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Polycystic ovary syndrome (PCOS) is a prevalent metabolic disorder among women of reproductive age, characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovaries. The pathogenesis of PCOS involves a complex interplay of genetic and environmental factors, including insulin resistance (IR) and resultant hyperinsulinemia. Insulin receptors, primarily in skeletal muscle, liver, and adipose tissue, activate downstream signaling pathways like PI3K-AKT and MAPK-ERK upon binding. These pathways regulate glucose uptake, storage, and lipid metabolism. Genome-wide association studies (GWASs) have identified several candidate genes related to steroidogenesis and insulin signaling. Environmental factors such as endocrine-disrupting chemicals and lifestyle choices also exacerbate PCOS traits. Other than lifestyle modification and surgical intervention, management strategies for PCOS can be achieved by using pharmacological treatments like antiandrogens, metformin, thiazolidinediones, aromatase inhibitor, and ovulation drugs to improve insulin sensitivity and ovulatory function, as well as combined oral contraceptives with or without cyproterone to resume menstrual regularity. Despite the complex pathophysiology and significant economic burden of PCOS, a comprehensive understanding of its molecular and cellular mechanisms is crucial for developing effective public health policies and treatment strategies. Nevertheless, many unknown aspects of PCOS, including detailed mechanisms of actions, along with the safety and effectiveness for the treatment, warrant further investigation.

Polycystic ovary syndrome (PCOS) is one of the most common gynecological endocrine disorders. Most pathophysiological changes of PCOS begin in the peripubertal phase, and these pathophysiological changes will continuously affect women's health in the later stages of their lives. The pathogenic mechanisms of PCOS remain unclear, involving key aspects such as the regulation of hypothalamic-pituitary function, ovarian cellular functions, androgen levels, and insulin resistance. Herein, we summarized the latest findings on the pathogenesis of PCOS from the perspectives of the genetic background, intrauterine development, neuroendocrine function, inflammatory factors, gut microbiome, and environmental factors. This review will help provide new ideas for a deeper understanding of the disease, as well as its clinical diagnosis and treatment., Competing Interests: 利益冲突　所有作者均声明不存在利益冲突, (© 2024《四川大学学报（医学版）》编辑部 版权所有Copyright ©2024 Editorial Office of Journal of Sichuan University (Medical Sciences).)

Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder in women of reproductive age. It has a strong hereditary component estimated at 60 to 70% in daughters. It has been suggested that environmental factors during the fetal period may be involved in the development of the syndrome in adulthood. However, the underlying mechanisms of its transmission remain unknown, thus limiting the development of effective therapeutic strategies.This article highlights how an altered fetal environment (prenatal exposure to high levels of anti-Müllerian hormone) can contribute to the onset of PCOS in adulthood and lead to the transgenerational transmission of neuroendocrine and metabolic traits through alterations in the DNA methylation process.The originality of the translational findings summarized here involves the identification of potential biomarkers for early diagnosis of the syndrome, in addition to the validation of a promising therapeutic avenue in a preclinical model of PCOS, which can improve the management of patients suffering from the syndrome.

The purpose of this article is to explore the relationship between the total dose of follicle-stimulating hormone (FSH) applied during controlled ovulation stimulation and the live birth rates (LBRs) in non-PCOS population. Many studies have found no difference between the dose of FSH application and pregnancy outcomes such as clinical pregnancy rates after fresh embryo transfer. However, a recent large retrospective analysis found a negative correlation between live birth rates and increasing dose of FSH. It is still controversial about the association between FSH dose and LBRs. In addition, no studies have yet explored the nonlinear relationship between FSH and LBRs. This cohort study included a total of 11,645 patients who had accepted IVF/intracytoplasmic sperm injection (ICSI) at the second hospital of Hebei medical university between December 2014 to December 2019. PCOS was identified by Rotterdam PCOS criteria. We researched the association between FSH total dose and live birth rates (LBRs) using multivariate regression analysis. In addition, a model for nonlinear relationships based on a two-part linear regression was applied. The analysis of threshold effects indicated that LBR increased with every 1000 IU FSH when the concentration of FSH was lower than 1410 IU (OR 1.55, 95% CI [1.05, 2.28]); however, a negative association between FSH dose and LBR (OR 0.94, 95% CI [0.89, 0.99]) was found when the FSH total dose was higher than 1410 IU. It is worth noting that the relationship between LBR and FSH dose varied among patients of different ages (OR 0.92 vs 1.06, P for interaction < 0.05)., (© 2024. The Author(s).)

Polycystic ovary syndrome (PCOS) is one of the most pressing problems in endocrine gynecology. The main signs of the disease are hyperandrogenism, menstrual and/or ovulatory dysfunction, and polycystic ovarian structure according to ultrasound. Women with PCOS are at risk for developing metabolic syndrome, type 2 diabetes, cardiovascular disease, and endometrial cancer. In this connection, the pathogenetic mechanisms of the occurrence of this syndrome are continuously studied and new methods of treatment are being sought. PCOS is characterized by a wide range of various disorders of the neuroendocrine regulation of the reproductive system. The main focus of the review is aimed at summarizing information about the etiological role of neuropeptides and neurotransmitters, such as phoenixin, galanins, orexins, GABA, in the pathophysiology of PCOS and about the possibility of their use for diagnostic and therapeutic purposes. In recent decades, the interest of scientists has been focused on the study of KNDy neurons, because it is the kisspeptin synthesized by them that is one of the main regulators of the hypothalamic-pituitary-ovarian axis. This article discusses data on the significance of KNDy neurons in the pathogenesis of the syndrome. Information is provided on the effect of elevated levels of androgens and anti-Müllerian hormone on GnRH neurons. Also analyzed are studies on functional and structural disorders in the hypothalamus in PCOS. Literature search was carried out in national (eLibrary, CyberLeninka.ru) and international (PubMed, Cochrane Library) databases in Russian and English. The priority was free access to the full text of articles. The choice of sources was prioritized for the period from 2018 to 2023.However, taking into account the insufficient knowledge of the chosen topic, the choice of sources dates back to 1998.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age. Although promising strides have been made in the field of PCOS over the past decades, the distinct etiologies of this syndrome are not fully elucidated. Prenatal factors, genetic variation, epigenetic mechanisms, unhealthy lifestyles, and environmental toxins all contribute to the development of this intricate and highly heterogeneous metabolic, endocrine, reproductive, and psychological disorder. Moreover, interactions between androgen excess, insulin resistance, disruption to the hypothalamic-pituitary-ovary (HPO) axis, and obesity only make for a more complex picture. In this review, we investigate and summarize the related molecular mechanisms underlying PCOS pathogenesis from the perspective of the level of signaling pathways, including PI3K/Akt, TGF-β/Smads, Wnt/β-catenin, and Hippo/YAP. Additionally, this review provides an overview of prospective therapies, such as exosome therapy, gene therapy, and drugs based on traditional Chinese medicine (TCM) and natural compounds. By targeting these aberrant pathways, these interventions primarily alleviate inflammation, insulin resistance, androgen excess, and ovarian fibrosis, which are typical symptoms of PCOS. Overall, we hope that this paper will pave the way for better understanding and management of PCOS in the future., 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 © 2023 Wang and Li.)

