Journal articles on the topic 'Ovary; human PCOS; KITL'
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Henríquez, Soledad, Paulina Kohen, Xia Xu, Claudio Villarroel, Alex Muñoz, Ana Godoy, Jerome F. Strauss, and Luigi Devoto. "Significance of pro-angiogenic estrogen metabolites in normal follicular development and follicular growth arrest in polycystic ovary syndrome." Human Reproduction 35, no. 7 (June 19, 2020): 1655–65. http://dx.doi.org/10.1093/humrep/deaa098.
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Abstract STUDY QUESTION Do alterations in pro- and anti-angiogenic estrogen metabolites in follicular fluid (FF) contribute to the follicular growth arrest and anovulation associated with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER FF of PCOS women with anovulation have reduced levels of pro-angiogenic estrogen metabolites (EMs) and vascular endothelial growth factor (VEGF) compared to that of fertile women with regular menstrual cycles, but exogenous gonadotropins increase the pro-angiogenic EMs and VEGF levels in PCOS women. WHAT IS KNOWN ALREADY PCOS is characterized by the arrest of follicular development that leads to chronic anovulation. Follicular arrest is generally associated with elevated plasma levels of luteinizing hormone (LH), androgens and anti-Mullerian hormone (AMH). There is also reduced angiogenesis in the follicles of PCOS women compared to those of normal cycling women. It is known that angiogenesis is a critical factor during follicular development. We and other investigators have explored the role of EMs in ovarian angiogenesis, particularly in human corpus luteum function, showing that 4-hydroxyestrone (4-OHE1) and 16-ketoestradiol (16-kE2) have pro-angiogenic effects while 2-methoxyestradiol (2-ME2) and 2-methoxyestrone (2-ME1) have anti-angiogenic effects. Additionally, 2-hydroxyestradiol (2-OHE2), which is produced in the ovary, has proliferative and pro-angiogenic properties. We hypothesized that EMs could be involved in angiogenesis necessary for ovarian follicular development in fertile women, and that dysregulation of these factors may contribute to follicular arrest in PCOS. The relationship between EMs, VEGF and AMH in the pathophysiology of follicular arrest in PCOS has not been previously studied at a follicular level in anovulatory women without ovulation induction. STUDY DESIGN, SIZE, DURATION This is a comparative experimental study of serum and FF collected from different sized follicles (antral ˂10 mm and dominant ˃16 mm) of women with and without ovarian stimulation. The study included women with regular menstrual cycles who were proven to be fertile (n = 20) and PCOS women with follicular arrest who were candidates for ovarian drilling (n = 17), as well as other patients requiring ovarian stimulation, i.e. control women undergoing IVF for male factor infertility (n = 12) and PCOS women undergoing IVF (n = 17). In vitro studies were carried out on granulosa-lutein cells (GCs) obtained from subsets of women undergoing IVF for male factor infertility (n = 6) and PCOS women undergoing IVF (n = 6). GCs were maintained in culture for up to 6 days. PARTICIPANTS/MATERIALS, SETTING, METHODS Intrafollicular estradiol, estrone and EMs concentrations were determined by high performance liquid chromatography–mass spectrometry. Testosterone in serum was measured by RIA, and LH, FSH and sex hormone-binding globulin in serum were measured with IRMA kits. AMH was determined in serum and FF by enzyme linked immunosorbant assay (ELISA). VEGF levels were measured in FF and conditioned medium by ELISA. Conditioned medium were obtained from cultured GCs. The angiogenic potential was assessed by in vitro angiogenic assays. MAIN RESULTS AND THE ROLE OF CHANCE Pro-angiogenic EMs (4-OHE1, 16-kE2 and 2-OHE2) and VEGF were lower in FF of antral follicles of PCOS women with follicular arrest compared those of fertile women with ovulatory cycles (P < 0.05). In contrast, higher concentrations of AMH were found in FF of antral follicles from PCOS women with follicular arrest compared to those of fertile women with ovulatory cycles (P < 0.05). Exogenous gonadotropins used in IVF increased pro-angiogenic EMs and VEGF production in PCOS women, reaching similar profiles compared to control women receiving gonadotropins in their IVF treatment for male factor infertility. The pro-angiogenic EM 2-OHE2 increased the angiogenic potential and VEGF levels of GCs from PCOS women compared to the basal condition (P < 0.05). These findings suggest that there is a role for pro-angiogenic EMs in the control of follicular VEGF production. LIMITATIONS, REASONS FOR CAUTION The limitations include the possibility that in vitro analysis of GCs might not reflect the in vivo mechanisms involved in the pro-angiogenic action of 2-OHE2 since GCs obtained at the time of oocyte retrieval belong to a very early stage of the luteal phase and might not be representative of GCs during follicular growth. Therefore, our findings do not conclusively rule out the possibility that other in vivo mechanisms also account for defective angiogenesis observed in PCOS. WIDER IMPLICATIONS OF THE FINDINGS The present study highlights the significance of EMs, angiogenic factors and AMH and their interaction in the pathophysiology of follicular development in PCOS. This study provides new insights into the role of pro-angiogenic factors in follicular arrest in PCOS. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by CONICYT/FONDECYT 1140693 and NIH grant R01HD083323. All authors declare no conflict of interest. TRIAL REGISTRATION NUMBER N/A
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Diao, FY, M. Xu, Y. Hu, J. Li, Z. Xu, M. Lin, L. Wang, et al. "The molecular characteristics of polycystic ovary syndrome (PCOS) ovary defined by human ovary cDNA microarray." Journal of Molecular Endocrinology 33, no. 1 (August 1, 2004): 59–72. http://dx.doi.org/10.1677/jme.0.0330059.
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Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders; it is characterized by polycystic ovaries, hyperandrogenism and chronic anovulation. To obtain a global view of those genes that might be involved in the development of this complex clinical disorder, we used recently developed cDNA microarray technology to compare differential gene expressions between normal human ovary and ovaries from PCOS patients. A total of 9216 clones randomly selected from a commercial human ovary cDNA library were screened. Among them, 290 clones showed differential expressions, including 119 known genes and 100 known or unknown expressed sequence tags (ESTs). Among 119 known genes, 88 were upregulated and 31 downregulated in the PCOS ovary, as compared with normal human ovary. These differentially expressed genes are involved in various biologic functions, such as cell division/apoptosis, regulation of gene expression and metabolism, reflecting the complexity of clinical manifestations of PCOS. The molecular characteristics established from our study will further our understanding of the pathogenesis of PCOS and help us to identify new targets for further studies and for the development of new therapeutic interventions.
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Dumesic, Daniel A., R. Dee Schramm, and David H. Abbott. "Early origins of polycystic ovary syndrome." Reproduction, Fertility and Development 17, no. 3 (2005): 349. http://dx.doi.org/10.1071/rd04092.
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The prenatally androgenised female rhesus monkey has become a model for polycystic ovary syndrome (PCOS) in women, with early prenatal androgenisation entraining a permanent PCOS-like phenotype characterised by luteinising hormone (LH) hypersecretion due to reduced hypothalamic sensitivity to steroid negative feedback and relative insulin excess associated with increased abdominal adiposity. These combined reproductive and metabolic abnormalities occur in combination with ovarian hyperandrogenism and follicular arrest in adulthood, and with premature follicle differentiation and impaired embryo development during gonadotrophin therapy for in vitro fertilization (IVF). The ability of prenatal androgen excess in fetal rhesus monkeys to entrain multiple organ systems in utero provides evidence that the hormonal environment of intrauterine life programmes target tissue differentiation, raising the possibility that hyperandrogenism in human fetal development promotes PCOS in adulthood. This hypothesis developed in prenatally androgenised female rhesus monkeys, however, also must include data from clinical studies of PCOS to clarify the homology between human and non-human primates in intrafollicular steroidogenesis and its impact on oocyte developmental competency. By doing so, future studies promise to develop new clinical strategies that will lead to improved pregnancy outcome and reduced pregnancy loss in women with disorders of insulin action, including PCOS, obesity and diabetes mellitus.
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Szeliga, Anna, Ewa Rudnicka, Marzena Maciejewska-Jeske, Marek Kucharski, Anna Kostrzak, Marta Hajbos, Olga Niwczyk, Roman Smolarczyk, and Blazej Meczekalski. "Neuroendocrine Determinants of Polycystic Ovary Syndrome." International Journal of Environmental Research and Public Health 19, no. 5 (March 6, 2022): 3089. http://dx.doi.org/10.3390/ijerph19053089.
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Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women and a major cause of anovulatory infertility. A diagnosis of PCOS is established based the presence of two out of three clinical symptoms, which are criteria accepted by the ESHRE/ASRM (European Society of Human Reproduction and Embryology/American Society for Reproductive Medicine). Gonadotropin-releasing hormone (GnRH) is responsible for the release of luteinizing hormone, and follicle stimulating hormone from the pituitary and contributes a leading role in controlling reproductive function in humans. The goal of this review is to present the current knowledge on neuroendocrine determinations of PCOS. The role of such neurohormones as GnRH, and neuropeptides kisspeptin, neurokinin B, phoenixin-14, and galanin is discussed in this aspect. Additionally, different neurotransmitters (gamma-aminobutyric acid (GABA), glutamate, serotonin, dopamine, and acetylcholine) can also be involved in neuroendocrine etiopathogenesis of PCOS. Studies have shown a persistent rapid GnRH pulse frequency in women with PCOS present during the whole ovulatory cycle. Other studies have proved that patients with PCOS are characterized by higher serum kisspeptin levels. The observations of elevated serum kisspeptin levels in PCOS correspond with the hypothesis that overactivity in the kisspeptin system is responsible for hypothalamic-pituitary-gonadal axis overactivity. In turn, this causes menstrual disorders, hyperandrogenemia and hyperandrogenism. Moreover, abnormal regulation of Neurokinin B (NKB) is also suspected of contributing to PCOS development, while NKB antagonists are used in the treatment of PCOS leading to reduction in Luteinizing hormone (LH) concentration and total testosterone concentration. GnRH secretion is regulated not only by kisspeptin and neurokinin B, but also by other neurohormones, such as phoenixin-14, galanin, and Glucagon-like peptide-1 (GLP-1), that have favorable effects in counteracting the progress of PCOS. A similar process is associated with the neurotransmitters such as GABA, glutamate, serotonin, dopamine, and acetylcholine, as well as the opioid system, which may interfere with secretion of GnRH, and therefore, influence the development and severity of symptoms in PCOS patients. Additional studies are required to explain entire, real mechanisms responsible for PCOS neuroendocrine background.
