Journal articles on the topic 'Human PCOS'
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1
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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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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Hu, Junhe, Tao Tang, Zhi Zeng, Juan Wu, Xiansheng Tan, and Jiao Yan. "The expression of small RNAs in exosomes of follicular fluid altered in human polycystic ovarian syndrome." PeerJ 8 (February 19, 2020): e8640. http://dx.doi.org/10.7717/peerj.8640.
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Polycystic ovary syndrome (PCOS) can cause reproductive disorders that may affect oocyte quality from punctured follicles in human follicular fluid (HFF). The non-coding RNA family includes micro RNA (miRNA), piwi-interacting RNA (piRNA) and transfer RNA (tRNA); these non-coding RNA transcripts play diverse functions and are implicated in a variety of diseases and health conditions, including infertility. In this study, to explore the role of HFF exosomes in PCOS, we extracted and sequenced RNA from HFF exosomes of PCOS patients and compared the analysis results with those of non-PCOS control group. The HFF exosomes were successfully isolated and characterized in a variety of ways. The sequencing results of the HFF exosomal RNA showed that about 6.6% of valid reads in the PCOS group and 8.6% in the non-PCOS group were successfully mapped to the human RNA database. Using a hierarchical clustering method, we found there were ten small RNA sequences whose expression was significantly different between the PCOS and non-PCOS groups. We chose six of them to predict target genes of interest for further GO analysis, and pathway analysis showed that the target genes are mainly involved in biosynthesis of amino acids, glycine, serine and glycosaminoglycan, as well as threonine metabolism. Therefore, the small RNA sequences contained in HFF EXs may play a key role in the mechanism that drives PCOS pathogenesis, and thereby can act as molecular biomarkers for PCOS diagnosis in the future.
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Krishnan, Abhaya, Sridhar Muthusami, Loganayaki Periyasamy, Jone A. Stanley, Vasudevan Gopalakrishnan, and Ilangovan Ramachandran. "Effect of DHT-Induced Hyperandrogenism on the Pro-Inflammatory Cytokines in a Rat Model of Polycystic Ovary Morphology." Medicina 56, no. 3 (February 27, 2020): 100. http://dx.doi.org/10.3390/medicina56030100.
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Background and Objectives: Polycystic ovary syndrome (PCOS) is one of the most prevalent disorders among women of reproductive age. It is considered as a pro-inflammatory state with chronic low-grade inflammation, one of the key factors contributing to the pathogenesis of this disorder. Polycystic ovary is a well-established criterion for PCOS. The present investigation aimed at finding the role of hyperandrogenism, the most important feature of PCOS, in the development of this inflammatory state. To address this problem, we adopted a model system that developed polycystic ovary morphology (PCOM), which could be most effectively used in order to study the role of non-aromatizable androgen in inflammation in PCOS. Materials and Methods: Six rats were used to induce PCOM in 21-days-old female Wistar albino rats by using a pre-determined release of dihydrotestosterone (DHT), a potent non-aromatizable androgen, achieved by implanting a DHT osmotic pump, which is designed to release a daily dose of 83 μg. Results: After 90 days, the rats displayed irregular estrous cycles and multiple ovarian cysts similar to human PCOS. Elevated serum inflammatory markers such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and the presence of a necrotic lesion in the liver, osteoclast in the femur, multinucleated giant cells and lymphocytes in the ovary based on histopathological observation of DHT-treated rats clearly indicated the onset of inflammation in the hyperandrogenic state. Our results show no significant alterations in serum hormones such as luteinizing hormone (LH), follicle stimulating hormone (FSH), insulin, and cortisol between control and hyperandrogenised rats. DHT was significantly elevated as compared to control. mRNA studies showed an increased expression level of TNF-α and IL-1β, further, the mRNA expression of urocortin 1 (Ucn-1) was stupendously elevated in the liver of hyperandrogenised rats. Conclusions: Thus, results from this study provide: (1) a good PCOM model system in order to study the inflammatory changes in PCOS aspects, (2) alteration of inflammatory markers in PCOM rats that could be either due to its direct effect or by the regulation of various inflammatory genes and markers in the liver of hyperandrogenic state suggesting the regulatory role of DHT, and (3) alteration in stress-related protein in the liver of PCOM rats.
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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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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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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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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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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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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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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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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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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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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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Wood, Jennifer R., Velen L. Nelson-Degrave, Erik Jansen, Jan M. McAllister, Sietse Mosselman, and Jerome F. Strauss. "Valproate-induced alterations in human theca cell gene expression: clues to the association between valproate use and metabolic side effects." Physiological Genomics 20, no. 3 (February 10, 2005): 233–43. http://dx.doi.org/10.1152/physiolgenomics.00193.2004.
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Valproic acid (VPA) is an anti-epileptic drug that has been associated with polycystic ovary syndrome (PCOS)-like symptoms, including increased ovarian androgen production. The hyperandrogenemia likely reflects the stimulatory action of VPA on theca cell androgen synthesis and has been correlated to its activity as a histone deacteylase inhibitor in these cells. To determine whether VPA induces a PCOS-like genomic phenotype, we compared the gene expression profiles of untreated (UNT) normal, VPA-treated normal, and UNT PCOS theca cells. Hierarchal cluster analysis demonstrated similarities in the gene expression profiles of VPA-treated normal and PCOS theca cells. Statistical analysis identified 1,050 transcripts that have significantly altered mRNA abundance in both VPA-treated normal and UNT PCOS theca cells compared with normal UNT theca cells. Among these 1,050 transcripts were cAMP-GEFII and TRB3, which have increased and decreased mRNA abundance, respectively. The altered abundance of these two mRNAs was correlated to increased basal and insulin-induced phosphorylation of protein kinase B (Akt/PKB). Thus these studies indicate that VPA- and PCOS-induced changes in gene expression enhance Akt/PKB signal transduction in human theca cells. Furthermore, common changes in gene expression in PCOS and VPA-treated normal theca cells suggest a possible mechanism for the development of PCOS-like symptoms, including increased steroid synthesis and arrested follicle development in women receiving chronic VPA therapy.
