abdominal adipose stem cell differentiation into adipocytes in vitro predicts insulin sensitivity (Si) in vivo in normal-weight women with polycystic ovary syndrome (PCOS) and controls., Design: Prospective cohort study., Setting: Academic medical center., Patient(s): Eight normal-weight women with PCOS and 8 age- and body mass index-matched controls., Intervention(s): Women underwent circulating hormone/metabolic determinations, intravenous glucose tolerance testing, total-body dual-energy x-ray absorptiometry, and SC abdominal fat biopsy., Main Outcome Measure(s): PPARγ and CEBPa gene expression and lipid content of adipocytes matured in vitro were compared between women with PCOS and control women, and correlated with patient characteristics, systemic Si, and adipose insulin resistance (adipose-IR)., Result(s): Serum androgen levels, adipose-IR, and percentage of android fat were greater in women with PCOS than control women. Stem cell PPARγ and CEBPa gene expression increased maximally by day 12 without a female-type effect. In control cells, gene expression positively correlated with fasting serum insulin levels (both genes) and adipose-IR (CEBPa) and negatively correlated with Si (CEBPa). Conversely, CEBPa gene expression in PCOS cells negatively correlated with adipose-IR and serum free testosterone, whereas total lipid accumulation in these cells positively corelated with Si., Conclusion: In normal-weight women with PCOS, accelerated SC abdominal adipose stem cell differentiation into adipocytes in vitro favors Si in vivo, suggesting a role for hyperandrogenism in the evolution of metabolic thrift to enhance fat storage through increased cellular glucose uptake., (Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Polycystic ovary syndrome (PCOS) in women is characterized by hyperandrogenemia, obesity, and oligo- or anovulation. In addition, women with PCOS are often obese, with insulin resistance, hyperlipidemia, and elevated blood pressure. The cardiometabolic consequences for the male offspring of maternal hyperandrogenemia are unclear. The present studies tested the hypothesis that male offspring of a rat model of PCOS would develop cardiometabolic disease as adults. Female Sprague-Dawley rats (hyperandrogenemic females (HAF)) were implanted with dihydrotestosterone or placebo pellets (controls) at 4 weeks of age, and were mated at 10-12 weeks and allowed to lactate their offspring after birth. Body weights in male HAF offspring were lower at birth than in controls until postnatal day 4, but body weights remained similar between male control and HAF offspring from 2 to 8 weeks of age. However, at 16 weeks of age, body weight was lower in HAF male offspring, but there were no differences in fat mass or lean mass factored for body weight in HAF males, compared to controls. Plasma total cholesterol and HDL and proteinuria were higher and nitrate/nitrite excretion was lower in male HAF offspring than in controls. Baseline blood pressure was similar between HAF male offspring and controls, but HAF offspring had an exaggerated pressor response to angiotensin II infusion. These data suggest that adult sons of PCOS mothers may be at increased risk of cardiometabolic disease., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Polycystic Ovary Syndrome (PCOS) is a metabolic condition that affects women in their reproductive age by altering the ovarian hormone levels, leading to infertility. Increased inflammation, insulin resistance, hyperandrogenism, irregular menses, and infertility are the causes of morbidity when PCOS is the disease in question. PCOS is considered a multifactorial disease resulting from the disruption of multiple signalling pathways. Hence, the mono-targeted drugs are hardly adequate and conventional therapeutic strategies provide only palliative care. Studies show that the consumption of polyunsaturated fatty acids (PUFAs) regulates menstrual cycle, decrease testosterone and insulin levels, and improve metabolic health. This could favourably affect diabetes and infertility. In recent years, the fibrillin-3 gene has been linked to PCOS. Fibrillins along with the molecules in the extracellular matrix modulate the Transforming Growth Factor-β (TGF-β) signalling. So, mutations in the fibrillin-3 gene could cause TGF-β dysregulation, which might further contribute to PCOS pathogenesis. Therefore, the current study aimed to understand whether PUFAs could manage PCOS via the TGF-β pathway and function as a therapeutic agent for PCOS and its complications. To understand this, we have focused on the involvement of TGF-β in PCOS pathogenesis, discussed the effect of PUFA on hormones, insulin resistance, inflammation, obesity, adiponectin, and cardiovascular conditions. Using PUFAs to target TGF-β or its receptor molecules