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Tamadon, Amin, Wei Hu, Peng Cui, Tong Ma, Xiaoyu Tong, Feifei Zhang, Xin Li, Linus R. Shao, and Yi Feng. "How to choose the suitable animal model of polycystic ovary syndrome?" Traditional Medicine and Modern Medicine 01, no. 02 (June 2018): 95–113. http://dx.doi.org/10.1142/s2575900018300047.
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Polycystic ovary syndrome (PCOS) is a gynecological metabolic and endocrine disorder with uncertain etiology. To understand the etiology of PCOS or the evaluation of various therapeutic agents, different animal models have been introduced. Considering this fact that is difficult to develop an animal model that mimics all aspects of this syndrome, but, similarity of biological, anatomical, and/or biochemical features of animal model to the human PCOS phenotypes can increase its application. This review paper evaluates the recently researched animal models and introduced the best models for different research purposes in PCOS studies. During January 2013 to January 2017, 162 studies were identified which applied various kinds of animal models of PCOS including rodent, primate, ruminant and fish. Between these models, prenatal and pre-pubertal androgen rat models and then prenatal androgen mouse model have been studied in detail than others. The comparison of main features of these models with women PCOS demonstrates higher similarity of these three models to human conditions. Thereafter, letrozole models can be recommended for the investigation of various aspects of PCOS. Interestingly, similarity of PCOS features of post-pubertal insulin and human chorionic gonadotropin rat models with women PCOS were considerable which can make it as a good choice for future investigations.
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Nahar, Kamrun. "Polycystic Ovary Syndrome in Teenage and Young Women." Journal of Bangladesh College of Physicians and Surgeons 37, no. 2 (March 13, 2019): 78–82. http://dx.doi.org/10.3329/jbcps.v37i2.40564.
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Polycystic ovary syndrome (PCOS) is an inherent ovarian dysfunction. It is a common health problem that can affect teen girls and young women. PCOS is characterized by hyperandrogenism, irregular ovulatory cycle and metabolic derangement , including glucose intolerance and hyperinsulinaemia. Hyperandrogenism is a clinical hallmark of PCOS. Hypersecretion of androgen by the stromal theca cell of polycystic ovary is cardinal clinical manifestation. Though the exact cause of PCOS is not known , the syndrome can result from disturbance in the hypothalamo pituitary ovarian axis and hyperinsulinaemia. Several definitions have been produced to describe the disease. European society of human reproduction and embryology and the American society for reproductive medicine in 2004 define PCOS as manifestation of two of the following three
J Bangladesh Coll Phys Surg 2019; 37(2): 78-82
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Piltonen, Terhi, Riitta Koivunen, Antti Perheentupa, Laure Morin-Papunen, Aimo Ruokonen, and Juha S. Tapanainen. "Ovarian Age-Related Responsiveness to Human Chorionic Gonadotropin in Women with Polycystic Ovary Syndrome." Journal of Clinical Endocrinology & Metabolism 89, no. 8 (August 1, 2004): 3769–75. http://dx.doi.org/10.1210/jc.2003-031851.
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Ovarian steroid secretion capacity starts to decline as early as around the age of 30 yr. Whether an age-related decrease in androgen secretion, as in normal women, also occurs in women with polycystic ovary syndrome (PCOS) and whether the enhanced androgen production in PCOS remains throughout the fertile period of life are not known. The aim of this study was to determine the age-related serum basal and gonadotropin-stimulated androgen levels in women with PCOS and to compare the results with those obtained from our previous study in healthy women with normal ovaries. Human chorionic gonadotropin (hCG) stimulation tests were carried out among 42 women with PCOS (age, 16–44 yr; body mass index, 31.02 ± 1.1 kg/m2). An im injection of 5000 IU hCG was given 2–4 d after spontaneous or progestin-induced menstrual bleeding, and blood samples for LH, FSH, inhibin B, 17-hydroxyprogesterone, androstenedione (A), testosterone (T), and estradiol assays were collected at 0, 24, 48, and 96 h. In women with PCOS, basal serum T and A levels were about 50% higher than in healthy women. The responses of A and T to hCG [area under the curve (AUC), 96 h)] were significantly higher in women with PCOS than in normal women [A, 1183.6 ± 60 (±se) vs. 814.4 ± 39 (P ≤ 0.001); T, 192.9 ± 12 vs. 117.4 ± 6; P ≤ 0.001]. In PCOS women, the hCG-stimulated A levels correlated negatively with age (AUC of A: r = −0.044; P = 0.004), and a similar trend was also observed in AUC T levels (AUC of T: r = −0.125, P = 0.425). Despite the higher androgen secretion capacity in PCOS, the basal and hCG-stimulated serum estradiol levels were similar to those observed in normal women. LH correlated positively with age, but basal FSH and inhibin B levels remained unchanged. In conclusion, in PCOS basal serum levels of androgens and ovarian androgen secretion capacity are markedly increased and remain high throughout the reproductive years, although the decreasing ovarian capacity to release androgens in response to hCG stimulation seen in healthy women also occurs in PCOS.
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Dumesic, Daniel A., Luis R. Hoyos, Gregorio D. Chazenbalk, Rajanigandha Naik, Vasantha Padmanabhan, and David H. Abbott. "Mechanisms of intergenerational transmission of polycystic ovary syndrome." Reproduction 159, no. 1 (January 2020): R1—R13. http://dx.doi.org/10.1530/rep-19-0197.
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Developmental origins of adult disease (DoHAD) refers to critical gestational ages during human fetal development and beyond when the endocrine metabolic status of the mother can permanently program the physiology and/or morphology of the fetus, modifying its susceptibility to disease after birth. The aim of this review is to address how DoHAD plays an important role in the phenotypic expression of polycystic ovary syndrome (PCOS), the most common endocrinopathy of women characterized by hyperandrogenism, oligo-anovulation and polycystic ovarian morphology. Clinical studies of PCOS women are integrated with findings from relevant animal models to show how intergenerational transmission of these central components of PCOS are programmed through an altered maternal endocrine–metabolic environment that adversely affects the female fetus and long-term offspring health. Prenatal testosterone treatment in monkeys and sheep have been particularly crucial in our understanding of developmental programming of PCOS because organ system differentiation in these species, as in humans, occurs during fetal life. These animal models, along with altricial rodents, produce permanent PCOS-like phenotypes variably characterized by LH hypersecretion from reduced steroid-negative feedback, hyperandrogenism, ovulatory dysfunction, increased adiposity, impaired glucose-insulin homeostasis and other metabolic abnormalities. The review concludes that DoHAD underlies the phenotypic expression of PCOS through an altered maternal endocrine–metabolic environment that can induce epigenetic modifications of fetal genetic susceptibility to PCOS after birth. It calls for improved maternal endocrine–metabolic health of PCOS women to lower their risks of pregnancy-related complications and to potentially reduce intergenerational susceptibility to PCOS and its metabolic derangements in offspring.
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Li, Da, Yue You, Fang-Fang Bi, Tie-Ning Zhang, Jiao Jiao, Tian-Ren Wang, Yi-Ming Zhou, Zi-Qi Shen, Xiu-Xia Wang, and Qing Yang. "Autophagy is activated in the ovarian tissue of polycystic ovary syndrome." Reproduction 155, no. 1 (January 2018): 85–92. http://dx.doi.org/10.1530/rep-17-0499.
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The importance of autophagy in polycystic ovary syndrome (PCOS)-related metabolic disorders is increasingly being recognized, but few studies have investigated the role of autophagy in PCOS. Here, transmission electron microscopy demonstrated that autophagy was enhanced in the ovarian tissue from both humans and rats with PCOS. Consistent with this, ovarian granulosa cells from PCOS rats showed increases in the autophagy marker protein light chain 3B (LC3B), whereas levels of the autophagy substrate SQSTM1/p62 were decreased. In addition, the ratio of LC3-II/LC3-I was markedly elevated in human PCOS ovarian tissue compared with normal ovarian tissue. Real-time PCR arrays indicated that 7 and 34 autophagy-related genes were down- and up-regulated in human PCOS , Signal-Net, and regression analysis suggested that there are a wide range of interactions among these 41 genes, and a potential network based on EGFR, ERBB2, FOXO1, MAPK1, NFKB1, IGF1, TP53 and MAPK9 may be responsible for autophagy activation in PCOS. Systematic functional analysis of 41 differential autophagy-related genes indicated that these genes are highly involved in specific cellular processes such as response to stress and stimulus, and are linked to four significant pathways, including the insulin, ERBB, mTOR signaling pathways and protein processing in the endoplasmic reticulum. This study provides evidence for a potential role of autophagy disorders in PCOS in which autophagy may be an important molecular event in the pathogenesis of PCOS.
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Kechagias, Konstantinos S., Anita Semertzidou, Antonios Athanasiou, Maria Paraskevaidi, and Maria Kyrgiou. "Bisphenol-A and polycystic ovary syndrome: a review of the literature." Reviews on Environmental Health 35, no. 4 (November 18, 2020): 323–31. http://dx.doi.org/10.1515/reveh-2020-0032.
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AbstractPolycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age with reproductive, metabolic and endocrine implications. While the exact pathophysiological mechanisms of the syndrome are unknown, its heterogeneity suggests a multifactorial causal background. In the last two decades, numerous environmental chemicals, including Bisphenol-A (BPA) that is used in the synthesis of polycarbonate plastics, have been proposed as potential contributors to the aetiology of PCOS. This review provides a holistic overview of the available data regarding the possible relation of PCOS with BPA exposure. We have included a total number of 24 studies. Eleven human case-control and 13 animal studies provided data regarding this potential relation. Accumulating evidence suggests that a correlation between high levels of BPA and the presence of PCOS may exist. Contradicting results from human and animal studies, however, render it difficult to conclude on the exact role of BPA in the pathogenesis of PCOS. BPA may constitute a consequence of the syndrome rather than a cause, but further research is still needed to clarify this. Continued efforts to study the early origins of PCOS, using prospective-designed studies, are required to identify the exact effect of BPA on women with PCOS.
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Wang, Fangfang, Jiexue Pan, Ye Liu, Qing Meng, Pingping Lv, Fan Qu, Guo-Lian Ding, et al. "Alternative splicing of the androgen receptor in polycystic ovary syndrome." Proceedings of the National Academy of Sciences 112, no. 15 (March 30, 2015): 4743–48. http://dx.doi.org/10.1073/pnas.1418216112.