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Estienne, Anthony, Namya Mellouk, Alice Bongrani, Ingrid Plotton, Ingrid Langer, Christelle Ramé, Claire Petit, Fabrice Guérif, Pascal Froment, and Joëlle Dupont. "Involvement of chemerin and CMKLR1 in the progesterone decrease by PCOS granulosa cells." Reproduction 162, no. 6 (December 1, 2021): 427–36. http://dx.doi.org/10.1530/rep-21-0265.
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Polycystic ovarian syndrome (PCOS) is the main cause of infertility in women. It is frequently associated with reduced progesterone production by human luteinised granulosa cells (hlGCs). However, the molecular mechanisms involved in these steroidogenesis alterations in PCOS patients are unclear. In a dihydrotestosterone-induced PCOS mouse model, steroid production is maintained in the setting of chemokine-like receptor 1 (Cmklr1) knockout. Thus, chemerin and chemerin receptors in terms of expression and progesterone regulation could be different in control and PCOS hlGCs. We first confirmed that progesterone levels in both plasma (P < 0.0001) and follicular fluid (FF) (P < 0.0001) were significantly reduced in PCOS normal weight women compared to control women. These data were associated with a lower STAR mRNA expression in both in vivo (P < 0.0001) and in vitro (P < 0.0001) hlGCs from PCOS women. Secondly, chemerin FF levels (P < 0.0001) and RARRES2 (P < 0.05) and CMKLR1 (P < 0.0001) mRNA levels in GCs were higher in PCOS normal weight patients. Thirdly, treatment of hlGCs with a specific nanobody (the VHH CA4910) targeting the human receptor for CMKLR1 leading to its inactivation abolished chemerin-induced progesterone inhibition, suggesting the involvement of CMKLR1 in this process. Furthermore, the inhibition of progesterone secretion induced by chemerin was two-fold higher in PCOS hlGCs (P < 0.05). Moreover, the VHH CA4910 reinstated a normal progesterone secretion with lower concentrations in PCOS hlGCs, suggesting a different chemerin sensitivity between PCOS and control hlGCs. Thus, chemerin, through CMKLR1, could be involved in the steroidogenesis alterations in PCOS hlGCs.
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Teves, Maria E., Bhavi P. Modi, Rewa Kulkarni, Angela X. Han, Jamaia S. Marks, Mark A. Subler, Jolene Windle, Jordan M. Newall, Jan M. McAllister, and Jerome F. Strauss. "Human DENND1A.V2 Drives Cyp17a1 Expression and Androgen Production in Mouse Ovaries and Adrenals." International Journal of Molecular Sciences 21, no. 7 (April 6, 2020): 2545. http://dx.doi.org/10.3390/ijms21072545.
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The DENND1A locus is associated with polycystic ovary syndrome (PCOS), a disorder characterized by androgen excess. Theca cells from ovaries of PCOS women have elevated levels of a DENND1A splice variant (DENND1A.V2). Forced expression of this variant in normal theca cells increases androgen biosynthesis and CYP17A1 expression, whereas knockdown of the transcript in PCOS theca cells reduced androgen production and CYP17A1 mRNA. We attempted to create a murine model of PCOS by expressing hDENND1A.V2 using standard transgenic approaches. There is no DENND1A.V2 protein equivalent in mice, and the murine Dennd1a gene is essential for viability since Dennd1a knockout mice are embryonically lethal, suggesting that Dennd1a is developmentally critical. Three different hDENND1A.V2 transgenic mice lines were created using CMV, Lhcgr, and TetOn promoters. The hDENND1A.V2 mice expressed hDENND1A.V2 transcripts. While hDENND1A.V2 protein was not detectable by Western blot analyses, appropriate hDENND1A.V2 immunohistochemical staining was observed. Corresponding Cyp17a1 mRNA levels were elevated in ovaries and adrenals of CMV transgenic mice, as were plasma steroid production by theca interstitial cells isolated from transgenic ovaries. Even though the impact of robust hDENND1A.V2 expression could not be characterized, our findings are consistent with the notion that elevated hDENND1A.V2 has a role in the hyperandrogenemia of 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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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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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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Chugh, Rishi Man, Hang-soo Park, Sahar Esfandyari, Amro Elsharoud, Mara Ulin, and Ayman Al-Hendy. "Mesenchymal Stem Cell-Conditioned Media Regulate Steroidogenesis and Inhibit Androgen Secretion in a PCOS Cell Model via BMP-2." International Journal of Molecular Sciences 22, no. 17 (August 25, 2021): 9184. http://dx.doi.org/10.3390/ijms22179184.