to modulate the TGF-β production might function as a treatment option for PCOS. PUFA therapy could be a good alternative, supportive medication for PCOS., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: In recent years, female infertility from Polycystic Ovary Syndrome (PCOS) has gained scientific interest. PCOS alters the metabolic and endocrine functioning in females. The elevation in androgens can damage the androgen receptors present on the kidney giving rise to renal disorders like Focal Segmental Glomerulosclerosis (FSGS). Transforming Growth Factor Beta (TGF-β) in the ovary is activated by activin for Follicle Stimulating Hormone (FSH) secretion and in the kidney by thrombospondin 1 (TSP1) for cell growth and apoptosis. Studies show that gamma-linolenic acid (GLA) effectively treats breast cancer, eczema, inflammatory conditions and PCOS., Aim: The study aimed to find out the possibility of FSGS development in PCOS and to understand the effect of GLA on FSGS via the TGF-β pathway., Method: To carry out the study, the dehydroepiandrosterone (DHEA) induced PCOS model was used. Three groups namely vehicle control, DHEA, and DHEA+GLA, were used with six animals in each. TGF-β1, TGF-β2, and TSP1 genes were studied using real-time PCR., Results: The study showed an increase in the level of renal fibrosis biomarker, TSP1, in the DHEA group, which was further decreased by an anti-inflammatory agent, GLA. The TGF-β1 and TGF-β2 genes associated with the TGF-β pathway were seen to be increased in DHEA-induced PCOS rats which showed a possible relation between the two conditions., Conclusion: The study shows a possible development of renal fibrosis in the DHEA-induced PCOS model. The GLA might act as a ligand to regulate TGF-β signaling in glomerulosclerosis in a DHEA-induced PCOS model., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Reproductive disorders, including intrauterine adhesion (IUA), premature ovarian insufficiency (POI), and polycystic ovary syndrome (PCOS), are great threats to female reproduction. Recently, mesenchymal stem cells derived-extracellular vesicles (MSC-EVs) have presented their potentials to cure these diseases, not only for the propensity ability they stemmed from the parent cells, but also for the higher biology stability and lower immunogenicity, compared to MSCs. EVs are lipid bilayer complexes, functional as mediators by transferring multiple molecules to recipient cells, such as proteins, microRNAs, lipids, and cytokines. EVs appeared to have a therapeutic effect on the female reproductive disorder, such as repairing injured endometrium, suppressing fibrosis of endometrium, regulating immunity and anti-inflammatory, and repressing apoptosis of granulosa cells (GCs) in ovaries. Although the underlying mechanisms of MSC-EVs have reached a consensus, several theories have been proposed, including promoting angiogenesis, regulating immunity, and reducing oxidate stress levels. In the current study, we summarized the current knowledge of functions of MSC-EVs on IUA, POI, and PCOS. Given the great potentials of MSC-EVs on reproductive health, the critical issues discussed will guide new insights in this rapidly expanding field., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liao, Liu, Wang, Sui and Zhang.)

Background: Polycystic ovary syndrome (PCOS) is a common endocrine disease in women of reproductive age. Multiple studies have shown that long non-coding RNAs (lncRNA) and microRNAs (miRNA) play a role in PCOS. This study aimed to explore the role and molecular mechanism of lncRNA -Regulator of reprogramming (lncROR) in PCOS., Results: Expression level of lncROR in PCOS patients was up-regulated, while level of miR-206 was down-regulated in comparison with control group (P < 0.001). Logistics regression analysis showed that lncROR and miR-206 were independent predictors of PCOS. The ROC curve showed that lncROR had a high diagnostic value for PCOS with an AUC value of 0.893. Pearson correlation coefficient indicated that the expression level of miR-206 was negatively correlated with the level of lncROR. CCK-8 assay and apoptosis assay revealed that downregulation of lncROR up-regulated the expression of miR-206, thereby inhibiting cell proliferation and promoting cell apoptosis. However, silencing the expression of miR-206 reversed the above effects caused by down-regulation of lncROR expression. Luciferase reporter gene assay suggested that there was a target relationship between lncROR and miR-206. VEGF was proved to be the target gene of miR-206., Conclusions: Highly expressed lncROR indirectly up-regulated the expression of VEGF by down-regulating the expression of miR-206, thereby promoting the proliferation of KGN cells and inhibiting apoptosis, and further promoting the development of PCOS.