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Polycystic ovary syndrome (PCOS) is one of the most common female endocrine disorders and a leading cause of female subfertility. The mechanism underlying the pathophysiology of PCOS remains to be illustrated. Here, we identify two alternative splice variants (ASVs) of the androgen receptor (AR), insertion and deletion isoforms, in granulosa cells (GCs) in ∼62% of patients with PCOS. AR ASVs are strongly associated with remarkable hyperandrogenism and abnormalities in folliculogenesis, and are absent from all control subjects without PCOS. Alternative splicing dramatically alters genome-wide AR recruitment and androgen-induced expression of genes related to androgen metabolism and folliculogenesis in human GCs. These findings establish alternative splicing of AR in GCs as the major pathogenic mechanism for hyperandrogenism and abnormal folliculogenesis in PCOS.
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Charifson, Mia A., and Benjamin C. Trumble. "Evolutionary origins of polycystic ovary syndrome: An environmental mismatch disorder." Evolution, Medicine, and Public Health 2019, no. 1 (January 1, 2019): 50–63. http://dx.doi.org/10.1093/emph/eoz011.
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Abstract Polycystic ovary syndrome (PCOS) is the most common female endocrine disorder and has important evolutionary implications for female reproduction and health. PCOS presents an interesting paradox, as it results in significant anovulation and potential sub-fecundity in industrialized populations, yet it has a surprisingly high prevalence and has a high heritability. In this review, we discuss an overview of PCOS, current diagnostic criteria, associated hormonal pathways and a review of proposed evolutionary hypotheses for the disorder. With a multifactorial etiology that includes ovarian function, metabolism, insulin signaling and multiple genetic risk alleles, PCOS is a complex disorder. We propose that PCOS is a mismatch between previously neutral genetic variants that evolved in physically active subsistence settings that have the potential to become harmful in sedentary industrialized environments. Sedentary obesogenic environments did not exist in ancestral times and exacerbate many of these pathways, resulting in the high prevalence and severity of PCOS today. Overall, the negative impacts of PCOS on reproductive success would likely have been minimal during most of human evolution and unlikely to generate strong selection. Future research and preventative measures should focus on these gene-environment interactions as a form of evolutionary mismatch, particularly in populations that are disproportionately affected by obesity and metabolic disorders. Lay Summary The most severe form of polycystic ovary syndrome (PCOS) is likely a result of interactions between genetic predispositions for PCOS and modern obesogenic environments. PCOS would likely have been less severe ancestrally and the fitness reducing effects of PCOS seen today are likely a novel product of sedentary, urban environments.
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Kelley, Angela S., Yolanda R. Smith, and Vasantha Padmanabhan. "A Narrative Review of Placental Contribution to Adverse Pregnancy Outcomes in Women With Polycystic Ovary Syndrome." Journal of Clinical Endocrinology & Metabolism 104, no. 11 (August 8, 2019): 5299–315. http://dx.doi.org/10.1210/jc.2019-00383.
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Abstract Context Polycystic ovary syndrome (PCOS) is the most common endocrinopathy of reproductive-aged women. In pregnancy, women with PCOS experience increased risk of miscarriage, gestational diabetes, preeclampsia, and extremes of fetal birth weight, and their offspring are predisposed to reproductive and cardiometabolic dysfunction in adulthood. Pregnancy complications, adverse fetal outcomes, and developmental programming of long-term health risks are known to have placental origins. These findings highlight the plausibility of placental compromise in pregnancies of women with PCOS. Evidence Synthesis A comprehensive PubMed search was performed using terms “polycystic ovary syndrome,” “placenta,” “developmental programming,” “hyperandrogenism,” “androgen excess,” “insulin resistance,” “hyperinsulinemia,” “pregnancy,” and “pregnancy complications” in both human and animal experimental models. Conclusions There is limited human placental research specific to pregnancy of women with PCOS. Gestational androgen excess and insulin resistance are two clinical hallmarks of PCOS that may contribute to placental dysfunction and underlie the higher rates of maternal–fetal complications observed in pregnancies of women with PCOS. Additional research is needed to prevent adverse maternal and developmental outcomes in women with PCOS and their offspring.
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Luo, Xiaodong, Yangyang Gong, Liuyun Cai, Lei Zhang, and Xiaojing Dong. "Chemerin regulates autophagy to participate in polycystic ovary syndrome." Journal of International Medical Research 49, no. 11 (November 2021): 030006052110583. http://dx.doi.org/10.1177/03000605211058376.
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Objective Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder in women of reproductive age. Chemerin has recently been discovered as a novel adipokine associated with obesity and metabolic syndrome. Excessive autophagy activity and overexpression of autophagy-related genes in follicular granulosa cells are important mechanisms of PCOS. This study aimed to investigate the effect of chemerin on autophagy in PCOS. Methods A rat model of PCOS was established by subcutaneous injection of testosterone propionate under a high-fat diet. Expression levels of chemerin and its receptor CMKLR1 were determined by real-time polymerase chain reaction and western blot. Proliferation and apoptosis of human granulosa cells in vitro and expression of autophagy-related genes were examined using bafilomycin A1 (autophagy inhibitor) and Torin1 (autophagy inducer). Results Chemerin and CMKLR1 expression were significantly increased in the ovary in a rat model of PCOS. Ectopic expression of chemerin promoted the proliferation and inhibited the apoptosis of COV434 cells. Ectopic expression of chemerin also induced autophagy by inhibiting the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway. Conclusions Chemerin and CMKLR1 were overexpressed in PCOS rats. Chemerin promoted autophagy through inhibiting the PI3K/Akt/mTOR pathway, and may provide a potential target and biomarker of PCOS.
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Koike, Hiroshi, Miyuki Harada, Akari Kusamoto, Chisato Kunitomi, Zixin Xu, Tsurugi Tanaka, Yoko Urata, et al. "Notch Signaling Induced by Endoplasmic Reticulum Stress Regulates Cumulus-Oocyte Complex Expansion in Polycystic Ovary Syndrome." Biomolecules 12, no. 8 (July 27, 2022): 1037. http://dx.doi.org/10.3390/biom12081037.
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Endoplasmic reticulum (ER) stress activated in granulosa cells contributes to the pathophysiology of polycystic ovary syndrome (PCOS). In addition, recent studies have demonstrated that Notch signaling plays multiple roles in the ovary via cell-to-cell interactions. We hypothesized that ER stress activated in granulosa cells of antral follicles in PCOS induces Notch signaling in these cells, and that activated Notch signaling induces aberrant cumulus-oocyte complex (COC) expansion. Expression of Notch2 and Notch-target transcription factors was increased in granulosa cells of PCOS patients and model mice. ER stress increased expression of Notch2 and Notch-target transcription factors in cultured human granulosa-lutein cells (GLCs). Inhibition of Notch signaling abrogated ER stress-induced expression of genes associated with COC expansion in cultured human GLCs, as well as ER stress-enhanced expansion of cumulus cells in cultured murine COCs. Furthermore, inhibition of Notch signaling reduced the areas of COCs in PCOS model mice with activated ER stress in the ovary, indicating that Notch signaling regulates COC expansion in vivo. Our findings suggest that Notch2 signaling is activated in granulosa cells in PCOS and regulates COC expansion. It remains to be elucidated whether aberrant COC expansion induced by the ER stress-Notch pathway is associated with ovulatory dysfunction in PCOS patients.
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Ahmad, Ayesha, and Tamkin Khan. "Polycystic Ovary Syndrome: Crossing the Frontiers in Management." International Journal of Human and Health Sciences (IJHHS) 6, no. 4 (September 18, 2022): 362. http://dx.doi.org/10.31344/ijhhs.v6i4.474.
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Polycystic ovarian syndrome (PCOS) is one of the most common endocrine disorders in women with a heterogeneous clinico-pathologic spectrum characterised by varying degrees of ovulatory dysfunction and clinical and/ or biochemical features of hyperandrogenism. The etiopathogenesis of PCOS remains controversial with multiple genetic variants and environmental factors interacting together to foster development of the spectrum of clinical features. This article explores the evolving concepts of PCOS, focusing on the role of circadian rhythm and white adipose tissue; the role of precision medicine involving interplay of pharmacogenomics, nutrigenomics, chronotherapy and psychotherapy.International Journal of Human and Health Sciences Vol. 06 No. 04 Oct’22 Page: 362-371
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Hu, Kai-Lun, Hongcui Zhao, Zheying Min, Yilei He, Tianjie Li, Xiumei Zhen, Yun Ren, Hsun-Ming Chang, Yang Yu, and Rong Li. "Increased Expression of KISS1 and KISS1 Receptor in Human Granulosa Lutein Cells—Potential Pathogenesis of Polycystic Ovary Syndrome." Reproductive Sciences 26, no. 11 (December 30, 2018): 1429–38. http://dx.doi.org/10.1177/1933719118818899.
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Kisspeptins are a family of neuropeptides that are essential for fertility. Recent experimental data suggest a putative role of kisspeptin signaling in the direct control of ovarian function. To explore the expression of KISS1 and KISS1 receptor (KISS1R) in human granulosa lutein cells and the potential role of KISS1/KISS1R system in the pathogenesis of polycystic ovary syndrome (PCOS), we measured the concentration of KISS1 in follicular fluid, the expression of KISS1 and KISS1R in granulosa lutein cells, and the circulating hormones. The expression levels of KISS1 and KISS1R were significantly upregulated in human granulosa lutein cells obtained from women with PCOS. The expression levels of KISS1 in human granulosa lutein cells highly correlated with those of KISS1R in non-PCOS patients, but not in patients with PCOS, most likely due to the divergent expression patterns in women with PCOS. Additionally, the expression levels of KISS1 highly correlated with the serum levels of anti-Müllerian hormone (AMH). The expression levels of KISS1 and KISS1R, as well as the follicular fluid levels of KISS1, were not significantly different between the pregnant and nonpregnant patients in both PCOS and non-PCOS groups. In conclusion, the increased expression of KISS1 and KISS1R in human granulosa lutein cells may contribute to the pathogenesis of PCOS. The expression levels of KISS1 highly correlated with the serum levels of AMH. The KISS1 and KISS1R system in the ovary may not have a remarkable role in predicting the in vitro fertilization (IVF) outcome.
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Dai, Guo, and Guangxiu Lu. "Different protein expression patterns associated with polycystic ovary syndrome in human follicular fluid during controlled ovarian hyperstimulation." Reproduction, Fertility and Development 24, no. 7 (2012): 893. http://dx.doi.org/10.1071/rd11201.