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Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women. Previous studies have demonstrated the therapeutic efficacy of human bone marrow mesenchymal stem cells (BM-hMSCs) for PCOS; however, the regulatory mechanism remains unknown. Bone morphogenetic proteins (BMPs) secreted by BM-hMSCs may underlie the therapeutic effect of these cells on PCOS, based on the ability of BMPs to modulate androgen production and alter steroidogenesis pathway enzymes. In this study, we analyze the effect of BMP-2 on androgen production and steroidogenic pathway enzymes in H295R cells as a human PCOS in vitro cell model. In H295R cells, BMP-2 significantly suppressed cell proliferation, androgen production, and expression of androgen-synthesizing genes, as well as inflammatory gene expression. Furthermore, H295R cells treated with the BM-hMSCs secretome in the presence of neutralizing BMP-2 antibody or with BMP-2 gene knockdown showed augmented expression of androgen-producing genes. Taken together, these results indicate that BMP-2 is a key player mediating the favorable effects of the BM-hMSCs secretome in a human PCOS cell model. BMP-2 overexpression could increase the efficacy of BM-hMSC-based therapy, serving as a novel stem cell therapy for patients with intractable PCOS.
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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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Cabrera-Cruz, Heidy, Lorena Oróstica, Francisca Plaza-Parrochia, Ignacio Torres-Pinto, Carmen Romero, and Margarita Vega. "The insulin-sensitizing mechanism of myo-inositol is associated with AMPK activation and GLUT-4 expression in human endometrial cells exposed to a PCOS environment." American Journal of Physiology-Endocrinology and Metabolism 318, no. 2 (February 1, 2020): E237—E248. http://dx.doi.org/10.1152/ajpendo.00162.2019.
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Polycystic ovary syndrome (PCOS) is an endocrine-metabolic disorder characterized by hyperandrogenism and ovulatory dysfunction but also obesity and hyperinsulinemia. These characteristics induce an insulin-resistant state in tissues such as the endometrium, affecting its reproductive functions. Myo-inositol (MYO) is an insulin-sensitizing compound used in PCOS patients; however, its insulin-sensitizing mechanism is unclear. To understand the relationship of MYO with insulin action in endometrial cells, sodium/myo-inositol transporter 1 (SMIT-1) (MYO-transporter), and MYO effects on protein levels related to the insulin pathway were evaluated. SMIT-1 was assessed in endometrial tissue from women with normal weight, obesity, insulin resistance, and PCOS; additionally, using an in vitro model of human endometrial cells exposed to an environment resembling hyperinsulinemic-obese-PCOS, MYO effect was evaluated on p-AMPK and GLUT-4 levels and glucose uptake by Western blot, immunocytochemistry, and confocal microscopy, respectively. SMIT-1 was detected in endometrial tissue from all groups and decreased in PCOS and obesity ( P < 0.05 vs. normal weight ). In the in vitro model, PCOS conditions decreased p-AMPK levels, while they were restored with MYO ( P < 0.05). The diminished GLUT-4 protein levels promoted by PCOS environment were restored by MYO through SMIT-1 and p-AMPK-dependent mechanism ( P < 0.05). Also, MYO restored glucose uptake in cells under PCOS condition through a p-AMPK-dependent mechanism. Finally, these results were similar to those obtained with metformin treatment in the same in vitro conditions. Consequently, MYO could be a potential insulin sensitizer through its positive effects on insulin-resistant tissues as PCOS-endometrium, acting through SMIT-1, provoking AMPK activation and elevated GLUT-4 levels and, consequently, increase glucose uptake by human endometrial cells. Therefore, MYO may be used as an effective treatment option in insulin-resistant PCOS women.
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Maas, Kevin H., Sandy S. Chuan, Heidi Cook-Andersen, H. Irene Su, A. Duleba, and R. Jeffrey Chang. "Relationship Between 17-Hydroxyprogesterone Responses to Human Chorionic Gonadotropin and Markers of Ovarian Follicle Morphology in Women With Polycystic Ovary Syndrome." Journal of Clinical Endocrinology & Metabolism 100, no. 1 (January 1, 2015): 293–300. http://dx.doi.org/10.1210/jc.2014-2956.
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Abstract Context: Women with polycystic ovary syndrome (PCOS) have increased 17-hydroxyprogesterone (17-OHP) responses to gonadotropin stimulation although individual variability is substantial, as reflected by exaggerated as well as normal responses. The relationship between 17-OHP responses to gonadotropin stimulation and markers of ovarian function has not been assessed. Objective: To determine whether 17-OHP responses are associated with antral follicle count (AFC), anti-Mullerian hormone (AMH), or inhibin B (Inh B) levels in PCOS and normal women. Design: Prospective study. Setting: Research center at an academic medical center. Participants: Women with PCOS (n = 18) and normal controls (n = 18). Interventions: Blood samples were obtained before and 24 hours after administration of 25 μg recombinant-human chorionic gonadotropin. Ovarian imaging was conducted with three-dimensional pelvic ultrasound. Main Outcome Measures: Basal and stimulated levels of 17-OHP, androgens, estrogen, AMH, Inh B, and AFC. Results: In women with PCOS, 17-OHP responses were heterogeneous and inversely correlated with AMH and Inh B levels, but not AFC. In a subgroup of PCOS women with exaggerated 17-OHP responses, AMH levels were equivalent to that of normal women. In PCOS women with normal 17-OHP responses, AMH levels were markedly elevated. Conclusion: Based on heterogeneous 17-OHP responses to human chorionic gonadotropin in women with PCOS, AMH levels are inversely linked to ovarian androgen production while positively correlated with AFC. These findings suggest that in PCOS, AMH production may reflect redistribution of the follicle population or regulation by intraovarian mechanisms.