Background: To explore the development mechanism of PCOS and Transcriptomics was applied to seek the key gene., Methods: Transcriptomics marked by UID (unique identifier) technique of granulosa cell in PCOS and control women was carried out and key gene was picked up. Then the key gene in granulosa cell was measured by RT-PCR. Two PCOS models modeling with Letrozole and Testosterone Propionate were implemented and the key gene in granulosa cell of ovary was measured by immunohistochemistry to verify the relation with PCOS., Results: GO-enrich of transcriptomics concentrated in domain steroid metabolism and domain mitochondria. Different genes were sought from coexisting in both domain steroid metabolism and domain mitochondria. Finally, five different genes including CYP11A1、CYB5R1、STAR、FDX1 and AMACR were obtained. RT-PCR was implemented to furtherly verify the downregulating mRNA of FDX1 in PCOS, which showed the consistent outcome with the transcriptomics. Level of FDX1 protein in granulosa cell of antral follicle in two PCOS models was measured and decreased., Conclusions: FDX1 was related with steroid metabolism and mitochondrial and may participate in the development of PCOS.

Ethnopharmacological Relevance: Eucommia ulmoides Oliv. leaves are the dry leaves of Eucommia ulmoides Oliv. Modern studies have shown that Eucommia ulmoides Oliv. leaves and its extracts have many pharmacological effects, such as regulating hypothalamus pituitary ovary (HPO) axis function, estrogen like effects, correcting insulin resistance (IR), regulating lipids, and reducing weight, which are consistent with the clinical manifestations in polycystic ovary syndrome (PCOS) patients. PCOS patients often have HPO axis disorder, low estrogen, high androgen, high IR complication rate, and obesity. Previous preclinical studies have shown that total flavonoids from Eucommia ulmoides Oliv. leaves (TFEL) can improve the imbalance in sex hormone secretion in perimenopausal animal models by regulating the function of the HPO axis. Thus, it is important to understand if flavonoids are the active parts of Eucommia ulmoides Oliv. leaves that interfere with polycystic ovary syndrome with insulin resistance (PCOS-IR), and determine the regulatory role they play in sex hormones and IR?, Aim of the Study: Investigate the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway in the ovary and kisspeptin/insulin like growth factor/leptin receptor1/androgen receptor (Kiss1/IGF-1/LEPR/AR) in the HPO axis to determine the mechanism of TFEL intervention in a rat model of PCOS-IR model rats., Materials and Methods: A rat model of PCOS-IR was established using a high-fat diet (49 d) combined with letrozole (1 mg/kg·d, for 28 d). Then, metformin (300 mg/kg·d) and TFEL (220 mg/kg·d, 110 mg/kg·d, and 55 mg/kg·d) were administered continuously for 21 days. At the end of the experiment, samples were taken and the related indexes were measured., Results: TFEL reduced the body weight, Lee's index, ovarian index, ovarian area and ovarian volume, increased serum E 2 , SHBG levels and ISI, decreased serum levels of T, LEP, INS, and FBG (whole blood), and reduced the HOMA-IR in rats with PCOS-IR. TFEL downregulate Kiss1, IGF-1, and AR in the arcuate nucleus of hypothalamus, and upregulate Kiss1, downregulate IGF-1 and AR in the pituitary gland, and upregulate Kiss1, downregulate IGF-1, LEPR, and AR in the ovary of rats with PCOS-IR. TFEL could downregulate p-IRS-1 Ser307 , upregulate IRS-1, p-IRS-1 Tyr895 , PI3Kp85α, p-PI3Kp85α, AKT, p-AKT, and GLUT4 in the ovary, and ameliorated histopathological changes in the ovary and pancreas of rats with PCOS-IR., Conclusion: TFEL can inhibit ovarian hyperplasia, regulate disorders of glucose and lipid metabolism and improve the secretion of sex hormones, by regulating the expression of PI3K/AKT signaling pathway-related proteins in the ovary and Kiss1/IGF-1/LEPR/AR in the HPO axis., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Polycystic ovary syndrome is a common endocrine disorder worldwide. Recently, quercetin has been extensively investigated as a therapeutic option in patients with PCOS. Therefore, this study aimed to investigate the mechanisms underlying quercetin's positive effects by modulating key components of energy homeostasis and adipose tissue hormones in rats with letrozole-induced PCOS. Eighteen female Wistar rats were divided into three groups including control group (received carboxy methylcellulose (CMC 0.5%)), letrozole-induced PCOS ± quercetin group (received 1 mg/kg letrozole in CMC 0.5%), and letrozole-induced PCOS +/+ quercetin group (received same dose of letrozole + 100 mg/kg quercetin in CMC 0.5%). The estrous cycle, biochemical and hormonal parameters, as well as insulin resistance (IR) were evaluated in all groups. Western blotting was used to assess the expression levels of sirtuin-1 (SIRT-1), 5' AMP-activated protein kinase (AMPK), and adiponectin in target tissues of rats. The expression levels of visfatin and resistin were also evaluated through Real-time polymerase chain reaction (PCR). Treatment with quercetin improved the PCOS related disturbances in estrous cycle, lipid profile, serum levels of testosterone, estradiol and progesterone, and IR. Besides, the expression levels of AMPK and SIRT-1 in ovarian tissue were upregulated in the rats which received quercetin. Quercetin also reversed the PCOS-induced alteration in adipose tissue levels of adiponectin, visfatin, and resistin. Modulation of energy homeostasis through key components involved in this axis, as well as regulation of hormones releasing from adipose tissue may be the main underlying mechanisms for positive effects of quercetin in PCOS., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: To evaluate the histomorphometric and immunohistochemical changes in interstitial cells and ovarian follicles of rats treated with clomiphene citrate during and after induction of permanent estrus., Methods: Twenty four adult-female rats with regular estrous cycle were equally divided into three groups: (1) GCtrl-at estrous phase. (2) GPCOS-at permanent-estrous phase. (3) GCC-PCOS rats, which remained exposed to 60 days of continuous illumination and treated with Clomiphene Citrate. After that, the animals were euthanized, and the ovaries were removed and processed for paraffin embedding. Sections were stained with H.E. for histomorphometry or subjected to immunohistochemistry for Ki-67 and cleaved caspase-3 detections., Results: The GPCOS showed lack of corpus luteum and several ovarian cysts, as well as interstitial-like cells. The presence of corpus luteum and a significant increase in primary and antral follicles were observed in GCC, which also showed a decrease in the number of ovarian cysts and in the area occupied by interstitial-like cells, as well as a decrease in nuclear volume of interstitial cells. The percentage of cell proliferation was significantly higher in granulosa cells of the GCC. On the other hand, the percentage of apoptosis was significantly higher in the granulosa cells of GPCOS than the GCC., Conclusion: The ovaries of rats treated with clomiphene citrate showed a decrease in the number of cysts, an increase in the number of ovarian follicles, the presence of corpus luteum along with a decrease in the nuclear volume in the area occupied by interstitial cells.

Polycystic ovary syndrome (PCOS) is an endocrine disorder characterized by elevated secretion of androgen, commonly associated with insulin resistance (IR), which could exacerbate patient with PCOS. Development of a safe and effective treatment in preventing and treating PCOS will be beneficial to women of reproductive age. Female Sprague-Dawley rats were randomly divided into four groups: sham group treated with vehicle (saline) or luteolin; letrozole and high-fat-diet-induced PCOS group treated with vehicle or luteolin (25, 50, 100 mg/kg ip). Ovary tissue and blood were collected for further analysis. Luteolin normalized estrus cycle and improved ovarian morphology, including reduced polycystic and alleviated the loss of oocytes and corpus luteum in PCOS rats. Serum follicle stimulating hormone and estradiol were reduced, whereas luteinizing hormone and testosterone were elevated in PCOS rats relative to that of sham, which were significantly normalized by luteolin. Notably, luteolin significantly inhibited IR and upregulated protein levels of PI3K p85α and pAKT compared with PCOS rats treated with vehicle. In addition, the activities of antioxidants such as SOD, GPx, CAT, and GSH were reduced in PCOS rats, which were significantly increased by luteolin. Protein and mRNA expressions of Nrf2 and downstream genes such as Hmox1 and Nqo1 were restored by luteolin in PCOS rats. Collectively, this study demonstrated that luteolin inhibited IR by prompting PI3K/AKT signaling pathway and enhanced antioxidative response through the restoration of Nrf2 pathway. NEW & NOTEWORTHY Luteolin normalizes the estrus cycle, ovarian morphological changes, improves serum sexual hormone levels, reduces insulin resistance, prompts PI3K/Akt signaling, improves antioxidative response, and upregulates Nrf2 signaling in PCOS rats. Luteolin has a potential to serve as a therapeutic agent in preventing and treating PCOS.