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Polycystic ovary syndrome (PCOS) is one of the most common causes of anovulatory infertility, affecting 5–10% of females during their reproductive life. Currently the pathology of PCOS is largely unknown. To identify the differential protein expression in follicular fluids from PCOS and normal subjects during controlled ovarian hyperstimulation, we performed an initial proteomic study including two-dimensional gel electrophoresis (2DE) analysis and mass spectroscopy, and confirmed results by western blot. Thirty-two protein spots were shown to be significantly differentially expressed between PCOS and normal follicular fluids, of which 20 unique proteins were identified to be associated with cellular metabolism and physiological processes; 13 of these proteins were upregulated while seven were downregulated in PCOS follicular fluids. Western blotting analyses confirmed the differential expressions for three randomly selected proteins, i.e. upregulated α1-antitrypsin, apolipoprotein A-I and transferrin in follicular fluid from PCOS patients than normal controls. Furthermore, semiquantitative reverse transcription-polymerase chain reaction (RT–PCR) analyses revealed that mRNA levels of serine palmitoyltransferase 2, serine/threonine-protein kinase male germ cell-associated kinase (MAK) and DNA damage-regulated autophagy modulator protein 2 decreased significantly in granulosa cells of PCOS patients compared with normal samples. These results increase our understanding of PCOS and the identified genes may serve as candidate biomarkers to develop diagnostic and therapeutic tools.
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Ryu, Youngjae, Sung Woo Kim, Yoon Young Kim, and Seung-Yup Ku. "Animal Models for Human Polycystic Ovary Syndrome (PCOS) Focused on the Use of Indirect Hormonal Perturbations: A Review of the Literature." International Journal of Molecular Sciences 20, no. 11 (June 3, 2019): 2720. http://dx.doi.org/10.3390/ijms20112720.
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Hormonal disturbances, such as hyperandrogenism, are considered important for developing polycystic ovary syndrome (PCOS) in humans. Accordingly, directly hormone-regulated animal models are widely used for studying PCOS, as they replicate several key PCOS features. However, the pathogenesis and treatment of PCOS are still unclear. In this review, we aimed to investigate animal PCOS models and PCOS-like phenotypes in animal experiments without direct hormonal interventions and determine the underlying mechanisms for a better understanding of PCOS. We summarized animal PCOS models that used indirect hormonal interventions and suggested or discussed pathogenesis of PCOS-like features in animals and PCOS-like phenotypes generated in other animals. We presented integrated physiological insights and shared cellular pathways underlying the pathogenesis of PCOS in reviewed animal models. Our review indicates that the hormonal and metabolic changes could be due to molecular dysregulations, such as upregulated PI3K-Akt and extracellular signal-regulated kinase (ERK) signalling, that potentially cause PCOS-like phenotypes in the animal models. This review will be helpful for considering alternative animal PCOS models to determine the cellular/molecular mechanisms underlying PCOS symptoms. The efforts to determine the specific cellular mechanisms of PCOS will contribute to novel treatments and control methods for this complex syndrome.
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Hirshfeld-Cytron, Jennifer, Randall B. Barnes, David A. Ehrmann, Anthony Caruso, Monica M. Mortensen, and Robert L. Rosenfield. "Characterization of Functionally Typical and Atypical Types of Polycystic Ovary Syndrome." Journal of Clinical Endocrinology & Metabolism 94, no. 5 (May 1, 2009): 1587–94. http://dx.doi.org/10.1210/jc.2008-2248.
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Abstract Context: The typical polycystic ovary syndrome (PCOS) phenotype includes 17-hydroxyprogesterone (17OHP) hyperresponsiveness to GnRH agonist (GnRHag) testing. Functionally atypical PCOS lacks this feature. Objective: The hypothesis was tested that the typical PCOS ovarian dysfunction results from intrinsically increased sensitivity to LH/human chorionic gonadotropin (hCG) due to a flaw in FSH action. Participants/Design/Interventions/Main Outcome Measures: After phenotyping a cohort of 60 women, steroid and inhibin-B responses to gonadotropins were evaluated in representative typical (n = 7) and atypical (n = 5) PCOS and healthy controls (n = 8). Submaximal hCG testing before and after an FSH test dose was performed in random order before and after prolonged ovarian suppression by depot GnRHag. Setting: The study was performed at a Clinical Research Center. Results: Of our PCOS cohort, 68% were the typical type. Typical PCOS had 17OHP hyperresponsiveness and, unlike controls, significant androgen and estradiol responses to hCG. FSH increased inhibin-B and did not inhibit free testosterone or enhance estradiol responsiveness to hCG, all unlike controls. After ovarian suppression, 17OHP, androstenedione, and inhibin-B responsiveness to gonadotropin testing persisted. Atypical PCOS had significantly higher body mass index but lower ovarian volume and plasma free testosterone than typical PCOS. Steroid responses to hCG were insignificant and similar to controls. FSH suppressed free testosterone but stimulated inhibin-B. The estradiol level after combined hCG-FSH was subnormal. Free testosterone was less GnRHag suppressible than in typical PCOS. Conclusions: Typical PCOS is characterized by intrinsic ovarian hypersensitivity to hCG to which excessive paracrine FSH signaling via inhibin-B may contribute. Atypical PCOS is due to a unique type of ovarian dysfunction that is relatively gonadotropin hyposensitive.
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Fang, Lanlan, Sijia Wang, Yiran Li, Yiping Yu, Yuxi Li, Yang Yan, Jung-Chien Cheng, and Ying-Pu Sun. "High GDF-8 in follicular fluid is associated with a low pregnancy rate in IVF patients with PCOS." Reproduction 160, no. 1 (July 2020): 11–19. http://dx.doi.org/10.1530/rep-20-0077.
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Polycystic ovary syndrome (PCOS) is the most common cause of female infertility. Growth differentiation factor-8 (GDF-8) is expressed in the ovary and can be detected in human follicular fluid which provides an important microenvironment for maintaining physiological functions of the ovarian follicle. To date, the relationship between GDF-8 levels in follicular fluid and the risk of PCOS is completely unknown. In the present study, we show that during the process of the controlled ovarian hyperstimulation (COH), serum GDF-8 levels are higher on the day of gonadotropin administration and 14 days after embryo transfer in in vitro fertilization (IVF) patients with PCOS than they are in IVF patients without PCOS. Importantly, GDF-8 levels in follicular fluid at oocyte retrieval are also higher in PCOS patients than in non-PCOS patients. Treatment of primary human granulosa-lutein (hGL) cells with GDF-8 downregulates StAR protein expression and the inhibition is more pronounced in hGL cells from PCOS patients than it is in cells from non-PCOS patients. Importantly, high GDF-8 levels and low progesterone (P4) levels were associated with poor pregnancy outcomes in PCOS patients. Our results provide the first evidence that aberrant expression of GDF-8 in the follicular fluid of PCOS patients results in abnormal P4 expression, which leads to poor pregnancy outcomes.
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McCartney, Christopher R., Amy B. Bellows, Melissa B. Gingrich, Yun Hu, William S. Evans, John C. Marshall, and Johannes D. Veldhuis. "Exaggerated 17-hydroxyprogesterone response to intravenous infusions of recombinant human LH in women with polycystic ovary syndrome." American Journal of Physiology-Endocrinology and Metabolism 286, no. 6 (June 2004): E902—E908. http://dx.doi.org/10.1152/ajpendo.00415.2003.
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Studies using pharmacological gonadotropin stimulation suggest that ovarian steroidogenesis is abnormal in the polycystic ovary syndrome (PCOS). We assessed ovarian steroid secretion in response to near-physiological gonadotropin stimuli in 12 ovulatory controls and 7 women with PCOS. A gonadotropin-releasing hormone-receptor antagonist (ganirelix, 2 mg sc) was given to block endogenous LH secretion, followed by dexamethasone (0.75 mg orally) to suppress adrenal androgen secretion. After ganirelix injection (12 h), intravenous infusions of recombinant human LH (0, 10, 30, 100, and 300 IU; each over 8 min) were administered at 4-h intervals in a pseudorandomized (highest dose last) manner. Plasma LH, 17-hydroxyprogesterone (17-OHP), androstenedione, and testosterone were measured concurrently. LH dose-steroid response relationships (mean sex-steroid concentration vs. mean LH concentration over 4 h postinfusion) were examined for each subject. Linear regression of 17-OHP on LH yielded a higher (mean ± SE) slope in PCOS (0.028 ± 0.010 vs. 0.005 ± 0.005, P < 0.05), whereas extrapolated 17-OHP at zero LH was similar. The slopes of other regressions did not differ from zero in either PCOS or controls. We conclude that near-physiological LH stimulation drives heightened 17-OHP secretion in patients with PCOS, suggesting abnormalities of early steps of ovarian steroidogenesis. With the exception of 17-OHP response in PCOS, no acute LH dose-ovarian steroid responses were observed in controls or PCOS. Defining the precise mechanistic basis of heightened precursor responsiveness to LH in PCOS will require further clinical investigation.
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McDonnell, Tara, Leanne Cussen, Marie McIlroy, and Michael W. O’Reilly. "Characterizing skeletal muscle dysfunction in women with polycystic ovary syndrome." Therapeutic Advances in Endocrinology and Metabolism 13 (January 2022): 204201882211131. http://dx.doi.org/10.1177/20420188221113140.
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Polycystic ovary syndrome (PCOS) is the most common endocrine condition affecting women. It has traditionally been viewed as a primarily reproductive disorder; however, it is increasingly recognized as a lifelong metabolic disease. Women with PCOS are at increased risk of insulin resistance (IR), type 2 diabetes mellitus, non-alcoholic fatty liver disease and cardiovascular disease. Although not currently a diagnostic criterion, IR is a cardinal pathophysiological feature and highly prevalent in women with PCOS. Androgens play a bidirectional role in the pathogenesis of IR, and there is a complex interplay between IR and androgen excess in women with PCOS. Skeletal muscle has a key role in maintaining metabolic homeostasis and is also a metabolic target organ of androgen action. Skeletal muscle is the organ responsible for the majority of insulin-mediated glucose disposal. There is growing interest in the relationship between skeletal muscle, androgen excess and mitochondrial dysfunction in the pathogenesis of metabolic disease in PCOS. Molecular mechanisms underpinning defects in skeletal muscle dysfunction in PCOS remain to be elucidated, but may represent promising targets for future therapeutic intervention. In this review, we aim to explore the role of skeletal muscle in metabolism, focusing particularly on perturbations in skeletal muscle specific to PCOS as observed in recent molecular and in vivo human studies. We review the possible role of androgens in the pathophysiology of skeletal muscle abnormalities in PCOS, and identify knowledge gaps, areas for future research and potential therapeutic implications. Despite increasing interest in the area of skeletal muscle dysfunction in women with PCOS, significant challenges and unanswered questions remain, and going forward, novel innovative approaches will be required to dissect the underlying mechanisms.
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Stepto, Nigel K., Alba Moreno-Asso, Luke C. McIlvenna, Kirsty A. Walters, and Raymond J. Rodgers. "Molecular Mechanisms of Insulin Resistance in Polycystic Ovary Syndrome: Unraveling the Conundrum in Skeletal Muscle?" Journal of Clinical Endocrinology & Metabolism 104, no. 11 (April 2, 2019): 5372–81. http://dx.doi.org/10.1210/jc.2019-00167.