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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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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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Chuang, Tung-Yueh, Hsiao-Li Wu, Chen-Chun Chen, Gloria Mabel Gamboa, Lawrence C. Layman, Michael P. Diamond, Ricardo Azziz, and Yen-Hao Chen. "MicroRNA-223 Expression Is Upregulated in Insulin Resistant Human Adipose Tissue." Journal of Diabetes Research 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/943659.
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MicroRNAs (miRNAs) are short noncoding RNAs involved in posttranscriptional regulation of gene expression and influence many cellular functions including glucose and lipid metabolism. We previously reported that adipose tissue (AT) from women with polycystic ovary syndrome (PCOS) or controls with insulin resistance (IR) revealed a differentially expressed microRNA (miRNA) profile, including upregulated miR-93 in PCOS patients and in non-PCOS women with IR. Overexpressed miR-93 directly inhibited glucose transporter isoform 4 (GLUT4) expression, thereby influencing glucose metabolism. We have now studied the role of miR-223, which is also abnormally expressed in the AT of IR subjects. Our data indicates that miR-223 is significantly overexpressed in the AT of IR women, regardless of whether they had PCOS or not. miR-223 expression in AT was positively correlated with HOMA-IR. Unlike what is reported in cardiomyocytes, overexpression of miR-223 in human differentiated adipocytes was associated with a reduction in GLUT4 protein content and insulin-stimulated glucose uptake. In addition, our data suggests miR-223 regulates GLUT4 expression by direct binding to its 3′ untranslated region (3′UTR). In conclusion, in AT miR-223 is an IR-related miRNA that may serve as a potential therapeutic target for the treatment of IR-related disorders.
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Schniewind, Hanna A., Lisa-Marie Sattler, Christoph W. Haudum, Julia Münzker, Waldemar B. Minich, Barbara Obermayer-Pietsch, and Lutz Schomburg. "Autoimmunity to the Follicle-Stimulating Hormone Receptor (FSHR) and Luteinizing Hormone Receptor (LHR) in Polycystic Ovarian Syndrome." International Journal of Molecular Sciences 22, no. 24 (December 20, 2021): 13667. http://dx.doi.org/10.3390/ijms222413667.
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Hyperandrogenemia and ovulatory dysfunction are hallmarks of polycystic ovary syndrome (PCOS), pointing to a deranged hypothalamus-pituitary-ovarian (HPO) axis. An autoimmune etiology of PCOS is suspected in a subset of patients due to the relatively high concordance of PCOS with common autoimmune diseases. For this reason, we tested the hypothesis that natural autoantibodies (aAb) to the follicle-stimulating hormone receptor (FSHR) or luteinizing hormone receptor (LHR) are prevalent in PCOS. To this end, new luminometric assays for quantifying aAb to the FSHR (FSHR-aAb) or LHR (LHR-aAb) were developed using full-length recombinant human receptors as fusion proteins with luciferase as reporter. Prevalence of FSHR-aAb and LHR-aAb was determined in serum samples from healthy controls and PCOS patients. Steroid hormone profiles were compared between patients with and without FSHR-aAb or LHR-aAb. Signal linearity and detection ranges were characterized and both methods passed basic performance quality checks. The analysis revealed a relatively low prevalence, with 4 out of 430 samples positive for FSHR-aAb in the control versus 11 out of 550 samples in the PCOS group, i.e., 0.9% versus 2.0%, respectively. Similarly, there were only 5 samples positive for LHR-aAb in the control versus 2 samples in the PCOS group, i.e., 1.2% versus 0.4%, respectively. Samples positive for FSHR-aAb displayed steroid hormones in the typical range of PCOS patients, whereas the two samples positive for LHR-aAb showed relatively elevated free testosterone in relation to total testosterone concentrations with unclear significance. We conclude that the FSHR and LHR constitute potential autoantigens in human subjects. However, the prevalence of specific autoantibodies to these receptors is relatively low, both in control subjects and in women with PCOS. It is therefore unlikely that autoimmunity to the LHR or FSHR constitutes a frequent cause of hyperandrogenemia or ovulatory dysfunction in PCOS.
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Sattler, Lisa-Marie, Hanna A. Schniewind, Waldemar B. Minich, Christoph W. Haudum, Petra Niklowitz, Julia Münzker, Gábor L. Kovács, Thomas Reinehr, Barbara Obermayer-Pietsch, and Lutz Schomburg. "Natural autoantibodies to the gonadotropin-releasing hormone receptor in polycystic ovarian syndrome." PLOS ONE 16, no. 4 (April 2, 2021): e0249639. http://dx.doi.org/10.1371/journal.pone.0249639.
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Context Polycystic ovarian syndrome (PCOS) is a complex disease with different subtypes and unclear etiology. Among the frequent comorbidities are autoimmune diseases, suggesting that autoantibodies (aAb) may be involved in PCOS pathogenesis. Objective As the gonadal axis often is dysregulated, we tested the hypothesis that aAb to the gonadotropin-releasing hormone receptor (GnRH-R) are of diagnostic value in PCOS. Design An in vitro assay for quantifying aAb to the GnRH-R (GnRH-R-aAb) was established by using a recombinant fusion protein of full-length human GnRH-R and firefly luciferase. A commercial rabbit antiserum to human GnRH-R was used for standardization. Serum samples of control subjects and different cohorts of European PCOS patients (n = 1051) were analyzed. Results The novel GnRH-R-aAb assay was sensitive, and signals were linear on dilution when tested with the commercial GnRH-R antiserum. Natural GnRH-R-aAb were detected in one control (0.25%) and two PCOS samples (0.31%), and 12 samples were slightly above the threshold of positivity. The identification of samples with positive GnRH-R-aAb was reproducible and the signals showed no matrix interferences. Conclusion Natural GnRH-R-aAb are present in a very small fraction of adult control and PCOS subjects of European decent. Our results do not support the hypothesis that the GnRH-R constitutes a relevant autoantigen in PCOS.