Polycystic ovary syndrome (PCOS) is a common disease of endocrine-metabolic disorder, and its etiology remains largely unknown. The gut microbiota is possibly involved in PCOS, while the association remains unclear. The comprehensive analysis combining gut microbiota with PCOS typical symptoms was performed to analyze the role of gut microbiota in PCOS in this study. The clinical patients and letrozole-induced animal models were determined on PCOS indexes and gut microbiota, and fecal microbiota transplantation (FMT) was conducted. Results indicated that the animal models displayed typical PCOS symptoms, including disordered estrous cycles, elevated testosterone levels, and ovarian morphological change; meanwhile, the symptoms were improved after FMT. Furthermore, the microbial diversity exhibited disordered, and the abundance of the genus Ruminococcus and Lactobacillus showed a consistent trend in PCOS rats and patients. The microbiota diversity and several key genera were restored subjected to FMT, and correlation analysis also supported relevant conclusions. Moreover, LEfSe analysis showed that Gemmiger, Flexispira, and Eubacterium were overrepresented in PCOS groups. Overall, the results indicate the involvement of gut microbiota in PCOS and its possible alleviation of endocrinal and reproductive dysfunctions through several special bacteria taxa, which can function as the biomarker or potential target for diagnosis and treatment. These results can provide the new insights for treatment and prevention strategies of PCOS., (© 2023. The Author(s), under exclusive licence to Microbiological Society of Korea.)

Background: Thyroid autoimmunity and polycystic ovary syndrome (PCOS) are the most common endocrinopathies and have close relationships based on common etiology and pathogenesis, including genetic susceptibility, metabolic disorders, hormonal dysregulation, immune response, and inflammatory activation. The co-occurrence of both diseases is associated with adverse reproductive outcomes, but its effect on neonatal outcomes remains largely unknown. We aim to explore the effect of thyroid autoimmunity on neonatal birth weight in PCOS women undergoing IVF/ICSI., Methods: This is a retrospective analysis of 486 PCOS women who underwent the first IVF/ICSI cycles and gave birth to 361 singletons and 125 twins during 2018 - 2020 at a reproductive center. The associations between maternal preconception serum thyroid function and autoimmunity indicators and birth weights of the singleton and twin groups were evaluated using generalized linear models (GLMs) and generalized estimate equations (GEEs), respectively. Analyses were further stratified by neonatal sex, maternal age, and maternal preconception BMI to assess the possible interaction effects., Results: Maternal preconception serum TPOAb had a significant negative association with singleton birth weight (P for trends = 0.03). Compared with women in the first tertile of TPOAb, women in the third tertile had a change in singleton birth weight of - 119.72 g (95% CI: - 222.68 g, - 16.70 g). Maternal preconception serum TPOAb had a significant positive association with twin birth weight (P for trends = 0.01). Compared with women in the first tertile of TPOAb, women in the third tertile had a change in twin birth weight of 138.62 g (95% CI: 33.96 g, 243.30 g). Besides, maternal preconception serum TPOAb had a specific association with increased twin birth weight for female neonates, a specific association with decreased singleton birth weight for PCOS women under 35 years, and a specific association with decreased twin birth weight for overweight PCOS women (all P for interactions < 0.05)., Conclusions: Maternal preconception thyroid autoimmunity may affect the birth weights of both singleton and twin neonates. Further large cohorts and experimental studies are required to confirm these findings and explore the underlying mechanisms., (© 2023. The Author(s).)

Competing Interests: Declaration of interests The author declares no conflict of interest.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine and metabolic disorder that affects premenopausal women. The etiology of PCOS is multifaceted, involving various genetic and epigenetic factors, hypothalamic-pituitary-ovarian dysfunction, androgen excess, insulin resistance, and adipose-related mechanisms. High-fat diets (HFDs) has been linked to the development of metabolic disorders and weight gain, exacerbating obesity and impairing the function of the hypothalamic-pituitary-ovarian axis. This results in increased insulin resistance, hyperinsulinemia, and the release of inflammatory adipokines, leading to heightened fat synthesis and reduced fat breakdown, thereby worsening the metabolic and reproductive consequences of PCOS. Effective management of PCOS requires lifestyle interventions such as dietary modifications, weight loss, physical activity, and psychological well-being, as well as medical or surgical interventions in some cases. This article systematically examines the pathological basis of PCOS and the influence of HFDs on its development, with the aim of raising awareness of the connection between diet and reproductive health, providing a robust approach to lifestyle interventions, and serving as a reference for the development of targeted drug treatments.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-aged individuals with ovaries. It is associated with anovulation and increased risk to fertility and metabolic, cardiovascular, and psychological health. The pathophysiology of PCOS is still inadequately understood, although there is evidence of persistent low-grade inflammation, which correlates with associated visceral obesity. Elevated proinflammatory cytokine markers and altered immune cells have been reported in PCOS and raise the possibility that immune factors contribute to ovulatory dysfunction. Because normal ovulation is modulated by immune cells and cytokines in the ovarian microenvironment, the endocrine and metabolic abnormalities associated with PCOS orchestrate the accompanying adverse effects on ovulation and implantation. This review evaluates the current literature on the relationship between PCOS and immune abnormalities, with a focus on emerging research in the field., (Copyright © 2023 The Authors.)

Background: Polycystic ovary syndrome (PCOS) is the primary cause of anovulatory infertility, bringing serious harm to women's physical and mental health. Acupuncture may be an effective treatment for PCOS. However, systematic reviews (SRs) on the efficacy and safety of acupuncture for PCOS have reported inconsistent results, and the quality of these studies has not been adequately assessed., Objective: To summarize and evaluate the current evidence on the efficacy and safety of acupuncture for PCOS, as well as to assess the quality and risks of bias of the available SRs., Search Strategy: Nine electronic databases (Cochrane Library, MEDLINE, Embase, PsycINFO, CINAHL, Chinese National Knowledge Infrastructure, Wanfang Data, Chongqing VIP Chinese Science and Technology Periodical Database, and China Biology Medicine disc) were searched from their establishment to July 27, 2022. Based on the principle of combining subject words with text words, the search strategy was constructed around search terms for "acupuncture," "polycystic ovary syndrome," and "systematic review.", Inclusion Criteria: SRs of randomized controlled trials that explored the efficacy and (or) safety of acupuncture for treating patients with PCOS were included., Data Extraction and Analysis: Two authors independently extracted study data according to a predesigned form. Tools for evaluating the methodological quality, risk of bias, reporting quality, and confidence in study outcomes, including A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2), Risk of Bias in Systematic Reviews (ROBIS), Preferred Reporting Items for Systematic Reviews and Meta-analyses for Acupuncture (PRISMA-A), and the Grading of Recommendations Assessment, Development and Evaluation (GRADE), were used to score the included SRs., Results: A total of 885 studies were retrieved, and 11 eligible SRs were finally included in this review. The methodological quality of 2 SRs (18.18%) was low, while the other 9 SRs (81.82%) were scored as extremely low. Four SRs (36.36%) were considered to be of low risk of bias. As for reporting quality, the reporting completeness of 9 SRs (81.82%) was more than 70%. Concerning the confidence in study results, 2 study results were considered to have a high quality of evidence (3.13%), 14 (21.88%) a "moderate" quality, 28 (43.75%) a "low" quality, and 20 (31.24%) considered a "very low" quality. Descriptive analyses suggested that combining acupuncture with other medicines can effectively improve the clinical pregnancy rate (CPR) and ovulation rate, and reduce luteinizing hormone/follicle-stimulating hormone ratio, homeostasis model assessment of insulin resistance, and body mass index (BMI). When compared with medicine alone, acupuncture alone also can improve CPR. Further, when compared with no intervention, acupuncture had a better effect in promoting the recovery of menstrual cycle and reducing BMI. Acupuncture was reported to cause no adverse events or some adverse events without serious harm., Conclusion: The efficacy and safety of acupuncture for PCOS remains uncertain due to the limitations and inconsistencies of current evidence. More high-quality studies are needed to support the use of acupuncture in PCOS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Shanghai Yueyang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine. Published by Elsevier B.V. All rights reserved.)