Background: Polycystic ovary syndrome (PCOS) is the most common metabolic and endocrine disorder among reproductive-age women, and the leading cause of anovulatory infertility. 11β-hydroxysteroid dehydrogenases-1 (11β-HSD1) catalysing the conversion of inactive cortisone to active cortisol plays a crucial role in various metabolic diseases. However, whether 11β-HSD1 is associated with the pathogenesis of PCOS and whether 11β-HSD1 can be a treating target of PCOS remain unknown., Methods: This study was first designed to explore the role of 11β-HSD1 in PCOS development and the effect of selective 11β-HSD1 inhibitor administration on PCOS treatment. Follicular fluid and granulosa cells (GCs) were collected from 32 non-PCOS patients and 37 patients with PCOS to measure cortisol and 11β-HSDs levels. Female Sprague-Dawley rats (3-week-old) were injected with dehydroepiandrosterone (DHEA) to induce PCOS and their ovaries were collected to measure the abundance of corticosterone (CORT) and 11β-HSDs. To determine the role of 11β-HSD1 in PCOS development, we overexpressed 11β-HSD1 in the ovaries of female rats (5-week-old) or knocked down the expression of 11β-HSD1 in the ovaries from PCOS rats via lentivirus injection. After lentivirus infection, the body weights, ovarian weights, estrous cycles, reproductive hormones and morphology of the ovary were analysed in rats from different experimental groups. Then to figure out the translational potential of the selective 11β-HSD1 inhibitor in treating PCOS, PCOS rats were treated with BVT.2733, a selective 11β-HSD1 inhibitor and a cluster of PCOS-like traits were analysed, including insulin sensitivity, ovulatory function and fertility of rats from the Control, PCOS and PCOS+BVT groups. Rat ovarian explants and human GCs were used to explore the effect of CORT or cortisol on ovarian extracellular matrix remodelling., Results: The elevated expression of 11β-HSD1 contributed to the increased cortisol and corticosterone (CORT) concentrations observed in the ovaries of PCOS patients and PCOS rats respectively. Our results showed that ovarian overexpression of 11β-HSD1 induced a cluster of PCOS phenotypes in rats including irregular estrous cycles, reproductive hormone dysfunction and polycystic ovaries. While knockdown of ovarian 11β-HSD1 of PCOS rats reversed these PCOS-like changes. Additionally, the selective 11β-HSD1 inhibitor BVT.2733 alleviated PCOS symptoms such as insulin resistance (IR), irregular estrous cycles, reproductive hormone dysfunction, polycystic ovaries, ovulatory dysfunction and subfertility. Moreover, we showed that cortisol target ovarian insulin signalling pathway and ovarian extracellular matrix (ECM) remodelling in vivo, in ovarian explants and in GCs., Conclusion: Elevated 11β-HSD1 abundance in ovarian is involved in the pathogenesis of PCOS by impairing insulin signalling pathway and ECM remodelling. Selective inhibition of 11β-HSD1 ameliorates a cluster of PCOS phenotypes. Our study demonstrates the selective 11β-HSD1 inhibitor as a novel and promising strategy for the treatment of PCOS., Competing Interests: Declaration of competing interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The association between subclinical hypothyroidism (SCH) and polycystic ovary syndrome (PCOS) has been shown in many studies. These findings are still controversial, however. It is unclear whether the co-incidence of subclinical hypothyroidism and polycystic ovary syndrome will affect the severity of metabolism. Therefore, we performed this meta-analysis to investigate the association. A comprehensive search strategy was developed to obtain all relevant studies published in PubMed, EMBASE, Cochrane Library, and Chinese Academic Journal Full-text Database (CNKI) up to 31 December 2020. We adopted the standardized mean difference (SMD) with 95% confidence intervals (CI) for evaluation, and sensitivity analysis was performed. Publication bias was analyzed and represented by a funnel plot, and funnel plot symmetry was assessed with Egger's test. Twenty-seven studies with 4821 participants (1300 PCOS patients with SCH, 3521 PCOS patients without SCH) were included in the present meta-analysis,among which 71.31% chinese patients out of the total. The results showed that PCOS patients with SCH had higher levels of HOMA-IR, TG, TC, LDL, FBG, FCP, PRL and lower levels of HDL, LH and T. It also recognized the limitation of the lack of a consistent definition of hypothyroidism in the 27 studies included. The results of this study indicated that SCH may aggravate lipid and glucose metabolism in patients with PCOS., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)