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Wilson-Pérez, Hilary E., and Randy J. Seeley. "The Effect of Vertical Sleeve Gastrectomy on a Rat Model of Polycystic Ovarian Syndrome." Endocrinology 152, no. 10 (August 2, 2011): 3700–3705. http://dx.doi.org/10.1210/en.2011-1241.
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Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder of women of reproductive age. Although some of the primary symptoms of PCOS are reproductive abnormalities, including hyperandrogenism, menstrual dysfunction, and hirsutism, other metabolic disturbances are also common, including obesity and insulin resistance. Women with PCOS who have undergone weight-loss bariatric surgery have reported surprising postoperative benefits beyond weight loss, including resolution of menstrual dysfunction and improvement of hirsutism. Here, we use a chronic dihydrotestosterone (DHT) exposure model of PCOS in female rats and investigate the efficacy of a specific type of bariatric surgery, namely vertical sleeve gastrectomy (VSG), to resolve the reproductive and metabolic disturbances induced by DHT treatment. We find that VSG causes loss of body weight and body fat in DHT-treated rats but does not improve glucose tolerance or restore estrous cyclicity. Although human PCOS patients have shown decreased androgen levels after bariatric surgery, the chronic nature of DHT administration in this rat model both before and after VSG renders this effect impossible in this case. Therefore, the lack of improvement in glucose tolerance and estrous cyclicity may implicate a direct effect of androgen knockdown as a mechanism for the improvements seen in human PCOS patients after bariatric surgery. In addition, the dissociation of body weight loss without improved glucose tolerance suggests that glucose intolerance may be a body weight-independent phenomenon in women with PCOS.
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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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Mukherjee, Anirban Goutam, Uddesh Ramesh Wanjari, Sandra Kannampuzha, Reshma Murali, Arunraj Namachivayam, Raja Ganesan, Abhijit Dey, et al. "The Implication of Mechanistic Approaches and the Role of the Microbiome in Polycystic Ovary Syndrome (PCOS): A Review." Metabolites 13, no. 1 (January 14, 2023): 129. http://dx.doi.org/10.3390/metabo13010129.
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As a complex endocrine and metabolic condition, polycystic ovarian syndrome (PCOS) affects women’s reproductive health. These common symptoms include hirsutism, hyperandrogenism, ovulatory dysfunction, irregular menstruation, and infertility. No one knows what causes it or how to stop it yet. Alterations in gut microbiota composition and disruptions in secondary bile acid production appear to play a causative role in developing PCOS. PCOS pathophysiology and phenotypes are tightly related to both enteric and vaginal bacteria. Patients with PCOS exhibit changed microbiome compositions and decreased microbial diversity. Intestinal microorganisms also alter PCOS patient phenotypes by upregulating or downregulating hormone release, gut-brain mediators, and metabolite synthesis. The human body’s gut microbiota, also known as the “second genome,” can interact with the environment to improve metabolic and immunological function. Inflammation is connected to PCOS and may be caused by dysbiosis in the gut microbiome. This review sheds light on the recently discovered connections between gut microbiota and insulin resistance (IR) and the potential mechanisms of PCOS. This study also describes metabolomic studies to obtain a clear view of PCOS and ways to tackle it.
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Krishnan, Abhaya, and Sridhar Muthusami. "Hormonal alterations in PCOS and its influence on bone metabolism." Journal of Endocrinology 232, no. 2 (February 2017): R99—R113. http://dx.doi.org/10.1530/joe-16-0405.
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According to the World Health Organization (WHO) polycystic ovary syndrome (PCOS) occurs in 4–8% of women worldwide. The prevalence of PCOS in Indian adolescents is 12.2% according to the Indian Council of Medical Research (ICMR). The National Institute of Health has documented that it affects approximately 5 million women of reproductive age in the United States. Hormonal imbalance is the characteristic of many women with polycystic ovarian syndrome (PCOS). The influence of various endocrine changes in PCOS women and their relevance to bone remains to be documented. Hormones, which include gonadotrophin-releasing hormone (GnRH), insulin, the leutinizing/follicle-stimulating hormone (LH/FSH) ratio, androgens, estrogens, growth hormones (GH), cortisol, parathyroid hormone (PTH) and calcitonin are disturbed in PCOS women. These hormones influence bone metabolism in human subjects directly as well as indirectly. The imbalance in these hormones results in increased prevalence of osteoporosis in PCOS women. Limited evidence suggests that the drugs taken during the treatment of PCOS increase the risk of bone fracture in PCOS patients through endocrine disruption. This review is aimed at the identification of the relationship between bone mineral density and hormonal changes in PCOS subjects and identifies potential areas to study bone-related disorders in PCOS women.
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Przybycień, Piotr, Danuta Gąsior-Perczak, and Wojciech Placha. "Cannabinoids and PPAR Ligands: The Future in Treatment of Polycystic Ovary Syndrome Women with Obesity and Reduced Fertility." Cells 11, no. 16 (August 18, 2022): 2569. http://dx.doi.org/10.3390/cells11162569.