The prevalence of pediatric obesity has been increasing during the last 30 years, and the subsequent metabolic consequences of obesity, which were mainly seen in adults, are now presenting in childhood. Type 2 diabetes, prediabetes, metabolic syndrome, and nonalcoholic fatty liver disease are serious metabolic ramifications of pediatric obesity; pediatricians need to be familiar in screening and treatment of these metabolic issues. This review will discuss the inflammation and insulin resistance involved in obesity that can lead to these conditions. We will explore the pathophysiology of type 2 diabetes and prediabetes, metabolic syndrome, and nonalcoholic fatty liver disease and review screening and treatment modalities. Finally, we will highlight other important endocrine related comorbidities in pediatric obesity, including polycystic ovary syndrome, precocious puberty, and early accelerated growth. [ Pediatr Ann . 2023;52(2):e62-e67.] .

Gonadotropin-releasing hormone (GnRH) neurons produce the final output from the brain to control pituitary gonadotropin secretion and thus regulate reproduction. Disruptions to gonadotropin secretion contribute to infertility, including polycystic ovary syndrome (PCOS) and idiopathic hypogonadotropic hypogonadism. PCOS is the leading cause of infertility in women and symptoms resembling PCOS are observed in girls at or near the time of pubertal onset, suggesting that alterations to the system likely occurred by that developmental period. Prenatally androgenized (PNA) female mice recapitulate many of the neuroendocrine phenotypes observed in PCOS, including altered time of puberty, disrupted reproductive cycles, increased circulating levels of testosterone, and altered gonadotropin secretion patterns. We tested the hypotheses that the intrinsic properties of GnRH neurons change with puberty and with PNA treatment. Whole-cell current-clamp recordings were made from GnRH neurons in brain slices from control and PNA females before puberty at three weeks of age and in adulthood to measure GnRH neuron excitability and action potential (AP) properties. GnRH neurons from adult females were more excitable and required less current to initiate action potential firing compared with three-week-old females. Further, the afterhyperpolarization (AHP) potential of the first spike was larger and its peak was delayed in adulthood. These results indicate development, not PNA, is a primary driver of changes to GnRH neuron intrinsic properties and suggest there may be developmentally-induced changes to voltage-gated ion channels in GnRH neurons that alter how these cells respond to synaptic input., Competing Interests: The authors declare no competing financial interests., (Copyright © 2022 Jaime and Moenter.)

Polycystic ovary syndrome (PCOS) is a reproductive dysfunction associated with endocrine disorders and is most common in women of reproductive age. Clinical and/or biochemical manifestations include hyperandrogenism, persistent anovulation, polycystic ovary, insulin resistance, and obesity. Presently, the aetiology and pathogenesis of PCOS remain unclear. In recent years, the role of circadian rhythm changes in PCOS has garnered considerable attention. Changes in circadian rhythm can trigger PCOS through mechanisms such as oxidative stress and inflammation; however, the specific mechanisms are unclear. Exosomes are vesicles with sizes ranging from 30-120nm that mediate intercellular communication by transporting microRNAs (miRNAs), proteins, mRNAs, DNA, or lipids to target cells and are widely involved in the regulation of various physiological and pathological processes. Circadian rhythm can alter circulating exosomes, leading to a series of related changes and physiological dysfunctions. Therefore, we speculate that circadian rhythm-induced changes in circulating exosomes may be involved in PCOS pathogenesis. In this review, we summarize the possible roles of exosomes and their derived microRNAs in the occurrence and development of PCOS and discuss their possible mechanisms, providing insights into the potential role of exosomes for PCOS treatment., 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 © 2022 Chen, Huang, Wang, Zhuang, Lin and Shi.)

Polycystic ovary syndrome (PCOS) affects up to 20% of women but remains poorly understood. It is a heterogeneous condition with many potential comorbidities. This review offers an overview of the dysregulation of the reproductive and metabolic systems associated with PCOS. Review of the literature informed the development of a comprehensive summarizing 'wiring' diagram of PCOS-related features. This review provides a justification for each diagram aspect from the relevant academic literature, and explores the interactions between the hypothalamus, ovarian follicles, adipose tissue, reproductive hormones and other organ systems. The diagram will provide an efficient and useful tool for those researching and treating PCOS to understand the current state of knowledge on the complexity and variability of PCOS., 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 © 2022 Emanuel, Roberts, Docherty, Lunt, Campbell and Möller.)

Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder among women of reproductive age. Current standard treatment includes lifestyle change, oral pharmacological agents, and surgical modalities. However, the efficacy of current therapies is less than satisfactory. Clinical evidence has shown that acupuncture is effective for regulating hormone levels, promoting ovulation, and attenuating insulin resistance in patients with PCOS. Acupuncture may affect the production of β-endorphin, which may lead to gonadotropin-releasing hormone secretion and then affect ovulation, menstrual cycle, and fertility. The mechanism of acupuncture for patients with PCOS has not been comprehensively reviewed so far. Better understanding of the mechanisms of acupuncture would help popularize the use of acupuncture therapy for patients with PCOS. In this narrative review, we aimed to overview the potential mechanisms and evidence-based data of acupuncture on PCOS, and analyze the most frequently used acupoints based on animal and clinical studies. The results of this study will contribute to a better understanding of the current situation in this 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 © 2022 Ye, Zhou, Hu, Fukuzawa and Zhang.)

Ovarian hyperstimulation syndrome (OHSS) is a serious complication that remains a threat to every patient experiencing stimulation of ovulation. Polycystic ovary syndrome (PCOS) appears to be the most important predisposing factor for OHSS. The severity of OHSS is associated with the degree of the follicular response to the ovulation inducing agents. The objective of this study was to investigate the relationship between PCOS with the risk of moderate-to-severe OHSS in intracytoplasmic sperm injection treatment patients. Sixty patients in the reproductive ages (20-38), including OHSS patients and age-matched normoresponders were included in this study. Patients who had larger follicle counts on the day of hCG injection were considered at risk for developing moderate-to-severe OHSS. In addition, oocyte quality was assessed about 20-30 min after oocyte pickup. The incidence of OHSS in PCOS patients increased significantly up to 13.9 times higher than in patients without PCOS ( OR =13.900; P =0.007). Moreover, moderate-to-severe OHSS increased significantly ( OR =3.860; P =0.043) in patients with primary infertility than those with secondary infertility. In addition, oocyte quality was not affected with the severity of OHSS. In conclusion, the risk of moderate-to-severe OHSS is correlated with PCOS and primary infertility without affecting oocyte quality., Competing Interests: The authors declare that they have no conflict of interest.