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Abstract Context Polycystic ovary syndrome (PCOS) is a common endocrine condition affecting 8% to 13% of women across the lifespan. PCOS affects reproductive, metabolic, and mental health, generating a considerable health burden. Advances in treatment of women with PCOS has been hampered by evolving diagnostic criteria and poor recognition by clinicians. This has resulted in limited clinical and basic research. In this study, we provide insights into the current and future research on the metabolic features of PCOS, specifically as they relate to PCOS-specific insulin resistance (IR), that may affect the most metabolically active tissue, skeletal muscle. Current Knowledge PCOS is a highly heritable condition, yet it is phenotypically heterogeneous in both reproductive and metabolic features. Human studies thus far have not identified molecular mechanisms of PCOS-specific IR in skeletal muscle. However, recent research has provided new insights that implicate energy-sensing pathways regulated via epigenomic and resultant transcriptomic changes. Animal models, while in existence, have been underused in exploring molecular mechanisms of IR in PCOS and specifically in skeletal muscle. Future Directions Based on the latest evidence synthesis and technologies, researchers exploring molecular mechanisms of IR in PCOS, specifically in muscle, will likely need to generate new hypothesis to be tested in human and animal studies. Conclusion Investigations to elucidate the molecular mechanisms driving IR in PCOS are in their early stages, yet remarkable advances have been made in skeletal muscle. Overall, investigations have thus far created more questions than answers, which provide new opportunities to study complex endocrine conditions.
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de Oliveira, Natália M., Jorge Machado, Zaiwei Huang, and Maria Begoña Criado. "Acupuncture in Women with Human Polycystic Ovary/Ovarian Syndrome: Protocol for a Randomized Controlled Trial." Healthcare 10, no. 10 (October 11, 2022): 1999. http://dx.doi.org/10.3390/healthcare10101999.
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(1) Background: Human polycystic ovary/ovarian syndrome (PCOS) is linked to endocrine, metabolic, and psychological complications. We propose a randomized controlled pilot study for an acupuncture protocol regarding the management of PCOS symptoms based on TCM diagnosis; (2) Methods: We will randomly allocate 120 women diagnosed with PCOS into two groups. The study group will be treated with acupuncture for points known to act upon the autonomous regulation of the hormonal, metabolic and emotional components. (3) Results and Conclusions: We expect to provide evidence of high methodological quality related to the effects and safety of an acupuncture protocol based on the perspective of a TCM diagnostic.
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Kang, Xuezhi, Lina Jia, and Xueyong Shen. "Manifestation of Hyperandrogenism in the Continuous Light Exposure-Induced PCOS Rat Model." BioMed Research International 2015 (2015): 1–9. http://dx.doi.org/10.1155/2015/943694.
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Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder, and its pathogenesis has yet to be completely clarified. A fully convincing animal model has not been established for PCOS. In earlier studies, researchers have shown that the exposure of rats to continuous light can induce PCOS; nevertheless, hyperandrogenism, a key characteristic observed in human PCOS, has not been reported previously. In the present study, we found that (1) body weights decreased in female rats in a continuous light environment with both ovarian and uterine augmentation; (2) the estrous cycle in rats under continuous light environment was disordered, and polycystic ovary-like changes occurred, accompanied with fur loss and lethargy; and (3) serum testosterone levels in rats in a continuous light environment significantly increased. Our data suggest that continuous light can lead to the occurrence of PCOS in female rats without the need for drugs; this is a reasonable PCOS animal model that is more consistent with the natural disease state in humans; and poor sleep habits or negligence of sleep hygiene may be an important lifestyle factor in pathogenesis of PCOS.
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Zhou, Rao, Cristin M. Bruns, Ian M. Bird, Joseph W. Kemnitz, Daniel A. Dumesic, and David H. Abbott. "Experimentally Induced Hyperinsulinemia Fails to Induce Polycystic Ovary Syndrome-like Traits in Female Rhesus Macaques." International Journal of Molecular Sciences 23, no. 5 (February 27, 2022): 2635. http://dx.doi.org/10.3390/ijms23052635.
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As in women with polycystic ovary syndrome (PCOS), hyperinsulinemia is associated with anovulation in PCOS-like female rhesus monkeys. Insulin sensitizers ameliorate hyperinsulinemia and stimulate ovulatory menstrual cycles in PCOS-like monkeys. To determine whether hyperinsulinemia (>694 pmol/L), alone, induces PCOS-like traits, five PCOS-like female rhesus monkeys with minimal PCOS-like traits, and four control females of similar mid-to-late reproductive years and body mass index, received daily subcutaneous injections of recombinant human insulin or diluent for 6–7 months. A cross-over experimental design enabled use of the same monkeys in each treatment phase. Insulin treatment unexpectedly normalized follicular phase duration in PCOS-like, but not control, females. In response to an intramuscular injection of 200 IU hCG, neither prenatally androgenized nor control females demonstrated ovarian hyperandrogenic responses while receiving insulin. An intravenous GnRH (100 ng/kg) injection also did not reveal evidence of hypergonadotropism. Taken together, these results suggest that experimentally induced adult hyperinsulinemia, alone, is insufficient to induce PCOS-like traits in female rhesus monkeys and to amplify intrinsic PCOS-like pathophysiology.
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Li, Miao, Han Zhao, Shi-Gang Zhao, Dai-Min Wei, Yue-Ran Zhao, Tao Huang, Tahir Muhammad, et al. "The HMGA2-IMP2 Pathway Promotes Granulosa Cell Proliferation in Polycystic Ovary Syndrome." Journal of Clinical Endocrinology & Metabolism 104, no. 4 (September 21, 2018): 1049–59. http://dx.doi.org/10.1210/jc.2018-00544.
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Abstract Context The high mobility group AT hook 2 (HMGA2) gene was previously identified in a genome-wide association study as a candidate risk gene that might be related to polycystic ovary syndrome (PCOS). Whether HMGA2 contributes to promoting granulosa cell (GC) proliferation in PCOS remains unknown. Objective We sought to determine whether HMGA2 is involved in the ovarian dysfunction of PCOS and in the mechanism of increased GC proliferation. Patients and Cells mRNA expression was analyzed in ovarian GCs from 96 women with PCOS and 58 healthy controls. Immortalized human GCs (KGN and SVOG cells) were used for the mechanism study. Main Outcome Measures mRNA expression in ovarian GCs was measured using quantitative RT-PCR, and KGN cells were cultured for proliferation assays after overexpression or knockdown of target genes. Protein expression analysis, luciferase assays, and RNA binding protein immunoprecipitation assays were used to confirm the mechanism study. Results HMGA2 and IGF2 mRNA binding protein 2 (IMP2) were highly expressed in the GCs of women with PCOS, and the HMGA2/IMP2 pathway promoted GC proliferation. Cyclin D2 and SERPINE1 mRNA binding protein 1 were regulated by IMP2 and were highly expressed in women with PCOS. Conclusions The HMGA2/IMP2 pathway was activated in women with PCOS and promoted the proliferation of GCs. This might provide new insights into the dysfunction of GCs in PCOS.
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Abbott, Rogers, Dumesic, and Levine. "Naturally Occurring and Experimentally Induced Rhesus Macaque Models for Polycystic Ovary Syndrome: Translational Gateways to Clinical Application." Medical Sciences 7, no. 12 (November 27, 2019): 107. http://dx.doi.org/10.3390/medsci7120107.
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Indian rhesus macaque nonhuman primate models for polycystic ovary syndrome (PCOS) implicate both female hyperandrogenism and developmental molecular origins as core components of PCOS etiopathogenesis. Establishing and exploiting macaque models for translational impact into the clinic, however, has required multi-year, integrated basic-clinical science collaborations. Paradigm shifting insight has accrued from such concerted investment, leading to novel mechanistic understanding of PCOS, including hyperandrogenic fetal and peripubertal origins, epigenetic programming, altered neural function, defective oocytes and embryos, adipogenic constraint enhancing progression to insulin resistance, pancreatic decompensation and type 2 diabetes, together with placental compromise, all contributing to transgenerational transmission of traits likely to manifest in adult PCOS phenotypes. Our recent demonstration of PCOS-related traits in naturally hyperandrogenic (High T) female macaques additionally creates opportunities to employ whole genome sequencing to enable exploration of gene variants within human PCOS candidate genes contributing to PCOS-related traits in macaque models. This review will therefore consider Indian macaque model contributions to various aspects of PCOS-related pathophysiology, as well as the benefits of using macaque models with compellingly close homologies to the human genome, phenotype, development and aging.
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Julania, Shital, Melanie L. Walls, and Roger Hart. "The Place of In Vitro Maturation in PCO/PCOS." International Journal of Endocrinology 2018 (July 31, 2018): 1–8. http://dx.doi.org/10.1155/2018/5750298.
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In vitro maturation (IVM) of human oocytes is an emerging treatment option for women with polycystic ovary/polycystic ovary syndrome (PCO/PCOS) in addition to the standard in vitro fertilization (IVF) treatment. There has been significant improvements in pregnancy rates with IVM over the last two decades. This article reviews the place of IVM for women with PCO/PCOS, placing an emphasis on the predictors of successful pregnancy, optimization of culture media, IVM protocols, pregnancy rates, and neonatal outcomes following IVM treatment.
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Srnovršnik, Tinkara, Irma Virant-Klun, and Bojana Pinter. "Polycystic Ovary Syndrome and Endocrine Disruptors (Bisphenols, Parabens, and Triclosan)—A Systematic Review." Life 13, no. 1 (January 4, 2023): 138. http://dx.doi.org/10.3390/life13010138.
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Exposure to endocrine disrupting chemicals (EDCs) can result in alterations of the female reproductive system, including polycystic ovary syndrome (PCOS). The aim of this review was to summarize the knowledge about the association of EDCs (bisphenols, parabens, and triclosan) with PCOS. We conducted an electronic literature search using PubMed for studies published between January 2007 and October 2022 on EDCs related to PCOS, and evaluated the association of PCOS with bisphenols, parabens and triclosan in 15 articles. Most studies revealed significantly higher plasma, urinary or follicular fluid levels of bisphenol A (BPA) in women with PCOS, and some showed a positive correlation of BPA with insulin resistance, polycystic morphology on ultrasound, hepatic steatosis, bilirubin levels, as well as free androgen index, androstenedione and testosterone serum levels, and markers of low-grade chronic inflammation. There was a negative correlation of BPA with markers of ovarian reserve, sex hormone binding globulin and vitamin D–binding protein. Parabens and triclosan have been studied in only one study each, with no significant associations with PCOS observed. Our review revealed an association of BPA with PCOS and negative effects of BPA on human ovaries; more research is needed to assess the potential associations of parabens and triclosan with PCOS.