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Cannabinoids (CBs) are used to treat chronic pain, chemotherapy-induced nausea and vomiting, and multiple sclerosis spasticity. Recently, the medicinal use of CBs has attracted increasing interest as a new therapeutic in many diseases. Data indicate a correlation between CBs and PPARs via diverse mechanisms. Both the endocannabinoid system (ECS) and peroxisome proliferator-activated receptors (PPARs) may play a significant role in PCOS and PCOS related disorders, especially in disturbances of glucose-lipid metabolism as well as in obesity and fertility. Taking into consideration the ubiquity of PCOS in the human population, it seems indispensable to search for new potential therapeutic targets for this condition. The aim of this review is to examine the relationship between metabolic disturbances and obesity in PCOS pathology. We discuss current and future therapeutic interventions for PCOS and related disorders, with emphasis on the metabolic pathways related to PCOS pathophysiology. The link between the ECS and PPARs is a promising new target for PCOS, and we examine this relationship in depth.
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Huang, Wei, Shanxia Li, Naxin Luo, Kena Lu, Sheng Ban, and Hanmei Lin. "Dynamic Analysis of the Biochemical Changes in Rats with Polycystic Ovary Syndrome (PCOS) Using Urinary 1H NMR-Based Metabonomics." Hormone and Metabolic Research 52, no. 01 (January 2020): 49–57. http://dx.doi.org/10.1055/a-1073-2346.
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AbstractPolycystic ovarian syndrome (PCOS) is the most common endocrine disease that causes reproductive abnormalities in fertile women. It is closely related to the persistent anovulatory, insulin resistance, and high androgen. However, the molecular mechanisms underlying the pathological development of PCOS are still unclear. In this study, we aimed to explore the distinctive metabolic patterns in insulin combined with human chorionic gonadotrophin induced PCOS. The dynamic changes of endogenous metabolites in the development of PCOS were studied using untargeted metabolomic approaches based on nuclear magnetic resonance. The results showed that the degree of PCOS disorder metabolites at different periods was not exactly the same. Twelve significantly differential endogenous metabolites from different time points were selected as potential biomarkers relate to pathological process of PCOS. Among them, six metabolites showed a good diagnostic accuracy with PCOS model. The arginine and proline metabolic pathway was considered as one of the most crucial pathways that affects occurrence and development of PCOS. In addition, IRS-1, Akt, PI3K, IκB, and NF-κB (p65) were significantly changed in the ovary tissue of PCOS rats, which revealed that the IRS-1-PI3K/Akt and NF-κB signal pathway may be involved in the development of PCOS. This study demonstrated that metabolomic analysis is a powerful tool for providing novel insight into understanding the pathogenesis of PCOS and provide a basic reference for the diagnosis of PCOS at the onset stage.
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Che, Qi, Miao Liu, Doudou Zhang, Yongning Lu, Jun Xu, Xinmei Lu, Xiang Cao, Yang Liu, Xi Dong, and Suying Liu. "Long Noncoding RNA HUPCOS Promotes Follicular Fluid Androgen Excess in PCOS Patients via Aromatase Inhibition." Journal of Clinical Endocrinology & Metabolism 105, no. 4 (February 4, 2020): 1086–97. http://dx.doi.org/10.1210/clinem/dgaa060.
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Abstract Context Androgen excess is a key feature of polycystic ovary syndrome (PCOS), but the underlying molecular mechanism remains unclear. Objective To determine the role and mechanism of novel long noncoding RNA (lncRNA) highly up-regulated in PCOS (HUPCOS) in the androgen excess of PCOS patients. Design The lncRNA expression profile in granulosa cells derived from PCOS and non-PCOS women were analyzed by using microarray assay. Human granulosa cell line KGN was used for mechanism investigation. Setting This was a university-based study. Patients Thirty-eight PCOS and 38 control patients were recruited: 8 PCOS and 8 control samples used for microarray discovery, the remaining 30 PCOS cases and 30 controls for quantitative RT-PCR validation. Main Outcome Measures The aberrant expression lncRNA profile of PCOS patients was measured using microarray. The relationship of HUPCOS and follicular fluid testosterone was measured. Aromatase expression were analyzed after HUPCOS downregulation. HUPCOS interaction protein was confirmed by RNA pull-down. Results The significantly elevated lncRNA in PCOS granulosa cells was named HUPCOS, which was positively correlated with follicular fluid testosterone of PCOS patients. HUPCOS downregulation increased aromatase expression and promoted conversion of androgen to estrogen. RNA-binding protein with multiple splicing (RBPMS) was the most likely protein that combined with HUPCOS. Conclusions Our findings suggested that HUPCOS mediated androgen excess in follicular fluid of PCOS patients by suppressing aromatase expression via interaction with RBPMS.
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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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Çapoğlu, İlyas, Fuat Erdem, Abdullah Uyanık, and Hamdullah Turhan. "Serum levels of resistin and hsCRP in women with PCOS." Open Medicine 4, no. 4 (December 1, 2009): 428–32. http://dx.doi.org/10.2478/s11536-009-0071-0.