Statistics indicate that at least 20-25% of women suffer from PCOS in the Gulf region. Despite its prevalence and negative implications on reproductive, metabolic, and physiological heath the exact cause of PCOS is unknown, in part due to the diversity of symptoms manifested by this disorder. In this review, we investigate causes of PCOS globally and draw on these studies, to determine the potential contributing factors for PCOS pathogenesis in the UAE population. The most frequently identified factors promoting PCOS pathogenesis that may be pertinent to this population include physiological factors such as insulin resistance, vitamin D deficiency, genetic factors, obesity, and anti-mullerian hormone (AMH) levels in the body as well as environmental factors such as air pollution, endocrine disrupting chemicals, and pesticide use. This evidence will help inform healthcare workers and government agencies to set up optimal guidelines for control and awareness of PCOS in the UAE., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Objective: The aim of the study was to explore the risk factors of ovarian hyperstimulation in patients undergoing long-acting gonadotropin-releasing hormone (GnRH) agonist protocol in follicular phase of ovulation induction therapy and to establish a predictive model., Patients and Methods: A total of 1289 patients who received Long-acting GnRH agonist protocol in follicular phase for ovulation induction in the Fujian Provincial Maternity and Child Health Hospital from July 1, 2018, to July 31, 2019, were selected. Among them, 33 patients developed moderate/severe ovarian hyperstimulation syndrome. The relevant indicators of the two groups were followed up for comparison, and Lasso regression was used to screen independent risk factors and construct a nomogram prediction model.  A receiver operating characteristic (ROC) curve and calibration curve were used to evaluate the discrimination and calibration of the prediction model., Results: Univariate analysis suggested that the woman's age, basal antral follicle number (AFC), total gonadotropin (Gn) dose, Gn starting dose, basal estradiol (E2) level, basal anti-Müllerian hormone (AMH) value, number of follicles obtained, Gn start day E2, the difference in follicle-stimulating hormone (FSH) value and Gn starting day were statistically significant. Significant indicators of univariate analysis and clinical significance were included in the Lasso regression model, and AFC, woman's age, polycystic ovary syndrome, Gn starting dose and number of follicles obtained were finally screened as final predictors. The ROC curve indicated that the area under the curve (AUC) was 0.812., Conclusions: Ovarian hyperstimulation caused by long-acting GnRH agonist protocol in follicular phase for ovulation stimulation has a certain predictability. Paying attention to the patient's age, AFC, Gn starting dose, number of follicles obtained, and whether PCOS is evident may lead to early detection of ovarian hyperstimulation syndrome, which has clinical guiding significance.

Polycystic ovary syndrome (PCOS) is a heterogeneous and extremely common disease with symptoms that vary with the age of the patient, typically characterized by hyperandrogenism, chronic oligo-anovulation, and/or several metabolic disorders. The syndrome includes various phenotypes, and the pathogenesis is multifactorial, often involving insulin resistance. This feature is closely related to ovarian dysfunction, inflammation, hyperandrogenism, and metabolic disorders, which characterize and complicate the syndrome. Therapy currently considers both lifestyle improvements and medications, and must be tailored on a case-by-case basis. To date, the published studies have not arrived at a definition of the most suitable therapy for each individual case and many of the drugs used are still off-label. In this review, we discuss some controversial diagnostic and therapeutic aspects of PCOS, such as the role of insulin resistance, inflammation, and hyperandrogenism. We also evaluated the advantages and disadvantages of contraceptive therapy and antiandrogens.

Polycystic ovary syndrome (PCOS) is a major endocrine disorder strongly associated with androgen excess and frequently leading to female infertility. Although classically considered an ovarian disease, altered neuroendocrine control of gonadotropin-releasing hormone (GnRH) neurons in the brain and abnormal gonadotropin secretion may underpin PCOS presentation. Defective regulation of GnRH pulse generation in PCOS promotes high luteinizing hormone (LH) pulsatile secretion, which in turn overstimulates ovarian androgen production. Early and emerging evidence from preclinical models suggests that maternal androgen excess programs abnormalities in developing neuroendocrine circuits that are associated with PCOS pathology, and that these abnormalities are sustained by postpubertal elevation of endogenous androgen levels. This article will discuss experimental evidence, from the clinic and in preclinical animal models, that has significantly contributed to our understanding of how androgen excess influences the assembly and maintenance of neuroendocrine impairments in the female brain. Abnormal central gamma-aminobutyric acid (GABA) signaling has been identified in both patients and preclinical models as a possible link between androgen excess and elevated GnRH/LH secretion. Enhanced GABAergic innervation and drive to GnRH neurons is suspected to contribute to the pathogenesis and early manifestation of neuroendocrine derangement in PCOS. Accordingly, this article also provides an overview of GABA regulation of GnRH neuron function from prenatal development to adulthood to discuss possible avenues for future discovery research and therapeutic interventions. © 2022 American Physiological Society. Compr Physiol 12:3347-3369, 2022., (Copyright © 2022 American Physiological Society. All rights reserved.)

Background: Obesity is observationally associated with altered risk of many female reproductive conditions. These include polycystic ovary syndrome (PCOS), abnormal uterine bleeding, endometriosis, infertility, and pregnancy-related disorders. However, the roles and mechanisms of obesity in the aetiology of reproductive disorders remain unclear. Thus, we aimed to estimate observational and genetically predicted causal associations between obesity, metabolic hormones, and female reproductive disorders., Methods and Findings: Logistic regression, generalised additive models, and Mendelian randomisation (MR) (2-sample, non-linear, and multivariable) were applied to obesity and reproductive disease data on up to 257,193 women of European ancestry in UK Biobank and publicly available genome-wide association studies (GWASs). Body mass index (BMI), waist-to-hip ratio (WHR), and WHR adjusted for BMI were observationally (odds ratios [ORs] = 1.02-1.87 per 1-SD increase in obesity trait) and genetically (ORs = 1.06-2.09) associated with uterine fibroids (UF), PCOS, heavy menstrual bleeding (HMB), and pre-eclampsia. Genetically predicted visceral adipose tissue (VAT) mass was associated with the development of HMB (OR [95% CI] per 1-kg increase in predicted VAT mass = 1.32 [1.06-1.64], P = 0.0130), PCOS (OR [95% CI] = 1.15 [1.08-1.23], P = 3.24 × 10-05), and pre-eclampsia (OR [95% CI] = 3.08 [1.98-4.79], P = 6.65 × 10-07). Increased waist circumference posed a higher genetic risk (ORs = 1.16-1.93) for the development of these disorders and UF than did increased hip circumference (ORs = 1.06-1.10). Leptin, fasting insulin, and insulin resistance each mediated between 20% and 50% of the total genetically predicted association of obesity with pre-eclampsia. Reproductive conditions clustered based on shared genetic components of their aetiological relationships with obesity. This study was limited in power by the low prevalence of female reproductive conditions among women in the UK Biobank, with little information on pre-diagnostic anthropometric traits, and by the susceptibility of MR estimates to genetic pleiotropy., Conclusions: We found that common indices of overall and central obesity were associated with increased risks of reproductive disorders to heterogenous extents in a systematic, large-scale genetics-based analysis of the aetiological relationships between obesity and female reproductive conditions. Our results suggest the utility of exploring the mechanisms mediating the causal associations of overweight and obesity with gynaecological health to identify targets for disease prevention and treatment., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: C.M.B. reports grants from Bayer AG, AbbVie Inc, Volition Rx, MDNA Life Sciences, Roche Diagnostics Inc., and consultancy for Myovant. He is a member of the independent data monitoring board at ObsEva; I.G. reports grants from Bayer AG; K.T.Z. reports grants from Bayer AG, AbbVie Inc, Volition Rx, MDNA Life Sciences, Roche Diagnostics Inc, and non-financial scientific collaboration with Population Diagnostics Ltd, outside the submitted work; M.V.H. has consulted for Boehringer Ingelheim, and in adherence to the University of Oxford’s Clinical Trial Service Unit & Epidemiological Studies Unit (CSTU) staff policy, did not accept personal honoraria or other payments from pharmaceutical companies; C.M.L. reports grants from Bayer AG and Novo Nordisk and has a partner who works at Vertex; no other relationships or activities that could appear to have influenced the submitted work. All disclosed competing interests are outside the submitted work.