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Wilson, Jenny L., Weiyi Chen, Gregory A. Dissen, Sergio R. Ojeda, Michael A. Cowley, Cecilia Garcia-Rudaz, and Pablo J. Enriori. "Excess of Nerve Growth Factor in the Ovary Causes a Polycystic Ovary-Like Syndrome in Mice, which Closely Resembles Both Reproductive and Metabolic Aspects of the Human Syndrome." Endocrinology 155, no. 11 (November 1, 2014): 4494–506. http://dx.doi.org/10.1210/en.2014-1368.
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Abstract Polycystic ovarian syndrome (PCOS), the most common female endocrine disorder of unknown etiology, is characterized by reproductive abnormalities and associated metabolic conditions comprising insulin resistance, type 2 diabetes mellitus, and dyslipidemia. We previously reported that transgenic overexpression of nerve growth factor (NGF), a marker of sympathetic hyperactivity, directed to the ovary by the mouse 17α-hydroxylase/C17–20 lyase promoter (17NF mice), results in ovarian abnormalities similar to those seen in PCOS women. To investigate whether ovarian overproduction of NGF also induces common metabolic alterations of PCOS, we assessed glucose homeostasis by glucose tolerance test, plasma insulin levels, and body composition by dual-energy x-ray absorptiometry scan in young female 17NF mice and wild-type mice. 17NF mice exhibited increased body weight and alterations in body fat distribution with a greater accumulation of visceral fat compared with sc fat (P < .01). 17NF mice also displayed glucose intolerance (P < .01), decreased insulin-mediated glucose disposal (P < .01), and hyperinsulinemia (P < .05), which, similar to PCOS patients, occurred independently of body weight. Additionally, 17NF mice exhibited increased sympathetic outflow observed as increased interscapular brown adipose tissue temperature. This change was evident during the dark period (7 pm to 7 am) and occurred concomitant with increased interscapular brown adipose tissue uncoupling protein 1 expression. These findings suggest that overexpression of NGF in the ovary may suffice to cause both reproductive and metabolic alterations characteristic of PCOS and support the hypothesis that sympathetic hyperactivity may contribute to the development and/or progression of PCOS.
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Subashree, Ilangovan, Umakant Ramchandra Valvekar, and Geetha Prasad. "Study of serum calcium and vitamin D levels with hormonal profile along with biochemical profile in women with polycystic ovary syndrome." International Journal of Reproduction, Contraception, Obstetrics and Gynecology 6, no. 9 (August 28, 2017): 4075. http://dx.doi.org/10.18203/2320-1770.ijrcog20174065.
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Background: The polycystic ovary syndrome (PCOS) is one of the commonest human endocrinopathies and is increasingly recognized as a variant of the metabolic syndrome in women with the characteristic features of insulin resistance, central obesity, impaired glucose metabolism, dyslipidemia, and hypertension.Methods: This study is mainly focused on study of parameters like gonadotropin hormonal profile, serum vitamin D and calcium levels in polycystic ovary disease (PCOD). The study comprised 45 clinically proven polycystic ovary disease patients in the age range of 19-34 years. The biochemical estimations carried out in the study were – Fasting Blood sugar, LH, FSH, prolactin, 25- OH vitamin D and calcium along with anthropometric data. The values obtained were compared with age matched equal number of healthy control female subjects from the same population.Results: The serum concentration of calcium and vitamin D levels are decreased significantly (P <0.001) when compared to controls. Insulin resistance is predominantly seen in PCOS subjects. The study outlines the importance of insulin resistance, dyslipidemia, decreased serum calcium and vitamin D levels in PCOS subjects may be a cause for the progression of polycystic ovary syndrome.Conclusions: In the present study vitamin D deficiency is highly prevalent in PCOS women from this area compared to control women. We also relations of vitamin D status with insulin sensitivity, HDL-C, and C-reactive protein in PCOS patients, which support the increasing evidence that vitamin D deficiency is associated with multiple metabolic risk factors in PCOS women. A high prevalence of vitamin D deficiency and low calcium levels were observed in PCOS women from our population when compared to controls. Insulin resistance was predominantly seen in PCOS subjects when compared with controls, indicating the association of vitamin D levels with insulin resistance.
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Qi, Jia, Wangsheng Wang, Qinling Zhu, Yaqiong He, Yao Lu, Yuan Wang, Xiaoxue Li, Zi-jiang Chen, and Yun Sun. "Local Cortisol Elevation Contributes to Endometrial Insulin Resistance in Polycystic Ovary Syndrome." Journal of Clinical Endocrinology & Metabolism 103, no. 7 (March 30, 2018): 2457–67. http://dx.doi.org/10.1210/jc.2017-02459.
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Abstract Context Endometrial insulin resistance (IR) may account for the endometrial dysfunction in polycystic ovary syndrome (PCOS). The underlying mechanism remains to be elucidated. Objective To investigate whether the abundance of 11β-hydroxysteroid dehydrogenases (11β-HSDs) 1 and 2 and cortisol as well as the insulin signaling pathway are altered in PCOS endometrium and to clarify the relationship between endometrial IR and local cortisol. Design We measured cortisol and cortisone concentrations, 11β-HSD1 and 11β-HSD2, and core insulin signaling molecules in endometrial biopsies collected from non-PCOS and PCOS with or without IR patients on the seventh day after human chorionic gonadotropin injection. We also studied the effects of cortisol on glucose uptake and the insulin signaling pathway in primary cultured endometrial epithelial cells (EECs). Results The cortisol concentration was elevated, whereas 11β-HSD2 expression was diminished in endometrial biopsies obtained from PCOS with IR patients compared with those from non-PCOS and PCOS without IR patients. The implantation rate was relatively impaired and the endometrial insulin signaling pathway was defective in PCOS with IR patients. In addition, cortisol attenuated insulin-stimulated glucose uptake in EECs, which was mediated by inhibition of Akt phosphorylation and glucose transporter type 4 translocation via induction of phosphatase and tensin homolog deleted on chromosome ten (PTEN). Conclusions Decreased oxidation of cortisol and defects of insulin signaling in endometrium were observed in PCOS with IR patients. The excessive cortisol level, derived from the reduction of 11β-HSD2, might contribute to the development of endometrial IR by inhibiting the insulin signaling pathway via induction of PTEN expression in EECs.
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Marsh, Kate, and Jennie Brand-Miller. "The optimal diet for women with polycystic ovary syndrome?" British Journal of Nutrition 94, no. 2 (August 2005): 154–65. http://dx.doi.org/10.1079/bjn20051475.
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An optimal diet is one that not only prevents nutrient deficiencies by providing sufficient nutrients and energy for human growth and reproduction, but that also promotes health and longevity and reduces the risk of diet-related chronic diseases. The composition of the optimal diet for women with polycystic ovary syndrome (PCOS) is not yet known, but such a diet must not only assist short term with weight management, symptoms and fertility, but also specifically target the long-term risks of type 2 diabetes, CVD and certain cancers. With insulin resistance and compensatory hyperinsulinaemia now recognised as a key factor in the pathogenesis of PCOS, it has become clear that reducing insulin levels and improving insulin sensitivity are an essential part of management. Diet plays a significant role in the regulation of blood glucose and insulin levels, yet research into the dietary management of PCOS is lacking and most studies have focused on energy restriction rather than dietary composition per se. On the balance of evidence to date, a diet low in saturated fat and high in fibre from predominantly low-glycaemic-index-carbohydrate foods is recommended. Because PCOS carries significant metabolic risks, more research is clearly needed.
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Liu, Honglin, Jiani Xie, Limin Fan, Yue Xia, Xia Peng, Jianhua Zhou, and Xiaorong Ni. "Cryptotanshinone Protects against PCOS-Induced Damage of Ovarian Tissue via Regulating Oxidative Stress, Mitochondrial Membrane Potential, Inflammation, and Apoptosis via Regulating Ferroptosis." Oxidative Medicine and Cellular Longevity 2022 (April 4, 2022): 1–21. http://dx.doi.org/10.1155/2022/8011850.
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Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of childbearing age. Cryptotanshinone (CRY) has been shown to be effective in reversing reproductive disorders, but whether it can be used in the treatment of polycystic ovary syndrome remains unclear. We aimed to explore whether the mechanism of cryptotanshinone (CRY) in the treatment of polycystic ovary syndrome (PCOS) can be driven via regulating ferroptosis. A rat model of PCOS was established by daily injection of human chorionic gonadotropin and insulin for 22 days. An in vitro model of ischemia-reperfusion (IR) of granulosa cells was established. The in vitro and rat models of PCOS were subjected to different treatments including ferroptosis activators and inhibitors, CRY, and MAPK inhibitor. Oxidative stress was evaluated by measuring the activities of SOD, MDA, and GSH-PX. Total body weight and ovarian weight, as well as the levels of LH and the LH to FSH ratio, significantly increased in rats with PCOS, compared with controls. The expression of Bax was increased in PCOS tissues while PGC1α, NFR1, GPX4, catalase p-ERK, and Bcl-2 were all downregulated. Ferroptosis activator, erastin, had effects similar to those of PCOS while the contrary was found with CRY and ferroptosis inhibitor treatment groups. In vitro, CRY inhibited oxidative stress, MMP, and NF-κB and activated MAPK/ERK signaling by regulating ferroptosis. Overall, this study indicated that CRY protects against PCOS-induced damage of the ovarian tissue, via regulating oxidative stress, MMP, inflammation, and apoptosis via regulating ferroptosis.
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Márquez-Arrico, Cecilia Fabiana, Javier Silvestre-Rangil, Laura Gutiérrez-Castillo, Mayte Martinez-Herrera, Francisco Javier Silvestre, and Milagros Rocha. "Association between Periodontal Diseases and Polycystic Ovary Syndrome: A Systematic Review." Journal of Clinical Medicine 9, no. 5 (May 23, 2020): 1586. http://dx.doi.org/10.3390/jcm9051586.
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Background: A convergent association between polycystic ovary syndrome (PCOS) and periodontal disease, in particular chronic periodontitis (CP), has recently been proposed. The underlying molecular mechanisms of this association are not fully understood, though it is thought that chronic inflammation is responsible. Therefore, the aim of this study was to evaluate the association between periodontal disease—gingivitis and CP—and PCOS. Materials and Methods: The PICO (Participants, Intervention, Control, and Outcomes) question was as follows: “Is there an association between PCOS and CP?” A systematic review of three databases—PubMed, Embase and Scopus—was performed following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Original studies in human cohorts carried out in the last 10 years and including a control group were eligible for inclusion. Letters to the editor, case reports, and reviews were not considered. Results: Ten articles met all the selection criteria and provided a positive answer to the PICO question. Our review of these articles revealed an association between CP and PCOS, since periodontal parameters were altered more frequently in patients with these conditions than in healthy young women. This altered periodontal response in PCOS was associated with a proinflammatory status that seemed to increase susceptibility to periodontal disease. Conclusion: Patients with PCOS appear to be more susceptible to developing periodontal diseases than women without the pathology.