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AbstractResistin has been associated with obesity and type 2 diabetes. The elevated serum resistin level in human diabetes is often associated with a pro-inflammatory milieu. In vitro data suggest that C-reactive protein (CRP) significantly increases resistin expression in cultured human PBMC, yet the relationship in vivo is largely unknown. The purpose of this study was to determine the concentrations of CRP and resistin in women with polycystic ovary syndrome (PCOS) and to clarify whether or not there are correlations between CRP and resistin levels that have not previously been studied in PCOS in the context of resistin. Serum resistin and hsCRP levels of forty-five women with PCOS were analyzed. Compared with the control group, women with PCOS had significantly higher serum concentrations of resistin (p=0.009). Women with PCOS had higher hsCRP levels compared with controls, but these differences were not statistically significant (p>0.05). There was no correlation between serum resistin and hsCRP levels (r=0.128, p=0.404). Our study suggests that resistin concentrations was not associated with hsCRP levels
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Lin, Chang, Wu, Shih, Chiang, Chen, Shih, et al. "Dietary Glycotoxins, Advanced Glycation End Products, Inhibit Cell Proliferation and Progesterone Secretion in Ovarian Granulosa Cells and Mimic PCOS-like Symptoms." Biomolecules 9, no. 8 (July 31, 2019): 327. http://dx.doi.org/10.3390/biom9080327.
Full textAbstract:
Women with polycystic ovary syndrome (PCOS) have been reported to have an elevated serum advanced glycation end product (AGE) level. However, the effect of AGEs on the pathophysiological ovarian granulosa cells of PCOS is still unclear. In this study, five indented BSA-derived AGE products were used to evaluate their effect on the function of human granulosa cells. We found that the proliferation of both primary human ovarian granulosa (hGC) cells and human granulosa-like tumor (KGN) cells were inhibited by treatment with these five AGE products. The progesterone secretion level was also reduced in both hGC and KGN cells by treatment with these AGE products through downregulation of LH receptor/cAMP regulatory activity. The granulosa cell layer and serum progesterone level were reduced in rats by treatment with MG-BSA; moreover, an increased number of follicle cysts and an irregular estrous cycle were observed. MG-BSA treatment had a similar effect on the phenotypes of the DHEA-induced PCOS model. Additionally, the insulin resistance and hepatic lesions seen in the DHEA-induced PCOS model were observed in the MG-BSA treatment group. Taken together, we found that AGEs exert a toxic effect on ovarian granulosa cells, ovarian morphology, and the estrous cycle that mimics the DHEA-induced PCOS phenotypes.
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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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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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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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Reda, Ahmed M., AhmedI Abul Soud, Ahmed H. El Sawaf, Omnia I. Ezzat, Tarek M. Salman, and Hussein AL Sawaf. "Association of altered serum levels of Chemerin, Paraoxonase-1 (PON1), Asymmetric Dimethyl arginine (ADMA) and obesitin the development of Polycystic Ovarian Syndrome (PCOS) in Egyptian women." Indian Journal of Pharmaceutical and Biological Research 3, no. 03 (September 30, 2015): 35–43. http://dx.doi.org/10.30750/ijpbr.3.3.6.
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Chemerinwas recently added to the adipokine family and was identified in human ovarian follicles and follicular fluid that suggests a direct correlation between chemerin and PCOS. Asymmetric dimethyl arginine (ADMA) is involved in endothelial dysfunctionthe atherogenic potential of ADMA has been investigated in young patients with PCOS. Oxidative stress is considered to be implicated in the pathophysiology of PCOS.Paraoxonase 1 (PON1) is an antioxidant enzyme and its concentration has been shown to be inversely associated with oxidative stress. Objectives: Evaluation of serum chemerin, ADMA, PON1in obese and non-obese polycystic ovarian patients to postulate their role in pathogenesis of PCOS. Methods: Ninetynuligravida women aged 20-35 (60 with PCOS and 30 controls) were recruited. Fasting blood was obtained on day 2 or 3 of the menstrual cycle. Clinical evaluation, hormonal profile, Chemerin, ADMA and PON1 were assessed. Results: There was a significant increase in serum chemerinlevels in PCOS obese group when compared with PCOS non obese patients and healthy controls non obese and obese respectively. Serum ADMA level was increased significantly in PCOS obese group as compared to the PCOS non obese group , control non obese and control obese. Paraoxonase was decreased stepwise significantly from the control non obese group and control obese group to PCOS non obese patients then PCOS obese patients to. Conclusions: it could be suggested that increased chemerin has a role in PCOS development andaltered ADMA and PON1 associated withobesity and oxidative stress may exacerbate the condition.
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Xita, N., and A. Tsatsoulis. "Review: Fetal Programming of Polycystic Ovary Syndrome by Androgen Excess — Evidence from Experimental, Clinical and Genetic Association Studies." Journal of South Asian Federation of Obstetrics and Gynaecology 6, no. 2 (2014): 129–30. http://dx.doi.org/10.5005/jsafog-6-2-129.