As a common endocrinopathy of reproductive-aged women, polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, oligo-anovulation and polycystic ovarian morphology. It is linked with insulin resistance through preferential abdominal fat accumulation that is worsened by obesity. Over the past two millennia, menstrual irregularity, male-type habitus and sub-infertility have been described in women and confirm that these clinical features of PCOS were common in antiquity. Recent findings in normal-weight hyperandrogenic PCOS women show that exaggerated lipid accumulation by subcutaneous (SC) abdominal stem cells during development to adipocytes in vitro occurs in combination with reduced insulin sensitivity and preferential accumulation of highly-lipolytic intra-abdominal fat in vivo. This PCOS phenotype may be an evolutionary metabolic adaptation to balance energy storage with glucose availability and fatty acid oxidation for optimal energy use during reproduction. This review integrates fundamental endocrine-metabolic changes in healthy, normal-weight PCOS women with similar PCOS-like traits present in animal models in which tissue differentiation is completed during fetal life as in humans to support the evolutionary concept that PCOS has common ancestral and developmental origins., (© 2022. The Author(s).)

Polycystic ovary syndrome (PCOS) is an endocrine-gynecology disorder affecting many women of childbearing age. Although a part of the involved mechanism in PCOS occurrence is discovered, the exact etiology and pathophysiology are not comprehensively understood yet. We searched PubMed for PCOS pathogenesis and management in this article and ClinicalTrials.gov for information on repurposed medications. All responsible factors behind PCOS were thoroughly evaluated. Furthermore, the complete information on PCOS commonly prescribed and repurposed medications is summarized through tables. Epigenetics, environmental toxicants, stress, diet as external factors, insulin resistance, hyperandrogenism, inflammation, oxidative stress, and obesity as internal factors were investigated. Lifestyle modifications and complementary and alternative medicines are preferred first-line therapy in many cases. Medications, including 3-hydroxy-3-methyl-3-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors, thiazolidinediones, sodium-glucose cotransporter-2 inhibitors, dipeptidyl peptidase-4 inhibitors, glucose-like peptide-1 receptor agonists, mucolytic agents, and some supplements have supporting data for being repurposed in PCOS. Since there are few completed clinical trials with a low population and mostly without results on PCOS repurposed medications, it would be helpful to do further research and run well-designed clinical trials on this subject. Moreover, understanding more about PCOS would be beneficial to find new medications implying the effect via the novel discovered routes.

Background: Polycystic ovary syndrome (PCOS) and migraine headaches are considered to be common health problems that may share some risk factors. This study aimed to discuss the possible association between migraine headache and polycystic ovary syndrome., Methods and Results: In this narrative review, PubMed, Scopus, Web of Science, and Google Scholar were systematically searched for retrieving and summarizing published studies up to January 2021 to explore the possible interplay between migraine headache and PCOS. We discuss the possible pathways that may explain the association between migraine headaches and PCOS signs/symptoms and complications. While genetic factors have profound effects on the pathogenesis of migraine headaches, sex hormones, including estrogen and progesterone may also play an important role in inducing migraine headaches. Some disorders, such as sleep apnea, amenorrhea, and vascular disease that are more likely to occur in women with PCOS, may cause or exacerbate migraine headaches in women with PCOS., Conclusions: Future comprehensive studies are needed to investigate the exact underlining mechanisms related to the association between PCOS and migraine headaches., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Polycystic ovarian syndrome is a heterogenous endocrine disorder characterized by irregular menstrual cycles, hirsuitism and polycystic ovaries. It is further complicated by metabolic syndrome, infertility and psychological stress. Although the etiopathogenesis is unclear, many studies have pointed out the role of stress in this syndrome. DHEA, being a stress marker is being used by scientists to compare the stress levels between polycystic ovarian cases and healthy controls. However, the results obtained from previous studies are equivocal., Objective: To perform meta-analysis and find the association between stress and the syndrome., Data Sources: Relevant data till January 2021 were retrieved from PubMed, Scopus, Embase and Web of Science using MeSH terms., Study Selection: Case-control studies having PCOS subjects as cases and healthy women as controls were selected provided; their basal DHEA levels were mentioned in the published articles., Data Extraction: Two authors independently extracted the articles and qualified the final studies., Data Synthesi: Pooled meta-analysis was done using random effect model and showed level of DHEA statistically significant in PCOS compared to healthy controls (SMD = 1.15, 95% CI = 0.59-1.71).Heterogeneity was statistically significant as well (I2 = 95%)., Conclusion: Thismeta-analysis on DHEA and PCOS has helped in generating evidence regarding the involvement of stress in the pathogenesis of PCOS., Competing Interests: The authors declare no competing interests.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with insulin resistance and impaired energy metabolism in skeletal muscle, the aetiology of which is currently unclear. Here, we mapped the gene expression profile of skeletal muscle from women with PCOS and determined if cultured primary myotubes retain the gene expression signature of PCOS in vivo. Transcriptomic analysis of vastus lateralis biopsies collected from PCOS women showed lower expression of genes associated with mitochondrial function, while the expression of genes associated with the extracellular matrix was higher compared to controls. Altered skeletal muscle mRNA expression of mitochondrial-associated genes in PCOS was associated with lower protein expression of mitochondrial complex II-V, but not complex I, with no difference in mitochondrial DNA content. Transcriptomic analysis of primary myotube cultures established from biopsies did not display any differentially expressed genes between controls and PCOS. Comparison of gene expression profiles in skeletal muscle biopsies and primary myotube cultures showed lower expression of mitochondrial and energy metabolism-related genes in vitro, irrespective of the group. Together, our results show that the altered mitochondrial-associated gene expression in skeletal muscle in PCOS is not preserved in cultured myotubes, indicating that the in vivo extracellular milieu, rather than genetic or epigenetic factors, may drive this alteration. Dysregulation of mitochondrial-associated genes in skeletal muscle by extracellular factors may contribute to the impaired energy metabolism associated with PCOS.