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Mahood, Rasha Abdul-Hussien. "Effects of Pimpinella anisum oil Extract on Some Biochemical Parameters in Mice experimentally induced for human Polycystic Ovary Syndrome." Journal of Biotechnology Research Center 6, no. 2 (June 1, 2012): 67–73. http://dx.doi.org/10.24126/jobrc.2012.6.2.228.
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n this study, the effect of Pimpinella anisum oil (Anise oil) extract is evaluated on some biochemical parameters in PCOS mice as a model for human PCOS. Estrous cyclicity of 24 adult cycling mice was monitored by vaginal smears. After about 4 days, 18 mice received an intramuscular (I.M.) injection of a single dose of estradiol valerate (EV), one mg in 0.1 ml of corn oil to induce (PCOS), corn oil was injected to the six mice in the control group. After 60 days from injection, mice with (PCOS) were orally administered multiple doses (200, 400) mg/kg Body weight of anise oil extract for 15 days. The histological (ovary) and hormonal (FSH, LH, estradiol and progesterone) results showed that anise oil can decrease signs of PCOS in the ovarian tissue and altered concentrations of luteinizing hormone.
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Wang, Yujiao, Qingling Yang, Huan Wang, Jing Zhu, Luping Cong, Hui Li, and Yingpu Sun. "NAD+ deficiency and mitochondrial dysfunction in granulosa cells of women with polycystic ovary syndrome‡." Biology of Reproduction 105, no. 2 (May 29, 2021): 371–80. http://dx.doi.org/10.1093/biolre/ioab078.
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Abstract Polycystic ovary syndrome (PCOS) is a prevalent heterogeneous endocrine disorder characterized by ovulation dysfunction, androgen excess, ovarian polycystic changes, insulin resistance, and infertility. Although underlying mechanisms for PCOS are still unknown, inflammation and mitochondrial dysfunction in granulosa cells (GCs) of PCOS patients have been reported. Here, we found that Nicotinamide Adenine Dinucleotide (NAD+) levels in GCs of PCOS patients was significantly decreased when compared with controls. Also, we found that higher expression of inflammation factors, increased reactive oxygen species (ROS) accumulation, lower adenosine triphosphate (ATP) generation, and decreased mitochondrial membrane potential, as well as abnormal mitochondrial dynamics in GCs of PCOS patients. In addition, the NAD+ levels were decreased after activation of inflammation in human granulosa-like tumor cell line (KGN) treated by Lipopolysaccharide (LPS). However, supplementation of nicotinamide riboside (NR), a NAD+ precursor, could largely restore the NAD+ content, reduce ROS levels and improve mitochondrial function demonstrated by increased mitochondrial membrane potential and ATP generation in LPS-treated KGN cells. Our data suggested that inflammation decreased NAD+ levels in GCs of PCOS patients, while supplementation of NR could restore NAD+ levels and alleviated mitochondrial dysfunction in GCs of PCOS patients.
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Liu, Ran, Shun Bai, Shengxia Zheng, Xinyi Zhu, Yan Zhang, Bo Xu, and Weidong Zhao. "Identification of the Metabolomics Signature of Human Follicular Fluid from PCOS Women with Insulin Resistance." Disease Markers 2022 (March 20, 2022): 1–10. http://dx.doi.org/10.1155/2022/6877541.
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Context. Polycystic ovary syndrome (PCOS) is a gynecological endocrine disease, and approximately 60% of patients with PCOS have different degrees of insulin resistance (IR). The regulatory role of metabolic networks in human follicular fluid (FF) related to IR in PCOS remains unclear. Aims. To explore the effect of IR on the metabolism of PCOS by analyzing the changes in FF metabolites in PCOS patients who are undergoing assisted reproductive technology based on the metabonomic platform of ultraperformance gas chromatography coupled to mass spectrometry (GC/MS). Method. Eight PCOS patients with IR (PCOS-IR) and 8 PCOS patients without IR (PCOS-NIR) were enrolled. All patients received controlled ovarian stimulation by using the gonadotropin-releasing hormone (GnRH) antagonist protocol, and the FF of a single dominant follicle was collected on the day of oocyte retrieval. The metabolite profiles of the FF were determined by GC/MS. Key Results. A total of 20 differentially expressed metabolites in FF were identified. Compared with levels in the PCOS-NIR group, stearic acid, palmitic acid, pentadecanoic acid, stigmasterol, citric acid, isocitric acid, thymine, and pyruvic acid in FF were significantly increased in the PCOS-IR group. Lithocholic acid and sinapinic acid in FF decreased significantly. The affected metabolic pathways with potential regulatory roles were identified by KEGG annotation. Conclusion. Compared with the PCOS-NIR group, the PCOS-IR group showed more significant metabolic abnormalities. Implications. These results will help us to understand the pathogenesis of PCOS combined with IR and will provide new clues for studying metabolic disorders associated with PCOS, e.g., IR.
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Du, Tao, Yu Duan, Kaiwen Li, Xiaomiao Zhao, Renmin Ni, Yu Li, and Dongzi Yang. "Statistical Genomic Approach Identifies Association between FSHR Polymorphisms and Polycystic Ovary Morphology in Women with Polycystic Ovary Syndrome." BioMed Research International 2015 (2015): 1–7. http://dx.doi.org/10.1155/2015/483726.
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Background.Single-nucleotide polymorphisms (SNPs) in the follicle stimulating hormone receptor (FSHR) gene are associated with PCOS. However, their relationship to the polycystic ovary (PCO) morphology remains unknown. This study aimed to investigate whether PCOS related SNPs in the FSHR gene are associated with PCO in women with PCOS.Methods. Patients were grouped into PCO (n=384) and non-PCO (n=63) groups. Genomic genotypes were profiled using Affymetrix human genome SNP chip 6. Two polymorphisms (rs2268361 and rs2349415) of FSHR were analyzed using a statistical approach.Results. Significant differences were found in the allele distributions of the GG genotype of rs2268361 between the PCO and non-PCO groups (27.6% GG, 53.4% GA, and 19.0% AA versus 33.3% GG, 36.5% GA, and 30.2% AA), while no significant differences were found in the allele distributions of the GG genotype of rs2349415. When rs2268361 was considered, there were statistically significant differences of serum follicle stimulating hormone, estradiol, and sex hormone binding globulin between genotypes in the PCO group. In case of the rs2349415 SNP, only serum sex hormone binding globulin was statistically different between genotypes in the PCO group.Conclusions. Functional variants in FSHR gene may contribute to PCO susceptibility in women with PCOS.
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Jordan, C. Diana, Sandra D. Bohling, Noe L. Charbonneau, and Lynn Y. Sakai. "Fibrillins in Adult Human Ovary and Polycystic Ovary Syndrome: Is Fibrillin-3 Affected in PCOS?" Journal of Histochemistry & Cytochemistry 58, no. 10 (October 2010): 903–15. http://dx.doi.org/10.1369/jhc.2010.956615.
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Hajizadeh-Sharafabad, Fatemeh, Jalal Moludi, Helda Tutunchi, Ehsaneh Taheri, Azimeh Izadi, and Vahid Maleki. "Selenium and Polycystic Ovary Syndrome; Current Knowledge and Future Directions: A Systematic Review." Hormone and Metabolic Research 51, no. 05 (May 2019): 279–87. http://dx.doi.org/10.1055/a-0890-6823.
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AbstractPolycystic ovary syndrome (PCOS), as the most common endocrine disorder in reproductive-aged women, is recognized by hyperandrogenism and insulin resistance. Selenium (Se) potentially possesses therapeutic effects on PCOS due to antioxidant and insulin-like properties. This systematic review evaluates the potential role of Se in the complications of PCOS. A systematic review was performed on published studies reporting the effects of Se on PCOS. Three major databases including PubMed, Scopus, and Google Scholar were searched until December 2018. A total of 7 human studies and two in vitro studies met the inclusion criteria. Two out of three case-control studies showed that serum Se levels tend to decrease in patients with PCOS. Of four studies that evaluated the impact of Se supplementation on insulin resistance, only one study showed protective effects of Se against insulin resistance. Two out of three studies reported the antioxidant effect of Se. Few studies investigating anti-androgenic effect of Se presented controversial results. There were three studies that evaluated the anti-hyperlipidemic effect of Se, of which two surveys indicated the lowering effects of Se on VLDL and LDL-cholesterol. The reviewed studies confirmed inverse relationships between serum Se levels and some androgenic hormones in PCOS. Se is able to attenuate insulin resistance and dyslipidemia. The available data are currently insufficient to support the protective effects of Se on PCOS.
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Jin, Yue, Qing Zhang, Jie-Xue Pan, Fang-Fang Wang, and Fan Qu. "The effects of di(2-ethylhexyl) phthalate exposure in women with polycystic ovary syndrome undergoing in vitro fertilization." Journal of International Medical Research 47, no. 12 (November 10, 2019): 6278–93. http://dx.doi.org/10.1177/0300060519876467.
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Objectives Di(2-ethylhexyl) phthalate (DEHP) is a common endocrine-disrupting chemical, which has potential reproductive toxicity. This study aimed to explore the effects of DEHP exposure in women with polycystic ovary syndrome (PCOS) undergoing in vitro fertilization. Methods In this case-control study, DEHP levels in follicular fluid (FF) of women with PCOS (n = 56) and controls (n = 51) were measured. The in vitro effects of DEHP exposure on primary-cultured human granulosa cells (GCs) and a steroidogenic human granulosa-like tumor cell line (KGN cells) were analyzed. Results Concentrations of DEHP in FF were significantly higher in women with PCOS than in controls. The clinical pregnancy rate was significantly lower in women with PCOS with high levels of DEHP than in controls. The levels of androgens produced by human GCs were significantly increased following DEHP exposure. Compared with controls, DEHP-treated human GCs and KGN cells showed significantly lower viability, cell cycle arrest, higher apoptosis, and altered expression of apoptosis-related genes. Conclusion Women with PCOS are exposed to increased levels of DEHP in follicles, which may be associated with pregnancy loss following in vitro fertilization. DEHP may disrupt steroid production, balance in cellular proliferation, and apoptosis in human granulosa cells.