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ABSTRACT Objective Polycystic ovary syndrome (PCOS) is a common endocrine disorder of premenopausal women, characterized by hyperandrogenism, polycystic ovaries, and chronic anovulation along with insulin resistance and abdominal obesity as frequent metabolic traits. Although, PCOS manifests clinically during adolescence, emerging data suggest that the natural history of PCOS may originate in intrauterine life. Evidence Acquisition Evidence from experimental, clinical, and genetic research supporting the hypothesis for the fetal origins of PCOS has been analyzed. Evidence Synthesis Female primates, exposed in utero to androgen excess, exhibit the phenotypic features of PCOS during adult life. Clinical observations also support a potential fetal origin of PCOS. Women with fetal androgen excess disorders, including congenital 21-hydroxylase deficiency and congenital adrenal virilizing tumors, develop features characteristic of PCOS during adulthood despite the normalization of androgen excess after birth. The potential mechanisms of fetal androgen excess leading to a PCOS phenotype in humans are not clearly understood. However, maternal and/or fetal hyperandrogenism can provide a plausible mechanism for fetal programming of PCOS, and this, in part, may be genetically determined. Thus, genetic association studies have indicated that common polymorphic variants of genes determining androgen activity or genes that influence the availability of androgens to target tissues are associated with PCOS and increased androgen levels. These genomic variants may provide the genetic link to prenatal androgenization in human PCOS. Conclusion Prenatal androgenization of the female fetus induced by genetic and environmental factors, or the interaction of both, may program differentiating target tissues toward the development of PCOS phenotype in adult life.
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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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García-Beltran, Cristina, Ruben Cereijo, Tania Quesada-López, Rita Malpique, Abel López-Bermejo, Francis de Zegher, Lourdes Ibáñez, and Francesc Villarroya. "Reduced circulating levels of chemokine CXCL14 in adolescent girls with polycystic ovary syndrome: normalization after insulin sensitization." BMJ Open Diabetes Research & Care 8, no. 1 (February 2020): e001035. http://dx.doi.org/10.1136/bmjdrc-2019-001035.
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ObjectiveCXCL14 (C-X-C motif chemokine ligand-14) is a chemokine released by active brown fat, showing protective effects against insulin resistance in experimental models. Polycystic ovary syndrome (PCOS) in adolescent girls is usually related to hepato-visceral fat excess and insulin resistance, and associates with comorbidities such as type 2 diabetes. Treatment with a low-dose combination of one antiandrogen and antimineralocorticoid drug (spironolactone) and two insulin sensitizers (pioglitazone/metformin) (SPIOMET) is particularly effective in improving these metabolic derangements. Adipose tissue may be involved in the metabolic alterations of PCOS, and it is a likely target of therapeutic action. We investigated the alterations in CXCL14 levels and the effects of drugs composing SPIOMET treatment on CXCL14 in human adipocytes.Research design and methodsWe studied 51 adolescent patients with PCOS and 21 age-matched healthy controls. Thirty-one adolescent patients with PCOS under SPIOMET or oral contraception-based treatment were also studied. For studies in vitro, Simpson Golabi Behmel Syndrome (SGBS) adipose cells were used. Gene expression for CXCL14 and other genes was quantified using quantitative real-time PCR. The levels of CXCL14 and adipokines in serum and cell culture media were determined by ELISA.ResultsSerum CXCL14 levels are reduced in patients with PCOS. One-year SPIOMET treatment normalized CXCL14 concentrations and improved the metabolic status of patients with PCOS. Pioglitazone induced CXCL14 expression in differentiating human SGBS adipocytes, in parallel with the induction of marker genes of brown adipogenesis. Spironolactone induced CXCL14 expression and release in differentiated human adipocytes.ConclusionInsulin sensitization with SPIOMET normalizes the abnormally low levels of CXCL14 in girls with PCOS. This is consistent with the effects of pioglitazone and spironolactone inducing CXCL14 expression and promoting a brown-like phenotype in adipocytes. CXCL14 may be a novel biomarker for PCOS as well as a potential mediator of the beneficial effects of the SPIOMET combination and may hold promise as a therapeutic modulator of the disorder.Trial registration numbersISRCTN29234515 and ISCRCTN11062950.
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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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Munir, Iqbal, Hui-Wen Yen, Talia Baruth, Rafal Tarkowski, Ricardo Azziz, Denis A. Magoffin, and Artur J. Jakimiuk. "Resistin Stimulation of 17α-Hydroxylase Activity in Ovarian Theca Cells in Vitro: Relevance to Polycystic Ovary Syndrome." Journal of Clinical Endocrinology & Metabolism 90, no. 8 (August 1, 2005): 4852–57. http://dx.doi.org/10.1210/jc.2004-2152.
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Context: A newly discovered hormone resistin has been shown to be increased in women with polycystic ovary syndrome (PCOS). Objective: The purpose of this study was to confirm increased resistin concentrations in women with PCOS and to test the direct effect of resistin on human theca cell androgen production. Design: Resistin was measured in fasting serum samples by RIA. To test the direct effects of resistin on ovarian androgen biosynthesis, human theca cells were cultured with resistin for 3 d in the presence and absence of forskolin and insulin. Patients: Fasting serum samples were obtained from 45 women with PCOS and 74 regularly cycling premenopausal control women in the follicular phase of their menstrual cycles, and ovarian theca cell cultures were established from two control women. Results: The mean serum resistin concentration was increased (40%) in women with PCOS. Serum resistin concentrations correlated positively with body mass index and testosterone in PCOS women but not in controls. There were no significant correlations between resistin and fasting insulin or indicators of insulin resistance when corrected for body mass index. In cultured human theca cells, basal 17α-hydroxylase activity was unchanged by resistin alone, but resistin enhanced 17α-hydroxylase activity in the presence of forskolin or a combination of forskolin plus insulin. Resistin (≥1 ng/ml) augmented forskolin and forskolin plus insulin stimulation of CYP17 mRNA expression in a concentration-dependent manner. Conclusion: These data indicate that abnormal resistin secretion in PCOS may play a role in causing ovarian hyperandrogenism.
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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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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.