Polycystic ovary syndrome (PCOS) is a global health concern for women of reproductive age, as 6.5% of women worldwide are affected by this syndrome. PCOS is marked by hyperandrogenism, anovulation, menstrual abnormalities, and polycystic ovaries. Metals such as arsenic, cadmium, lead and mercury are considered to be systemic toxicants/human carcinogens and seem to have devastating effects on humans, even at minimal exposures. One of the probable aetiological factors for PCOS has been identified as oxidative stress. In view of the probable associations among oxidative stress, metal toxicity and PCOS, the present study examined the role of heavy metals in the generation of oxidative stress among females. This prospective study included 106 women (56 women diagnosed with PCOS and 50 women who were not diagnosed with PCOS as control women). There were no significant differences in the sociodemographic characteristics between the two groups except for the irregularity of menses and the presence of acne. The serum As, Cd, Pb, and Hg levels increased and the serum glutathione (GSH) and superoxide dismutase (SOD) levels diminished significantly in the PCOS group compared to the control group at P < 0.001. The SOD levels were negatively correlated with the As and Pb levels at P < 0.05. Additionally, the PCOS group exhibited a strong negative correlation between the GSH and As levels (P < 0.01), GSH and Pb levels (P < 0.05) and GSH and Hg levels (P < 0.01). Furthermore, the As levels were positively correlated with increased levels of Cd, Pb and Hg among PCOS women. Significant positive correlations were observed between Pb and Cd and between Cd and Hg at P < 0.001. The outcome of the study provides clear insight into the role of metal-induced oxidative stress, which plays a vital role in the pathophysiology underlying PCOS and suggests the use of these markers as prognostic tools to reduce the consequences of high-risk exposure to these metals among females., (© 2021. The Author(s).)

This study was designed to assess for the first time the circulating and ovarian level of 14-3-3β protein in the PCOS mice and the possible correlation between 14-3-3β protein with PCOS related increase in testosterone (HA), insulin levels (HI) and reduced insulin sensitivity in the ovary. PCOS was induced in mice using treatment of letrozole (by oral gavage) for 21 days. Immunohistochemical study showed increased expression of 14-3-3β protein in PCOS ovary compared to the control ovary. The circulating testosterone and insulin levels, together with circulating and ovarian levels of 14-3-3β protein also showed significant increase in PCOS mice compared to the control mice. An increase in 14-3-3β protein was observed positively correlated with circulating testosterone and insulin levels but showed a negative correlation with ovarian expression of insulin receptor protein in PCOS mice. The treatment of 14-3-3β protein in vitro to the normal ovary showed a significant increase in testosterone synthesis but a significant decline in insulin receptor protein expression compared to the vehicle-treated ovary of adult mice. The present study showed the direct role of 14-3-3β protein in increasing testosterone synthesis along with decreasing insulin sensitivity. Thus, 14-3-3β protein may be playing possible role in PCOS pathogenesis., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The incidence of polycystic ovary syndrome (PCOS) due to high-fat diet (HFD) consumption has been increasing significantly. However, the mechanism by which a HFD contributes to the pathogenesis of PCOS has not been elucidated. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key protein that regulates cholesterol metabolism. Our previous study revealed abnormally high PCSK9 levels in serum from patients with PCOS and in serum and hepatic and ovarian tissues from PCOS model mice, suggesting that PCSK9 is involved in the pathogenesis of PCOS. However, the factor that induces high PCSK9 expression in PCOS remains unclear. In this study, Pcsk9 knockout mice were used to further explore the role of PCSK9 in PCOS. We also studied the effects of a HFD on the expression of PCSK9 and sterol regulatory element-binding protein 2 (SREBP2), a regulator of cholesterol homeostasis and a key transcription factor that regulates the expression of PCSK9, and the roles of these proteins in PCOS pathology. Our results indicated HFD may play an important role by inducing abnormally high PCSK9 expression via SREBP2 upregulation. We further investigated the effects of an effective SREBP inhibitor, fatostain, and found that it could reduce HFD-induced PCSK9 expression, ameliorate hyperlipidemia and improve follicular development in PCOS model mice. Our study thus further elucidates the important role of an HFD in the pathogenesis of PCOS and provides a new clue in the prevention and treatment of this disorder.

PCOS has a wide range of negative impacts on women's health and is one of the most frequent reproductive systemic endocrine disorders. PCOS has complex characteristics and symptom heterogeneity due to the several pathways that are involved in the infection and the absence of a comm14on cause. A recent study has shown that the main etiology and endocrine aspects of PCOS are the increased level of androgen, which is also known as "hyperandrogenemia (HA)" and secondly the "insulin resistance (IR)". The major underlying cause of the polycystic ovary is these two IR and HA, by initiating the disease and its severity or duration. As a consequence, study on Pathogenesis is crucial to understand the effect of "HA" and "IR" on the pathophysiology of numerous symptoms linked to PCOS. A deep understanding of the pattern of the growth in PCOS for HA and IR can help ameliorate the condition, along with adjustments in nutrition and life, as well as the discovery of new medicinal products. However, further research is required to clarify the mutual role of IR and HA on PCOS development., 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 Ding, Zhang, Zhang, Zhang, Chen, Liang and Xie.)

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.)

The increased global prevalence of obesity over the last 40-years has driven a rise in prevalence of obesity-related co-morbidities, including polycystic ovary syndrome (PCOS). On a background of genetic susceptibility, PCOS often becomes clinically manifest following weight gain, commonly during adolescence. A common endocrinopathy affecting between 6%-10% of reproductive-age women, PCOS presents with the cardinal features of hyperandrogenism, reproductive and metabolic dysfunction. PCOS associates with insulin resistance, independently of (but amplified by) obesity. Insulin resistance in PCOS is characterized by abnormal post-receptor signalling within the phosphatidylinositol-kinase (PI3-K) pathway. Multiple factors (including most notably, weight gain) contribute towards the severity of insulin resistance in PCOS. Compensatory hyperinsulinaemia ensues, resulting in over-stimulation of the (intact) post-receptor mitogen-activated protein kinase (MAP-K) insulin pathway, with consequent implications for steroidogenesis and ovarian function. In this concise review, we explore the effects of weight gain and obesity on the pathogenesis of PCOS from the perspective of its three cardinal features of hyperandrogenism, reproductive and metabolic dysfunction, with a focus on the central mediating role of the insulin pathway. We also consider key lifestyle strategies for the effective management of obese and overweight women with PCOS., (© 2021 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Little is known about the difference in effectiveness of lifestyle intervention between women with PCOS and non-PCOS women. In a post hoc longitudinal analysis of a randomized, controlled trial, we aimed to investigate whether infertile women with PCOS and obesity ( N = 87) responded differently to a 6-month lifestyle intervention program than infertile non-PCOS obese controls ( N = 172). We evaluated several aspects of the intervention such as changes in diet, physical activity, and dropout rate, as well as the effect on weight, quality of life (QoL), and cardiometabolic outcomes. Multilevel analyses were used, and analyses were adjusted for baseline characteristics such as age, education, and smoking. Although BMI in both groups significantly decreased at 3 months and 6 months, there were no significant differences between the groups at 3 months (adjusted B: -0.3, 95% CI: -0.9 to 0.3, p = 0.35) and 6 months (adjusted B: 0.5, 95% CI: -0.4 to 1.4, p = 0.29). Women with PCOS and non-PCOS women had similar compliance with the lifestyle intervention in terms of actual change in diet and physical activity. Mental QoL scores were not different at either 3 or 6 months. Physical QoL scores were lower in women with PCOS compared with non-PCOS women at 3 months (adjusted B: -2.4, 95% CI: -4.8 to -0.06, p = 0.045) but not at 6 months. Cardiometabolic parameters did not differ between the groups. Our results showed that infertile women with PCOS and obesity and non-PCOS obese controls responded largely similarly to our lifestyle intervention and achieved the same level of improvement in markers of cardiometabolic health.