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Dapas, Matthew, Ryan Sisk, Richard S. Legro, Margrit Urbanek, Andrea Dunaif, and M. Geoffrey Hayes. "Family-Based Quantitative Trait Meta-Analysis Implicates Rare Noncoding Variants in DENND1A in Polycystic Ovary Syndrome." Journal of Clinical Endocrinology & Metabolism 104, no. 9 (April 30, 2019): 3835–50. http://dx.doi.org/10.1210/jc.2018-02496.
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AbstractContextPolycystic ovary syndrome (PCOS) is among the most common endocrine disorders of premenopausal women, affecting 5% to15% of this population depending on the diagnostic criteria applied. It is characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology. PCOS is highly heritable, but only a small proportion of this heritability can be accounted for by the common genetic susceptibility variants identified to date.ObjectiveThe objective of this study was to test whether rare genetic variants contribute to PCOS pathogenesis.Design, Patients, and MethodsWe performed whole-genome sequencing on DNA from 261 individuals from 62 families with one or more daughters with PCOS. We tested for associations of rare variants with PCOS and its concomitant hormonal traits using a quantitative trait meta-analysis.ResultsWe found rare variants in DENND1A (P = 5.31 × 10−5, adjusted P = 0.039) that were significantly associated with reproductive and metabolic traits in PCOS families.ConclusionsCommon variants in DENND1A have previously been associated with PCOS diagnosis in genome-wide association studies. Subsequent studies indicated that DENND1A is an important regulator of human ovarian androgen biosynthesis. Our findings provide additional evidence that DENND1A plays a central role in PCOS and suggest that rare noncoding variants contribute to disease pathogenesis.
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Miller, Irit, Hadas Bar-Joseph, Luba Nemerovsky, Ido Ben-Ami, and Ruth Shalgi. "Pigment epithelium-derived factor (PEDF) negates hyperandrogenic PCOS features." Journal of Endocrinology 245, no. 2 (May 2020): 291–300. http://dx.doi.org/10.1530/joe-19-0603.
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Polycystic ovary syndrome (PCOS), one of the most common female endocrine disorder, is a prevalent cause of infertility. Hyperandrogenism is a key feature in PCOS and is correlated with increased expression of VEGF and cytokines in the ovaries. We have previously shown that pigment epithelium-derived factor (PEDF), an endogenous protein, presents potent anti-angiogenic and anti-inflammatory activities in the ovary and negates the effects of cytokines and VEGF. Additionally, PEDF plays a role in both pathophysiology and treatment of ovarian-hyperstimulation syndrome (OHSS), frequently seen in PCOS patients. We established hyperandrogenic-PCOS models, both in vivo, using mice exposed prenatally to dihydrotestosterone (DHT) and, in vitro, using human primary granulosa cells (hpGCs) and human granulosa cell line (KGN). In PCOS-induced mice, the mRNA levels of I l-6, V egf and Amh were higher than those of control; yet, treatment with rPEDF decreased these levels. Moreover, treating OHSS-induced PCOS-mice with rPEDF alleviated all OHSS symptoms. Stimulation of hpGCs with DHT resulted in downregulation of PEDF mRNA expression, concomitantly with a significant increase in IL-6 and IL-8 mRNAs expression. However, co-stimulation of DHT with rPEDF attenuated the increase in cytokines expression. The anti-inflammatory effect of PEDF was found to be mediated via PPARγ pathway. Our findings suggest that rPEDF treatment may normalize the ovarian angiogenic-inflammatory imbalance, induced by PCOS-associated hyperandrogenism. Moreover, the therapeutic potency of PEDF in preventing OHSS symptomes offers a rationale for using PEDF as novel physiological treatment for PCOS sequels.
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Rodriguez Paris, Valentina, and Michael J. Bertoldo. "The Mechanism of Androgen Actions in PCOS Etiology." Medical Sciences 7, no. 9 (August 28, 2019): 89. http://dx.doi.org/10.3390/medsci7090089.
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Polycystic ovary syndrome (PCOS) is the most common endocrine condition in reproductive-age women. By comprising reproductive, endocrine, metabolic and psychological features—the cause of PCOS is still unknown. Consequently, there is no cure, and management is persistently suboptimal as it depends on the ad hoc management of symptoms only. Recently it has been revealed that androgens have an important role in regulating female fertility. Androgen actions are facilitated via the androgen receptor (AR) and transgenic Ar knockout mouse models have established that AR-mediated androgen actions have a part in regulating female fertility and ovarian function. Considerable evidence from human and animal studies currently reinforces the hypothesis that androgens in excess, working via the AR, play a key role in the origins of polycystic ovary syndrome (PCOS). Identifying and confirming the locations of AR-mediated actions and the molecular mechanisms involved in the development of PCOS is critical to provide the knowledge required for the future development of innovative, mechanism-based interventions for the treatment of PCOS. This review summarises fundamental scientific discoveries that have improved our knowledge of androgen actions in PCOS etiology and how this may form the future development of effective methods to reduce symptoms in patients with PCOS.
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Bonfá, Ana Lúcia de Oliveira, Eduardo Donato Alves, Víctor Fabrício, Keico Okino Nonaka, Janete Aparecida Anselmo-Franci, Jorge Alberto Achcar, and LH Montrezor. "Simultaneous alterations in ovaries and bone as a result of Polycystic Ovary Syndrome." International Journal of Advances in Medical Biotechnology - IJAMB 3, no. 2 (April 28, 2021): 2–14. http://dx.doi.org/10.52466/ijamb.v3i2.81.
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Polycystic ovary syndrome (PCOS) is one of the most widely recognized endocrine disorders affecting reproductive-age women. The etiopathogenesis and mechanisms of this syndrome remain unclear. Diagnosis requires two of the following: polycystic ovaries, oligo- or anovulation, and hyperandrogenism. Most women with PCOS display conditions such as metabolic abnormalities, diabetes, obesity, cardiovascular disease, and/or bone dysfunction. Considering the ethical limitations of human studies, animal and cell culture models that reflect some features of PCOS are important for investigation of this syndrome. The aim of the present work was to study some of the endocrine relationships between ovaries and bone tissue in a polycystic ovary syndrome animal model. The study was performed using an estradiol valerate PCOS-induced rat model (n = 30) and bone mesenchymal stem cell cultured from bone marrow of those animals. It was hypothesized that changes of the endocrine relationship between ovaries and bones could be observed in from in vivo animal model and in vitro cell culture assays. The ovarian morphological and endocrine changes seem to be correlated with endocrine, biophysical, and biomechanical changes in bone properties. Mesenchymal stem cells obtained from PCOS-induced rats, cultured for up to 21 days and differentiated into osteoblasts, presented lower viability and reduced mineralization of the extracellular matrix. Taken together, these results indicate important endocrine and structural effects of PCOS in ovaries and bones, contributing to part of the understanding of the pathophysiological mechanisms of PCOS.
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Eyupoglu, Nesrin Damla, Koray Ergunay, Aylin Acikgoz, Yakut Akyon, Engin Yilmaz, and Bulent Okan Yildiz. "Gut Microbiota and Oral Contraceptive Use in Overweight and Obese Patients with Polycystic Ovary Syndrome." Journal of Clinical Endocrinology & Metabolism 105, no. 12 (August 29, 2020): e4792-e4800. http://dx.doi.org/10.1210/clinem/dgaa600.
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Abstract Context Polycystic ovary syndrome (PCOS) is a common and complex endocrine disorder. Emerging animal and human data point to various changes in microbiota that could be linked with the syndrome. However, the effects of therapeutic approaches on gut microbial composition in women with PCOS remain unknown. Objective We aimed to assess whether gut microbial composition is altered in PCOS and to determine the potential impact of oral contraceptive (OC) use on gut microbiota. Design Prospective observational study. Setting Tertiary referral hospital. Patients and Other Participants The study included 17 overweight/obese patients with PCOS and 15 age- and body mass index-matched healthy control women. Main Outcome Measures At baseline, clinical, hormonal, and metabolic evaluations and gut microbial composition assessment by 16S rRNA gene amplicon sequencing were performed for both groups. All measurements were repeated in patients after receiving an OC along with general lifestyle advice for 3 months. Results Alpha and beta diversity did not show a difference between patients with PCOS and healthy controls at baseline and remained unaltered after 3 months of OC use in the PCOS group. Relative abundance of Ruminococcaceae was higher in PCOS (P = 0.006) and did not show a significant change after treatment. Conclusion Women with PCOS have an increased abundance of Ruminococcaceae, whereas short-term OC use does not alter compositional features of gut microbiota in the syndrome.
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Zheng, Qin, Feifei Zhou, Xinyuan Cui, Mulin Liu, Yulin Li, Shuai Liu, Jichun Tan, and Qiu Yan. "Novel Serum Biomarkers Detected by Protein Array in Polycystic Ovary Syndrome with Low Progesterone Level." Cellular Physiology and Biochemistry 46, no. 6 (2018): 2297–310. http://dx.doi.org/10.1159/000489619.
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Background/Aims: Polycystic ovary syndrome (PCOS), characterized by female infertility and metabolic abnormalities, is one of the most common endocrine disorders. The etiology of PCOS remains unknown. The comprehensive analysis of protein alterations in PCOS patients is meaningful for identifying diagnostic biomarkers of PCOS. Here, we explored the clinical value of serum proteins as novel biomarkers to detect PCOS with low progesterone level. Methods: A total of 43 patients with PCOS and 30 healthy women were enrolled. Protein array was used to detect the variations of serum proteins between PCOS patients and healthy women. The level of five serum proteins was further confirmed by ELISA and western blot. The human ovarian granulosa cells (KGN) was cultured to examine the underlying mechanism of PCOS. CCK8 assay and western blot were carried out to evaluate the alterations in proliferative ability, TUNEL assay and DAPI staining to detect the apoptosis of KGN cells. Results: Among the 507 proteins, we identified 76 differentially expressed serum proteins (≧1.5 fold), with 40 elevated and 36 decreased proteins. Moreover, 47 proteins were newly reported in PCOS. The alterations in the five significantly decreased proteins (EREG, inhibin βA, IDE, PDGF-D and KNG1) were further confirmed by ELISA and western blot. The level of these proteins were directly associated with the low progesterone, and the expression could be upregulated by progesterone. EREG and inhibin βA also promoted the proliferation and inhibited the apoptosis of ovarian granulosa cells. Conclusion: The study highlights that serum proteins are differentially expressed in PCOS patients and healthy women, and EREG and inhibin βA levels are upregulated by progesterone, which are correlated with ovarian functions. The study suggests that EREG and inhibin βA may be applied as novel potential biomarkers for PCOS with low progesterone level.