Polycystic ovary syndrome (PCOS) is extremely heterogeneous in terms of clinical manifestations. The variability of the syndrome's phenotype is derived from the genetic and molecular heterogeneity, with a great deal of environmental factors that may have long-term health consequences, such as metabolic and cardiovascular (CV) diseases. There is no doubt that women with PCOS suffer from metabolic complications more than their age-matched counterparts in the general population and at an earlier age. Obesity, low steroid hormone-binding globulin (SHBG), hyperandrogenemia, insulin resistance, and compensatory hyperinsulinemia are biomediators and early predictors of metabolic complications in PCOS. Doubts remain about the real risk of CV diseases in PCOS and the molecular mechanisms at the basis of CV complications. Based on that assumption, this review will present the available evidence on the potential implications of some biomediators, in particular, hyperandrogenism, estrogen-progesterone imbalance, insulin resistance, and low SHBG, in the processes leading to CV disease in PCOS, with the final aim to propose a more accurate CV risk assessment.

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.

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.

A recent study by Mimouni et al. shows that late gestation exposure to anti-Müllerian hormone (AMH) results in transgenerational transmission of a polycystic ovary syndrome (PCOS)-like phenotype in mice. Altered DNA methylation underlies transmission and was also observed in women with PCOS. Epigenetics-based therapy reversed some PCOS-like phenotypic traits when applied to F 3 female mice., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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 and Aim: Anogenital distance (AGD) can serve as a life-long indicator of androgen action in gestational weeks 8-14. AGD has been used as an important tool to investigate the exposure to endocrine-disrupting compounds in newborns and in individuals with male reproductive disorder. Endometriosis and polycystic ovary syndrome (PCOS) are two common gynecological disorders and both are related to prenatal androgen levels. Therefore, we performed a systematic review to evaluate the relationships of AGD with these gynecological disorders., Methods: PubMed, Web of Science, and Embase were searched for published studies up to January 25, 2021. No language restriction was implemented., Results: Ten studies were included in this review. Five focused on women with endometriosis, and six investigated women with PCOS. According to these studies, PCOS patients had longer AGD than controls, while endometriosis patients had shorter AGD than controls. In conclusion, this study provides a detailed and accurate review of the associations of AGD with endometriosis and PCOS., Conclusion: The current findings indicate the longer AGD was related to PCOS and shorter AGD was related to endometriosis. However, further well-designed studies are needed to corroborate the current 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 Pan, Zhu and Zhou.)

Polycystic ovary syndrome (PCOS) is a common endocrine disease in females that is characterized by hyperandrogenemia, chronic anovulation, and polycystic ovaries. However, the exact etiology and pathogenesis of PCOS are still unknown. The aim of this study was to clarify the bacterial, stress status, and metabolic differences in the gut microbiomes of healthy individuals and patients with high body mass index (BMI) PCOS (PCOS-HB) and normal BMI PCOS (PCOS-LB), respectively. Here, we compared the gut microbiota characteristics of PCOS-HB, PCOS-LB, and healthy controls by 16S rRNA gene sequencing, FK506-binding protein 5 (FKBP5) DNA methylation and plasma metabolite determination. Clinical parameter comparisons indicated that PCOS patients had higher concentrations of total testosterone, androstenedione, dehydroepiandrosterone sulfate, luteinizing hormone, and HOMA-IR while lower FKBP5 DNA methylation. Significant differences in bacterial diversity and community were observed between the PCOS and healthy groups but not between the PCOS-HB and PCOS-LB groups. Bacterial species number was negatively correlated with insulin concentrations (both under fasting status and 120 min after glucose load) and HOMA-IR but positively related to FKBP5 DNA methylation. Compared to the healthy group, both PCOS groups had significant changes in bacterial genera, including Prevotella&#95;9, Dorea, Maihella, and Slackia, and plasma metabolites, including estrone sulfate, lysophosphatidyl choline 18:2, and phosphatidylcholine (22:6e/19:1). The correlation network revealed the complicated interaction of the clinical index, bacterial genus, stress indices, and metabolites. Our work links the stress responses and gut microbiota characteristics of PCOS disease, which might afford perspectives to understand the progression of PCOS., (© 2021. The Author(s).)

Objective: It has been suggested that adverse early life exposures increase the risk of developing polycystic ovary syndrome (PCOS) in later life. We hypothesized that women born preterm would have more biochemical and clinical signs of PCOS than women born at term., Design: The ESTER Preterm Birth Study participants were born in Northern Finland and identified from the Northern Finland Birth Cohort and the Finnish Medical Birth Register. Altogether, 74 women born very or moderately preterm (<34 gestational weeks, VMPT), 127 born late preterm (at 34-36 weeks, LPT), and 184 born full term (≥37 weeks, controls) were included in the analysis (mean age: 23.2 years)., Methods: We measured serum total testosterone and sex hormone-binding globulin (SHBG) and calculated the free androgen index (FAI). PCOS according to the clinical and biochemical signs was defined either as hirsutism and oligoamenorrhea (via questionnaire) or as oligoamenorrhea and elevated testosterone levels (>2.4 nmol/L)., Results: Women born VMPT/LPT exhibited 33.0% (8.7, 62.8)/16.4% (-2.0, 38.1) higher testosterone, 28.5% (5.3, 45.9)/24.1% (5.6, 38.9) lower SHBG levels, and 64.6% (19.4, 127.1)/42.5% (11.1, 82.9) higher FAI than controls after adjusting for age and recruitment cohort, maternal BMI, smoking, and pregnancy disorders, parental education, history of hypertension, diabetes, myocardial infarction or stroke, and subject's birth weight s.d. Odds ratios for having PCOS were 1.67 (0.44, 6.23)/3.11 (1.26, 7.70)., Conclusions: Women born preterm have a more hyperandrogenic hormonal profile, and those born LPT are approximately three times more likely at risk to have PCOS compared to women born at term.

Objectives: There is a growing evidence indicating an impact of endocrine distrupting chemicals such as bisphenol A (BPA) on human reproduction. Its higher levels in serum or urine have been documented in women with polycystic ovary syndrome (PCOS), however the relationship to ovarian steroidogenesis remains unclear. Aim of the study was to compare urinary BPA (U-BPA) concentrations among PCOS women and control group. Second aim was to assess the relationship of U-BPA to ovarian steroidogenesis in the group with PCOS., Methods: Eighty six Caucasian women (age 28.5 ± 5.1 years) diagnosed with PCOS and 32 controls of age 24.9 ± 4.4 years were included in the study. Fasting blood samples were analyzed for biochemical parameters and steroid hormones. U-BPA was measured in the morning urine sample using high pressure liquid chromatography., Results: PCOS women had significantly higher U-BPA as compared with control group (p=0.0001). Those with high levels of U-BPA (U-BPA ≥ 2.14 ug/g creatinine) demonstrated higher serum insulin (p=0.029) and HOMA IR (p=0.037), lower serum estrone (p=0.05), estradiol (p=0.0126), FSH (p=0.0056), and FAI (p=0.0088), as compared with low-BPA group (U- BPA <2.14 ug/g creatinine). In PCOS women, U-BPA positively correlated with age (p=0.0026; R 2 =0.17), negatively with estradiol (p=0.0001, R 2 =0.5), testosterone (p=0.0078, R 2 =0.15), free-testosterone (p=0.0094, R 2 =0.12) and FAI (p=0.0003, R 2 =0.32), respectively., Conclusions: PCOS women have significantly higher U-BPA concentrations than healthy controls. U-BPA positively correlates with age and negatively with ovarian steroid hormones suggesting a possible suppressive effect of bisphenol A on ovarian steroidogenesis., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Introduction: Polycystic ovary syndrome (PCOS) is caused by the hormonal environment in utero, abnormal metabolism, and genetics, and it is common in women of childbearing age. A large number of studies have reported that lncRNA is important to the biological process of cancer and can be used as a potential prognostic biomarker. Thus, we studied lncRNAs' roles in PCOS in this article., Methods: We obtained mRNAs', miRNAs', and lncRNAs' expression profiles in PCOS specimens and normal specimens from the National Biotechnology Information Gene Expression Comprehensive Center database. The EdgeR software package is used to distinguish the differentially expressed lncRNAs, miRNAs, and mRNAs. Functional enrichment analysis was carried out by the clusterProfiler R Package, and the lncRNA-miRNA-mRNA interaction ceRNA network was built in Cytoscape plug-in BiNGO and Database for Annotation, Visualization, and Integration Discovery (DAVID), respectively., Results: We distinguished differentially expressed RNAs, including 1087 lncRNAs, 14 miRNAs, and 566 mRNAs in PCOS. Among them, 410 lncRNAs, 11 miRNAs, and 185 mRNAs were contained in the ceRNA regulatory network. The outcomes from Gene Ontology (GO) analysis showed that the differentially expressed mRNAs (DEMs) were mainly enriched in response to the maternal process involved in female pregnancy, morphogenesis of embryonic epithelium, and the intracellular steroid hormone receptor signaling pathway. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis data showed that DEMs were primarily enriched in pathways related to the TGF- β signaling pathway, Type I diabetes mellitus, and glycolysis/gluconeogenesis. In addition, we chose NONHSAT123397, ENST00000564619, and NONHSAT077997 as key lncRNAs due to their high bearing on PCOS., Conclusion: ceRNA networks play an important role in PCOS. The research indicated that specific lncRNAs were related to PCOS development. NONHSAT123397, ENST00000564619, and NONHSAT077997 could be regarded as potential diagnostic mechanisms and biomarkers for PCOS. This discovery might provide more effective and more novel insights into the mechanisms of PCOS worthy of further exploration., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Yuanqi Li and Yong Tan.)

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.)

Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disease. PCOS patients are characterized by hyperandrogenemia, anovulation, and metabolic dysfunction. Hypothalamus-pituitary-ovary axis imbalance is considered as an important pathophysiology underlying PCOS, indicating that central modulation, especially the abnormal activation of hypothalamic GnRH neurons plays a vital role in PCOS development. Increased GnRH pulse frequency can promote LH secretion, leading to ovarian dysfunction and abnormal sex steroids synthesis. By contrast, peripheral sex steroids can modulate the action of GnRH neurons through a feedback effect, which is impaired in PCOS, thus forming a vicious cycle. Additionally, hypothalamic GnRH neurons not only serve as the final output pathway of central control of reproductive axis, but also as the central connection point where reproductive function and metabolic state inter-regulate with each other. Metabolic factors, such as insulin resistance and obesity in PCOS patients can regulate GnRH neurons activity, and ultimately regulate reproductive function. Besides, gut hormones act on both brain and peripheral organs to modify metabolic state. Gut microbiota disturbance is also related to many metabolic diseases and has been reported to play an essential part in PCOS development. This review concludes with the mechanism of central modulation and the interaction between neuroendocrine factors and reproductive or metabolic disorders in PCOS development. Furthermore, the role of the gut microenvironment as an important part involved in the abnormal neuronal-reproductive-metabolic circuits that contribute to PCOS is discussed, thus offering possible central and peripheral therapeutic targets for PCOS 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 Liao, Qiao and Pang.)

Context: Higher prevalence of polycystic ovary syndrome (PCOS) in women with type 1 diabetes (T1DM) is linked to exogenous insulin, especially when diabetes is diagnosed before puberty., Objective: The study evaluates the impact of prepubertal onset of T1DM and insulin therapy on PCOS diagnosis and phenotypic characteristics in women with T1DM., Design, Setting, and Patients: We studied 83 women with T1DM (age 26 ± 5 years, BMI 24 ± 3 kg/m2) 36 with premenarchal (PM) onset of T1DM [17 with PCOS diagnosed (PCOS+PM) and 19 without PCOS (noPCOS+PM)] and 47 women with postmenarchal onset of T1DM [24 with PCOS (PCOS-noPM) and 23 without PCOS (noPCOS-noPM)]., Outcome Measurements: Clinical examination, assessment of serum sex hormones, glycated hemoglobin (HbA1c) and ultrasonographic evaluation of the ovaries were performed in all women., Results: Applying Rotterdam criteria, 49% of women with T1DM were diagnosed with PCOS. There were no differences in hormonal profile and ovarian parameters between PCOS+PM and PCOS-noPM. Women with T1DM+PM had higher insulin dose/24 h and U/kg bw/24 h than T1DM-noPM (P-values = 0.014 and 0.001, respectively). Both PCOS+PM and noPCOS+PM groups had higher insulin dose U/kg bw/24 h in comparison to PCOS-noPM (P-values = 0.004 and = 0.006, respectively). In multivariable logistic regression analysis, age of menarche [odds ratio (OR): 0.672; 95% confidence interval (CI): 0.465-0.971] and HbA1c (OR: 0.569; 95% CI: 0.383-0.846) were associated with the diagnosis of PCOS., Conclusions: There were no differences in the prevalence of PCOS between T1DM+PM and T1DM-noPM; however, earlier menarche might have an influence on PCOS diagnosis in women with T1DM., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)