Polycystic ovary syndrome (PCOS) is the most common hormonal imbalance disease in reproductive-aged women Its basic characteristics are ovulatory dysfunction and ovarian overproduction of androgens that lead to severe symptoms such as insulin resistance, hirsutism, infertility, and acne Notwithstanding the disease burden, its underlying mechanisms remain unknown, and no causal therapeutic exists In recent years, further studies showed that inflammation processes are involved in ovulation and play a key role in ovarian follicular dynamics Visceral adipose tissue can cause inflammatory response and maintenance of the inflammation state in adipocytes by augmented production of inflammatory cytokines, monocyte chemoattractant proteins, and recruitment of the immune cell Therefore, the PCOS can be related to a low-grade inflammation state and inflammatory markers Investigating the inflammatory processes and mediators that contribute to the commencement and development of PCOS can be a critical step for better understanding the pathophysiology of the disease and its treatment through inhibition or control of related pathways In the present review, we discuss the pathophysiological roles of chronic low-grade inflammation mediators including inflammasome-related cytokines, interleukin-1β (IL-1β), and IL-18 in PCOS development

Pathophysiological roles of chronic low-grade inflammation mediators in polycystic ovary syndrome.

http://biostacs.com/pdf/Characterization.pdf

Characterization of microRNA profile in human cumulus granulosa cells: Identification of microRNAs that regulate Notch signaling and are associated with PCOS

Study question Does metformin inhibit excessive androgen-induced endoplasmic reticulum (ER) stress in mouse granulosa cells (GCs) in vivo and in vitro? Summary answer Metformin inhibits testosterone-induced ER stress and unfolded protein response (UPR) activation by suppressing p38 MAPK phosphorylation in ovarian GCs. What is known already Polycystic ovary syndrome (PCOS) is associated with hyperandrogenism. Excessive testosterone induces ER stress and UPR activation in human cumulus cells, leading to cell apoptosis. Metformin has potential inhibitory effects on ER stress and UPR activation, as demonstrated in human pancreatic beta cells and obese mice. Study design, size, duration Cumulus cells and follicular fluid were collected from 25 women with PCOS and 25 controls at our IVF centre. A dihydrotestosterone (DHT)-induced PCOS mouse model was constructed and treated with or without metformin. Primary mouse GCs and cumulus-oocyte complexes (COCs) were cultured with testosterone, metformin, a p38 MAPK inhibitor, or p38 MAPK small interfering RNA. Participants/materials, setting, methods The levels of UPR sensor proteins and UPR-related genes were measured in cumulus cells from PCOS and control patients by real-time quantitative PCR (qPCR) and western blot. The ovaries, oocytes, GCs and COCs were collected from PCOS mice treated with metformin and controls. The expressions of ER stress markers and p38 MAPK phosphorylation were assessed by qPCR, western blot and immunofluorescence. A subsequent in vitro analysis with primary cultured GCs and COCs was used to confirm the influence of metformin on ER stress activation by qPCR and western blot. Finally, the effects of ER stress activation on GCs and COCs in relation to LH responsiveness were examined by qPCR and COC expansion. Main results and the role of chance The expression of the ER stress markers GRP78, CHOP and XBP1s in the cumulus cells was higher in PCOS patients than in control patients, as were the levels of the UPR sensor proteins p-IRE1α, p-EIF2α and GRP78. Compared to those of control mice, the ovaries, GCs and COCs of DHT-treated PCOS mice showed increased levels of ER stress marker genes and proteins. Hyperandrogenism in PCOS mouse ovaries also induced p38 MAPK phosphorylation in COCs and GCs. Metformin inhibited ER stress activation was associated with decreased p-p38 MAPK levels. In vitro experiments, testosterone-induced ER stress was mitigated by metformin or p38 MAPK inhibition in primary cultured GCs and COCs. COCs expanded rapidly in the presence of testosterone during LH administration, and ovulation-related genes, namely, Areg, Ereg, Ptgs2, Sult1e1, Ptx3 and Tnfaip6, were strongly expressed in the COCs and GCs. These effects were reversed by treatment with metformin, an ER stress inhibitor or by knockdown of p38 MAPK. Limitations, reasons for caution The number of PCOS patients in this study was small. Wider implications of the findings This study provides further evidence for metformin as a PCOS treatment. Study funding/competing interest(s) This study was funded by the National Key Research and Developmental Program of China (2018YFC1004800), the Key Research and Development Program of Zhejiang Province (2017C03022), the Zhejiang Province Medical Science and Technology Plan Project (2017KY085, 2018KY457), the National Natural Science Foundation of China (31701260, 81401264, 81701514), and the Special Funds for Clinical Medical Research of the Chinese Medical Association (16020320648). The authors report no conflict of interest in this work and have nothing to disclose. Trial registration number N/A.

/pdf/metformin-inhibits-testosterone-induced-endoplasmic-49en9k3ba4.pdf

Metformin inhibits testosterone-induced endoplasmic reticulum stress in ovarian granulosa cells via inactivation of p38 MAPK

A brief insight into the etiology, genetics, and immunology of polycystic ovarian syndrome (PCOS)

The heterogeneous and multifactorial essence of polycystic ovary syndrome (PCOS) renders a remarkable significance to microRNAs (miRNAs). Normo-androgenic (NA) and hyperandrogenic (HA) PCOS patients were compared with matched healthy women. Expression of miRNAs and TGFβ signaling genes was studied by qRT-PCR and western blotting. Effect of androgen on expression of miR-93 and miR-21 and involvement of androgen receptor were appraised. In granulosa cells (GCs), miR-93 and miR-21 showed significantly increased levels in HA patients compared to NA patients. On the contrary, follicular fluid (FF) levels of both miRNAs were significantly decreased in HA group compared to control women. No significant change in the expression of miRNAs in serum samples was detected. Furthermore, mRNA levels of SMAD7 and TGFBR2 were significantly downregulated in GCs of HA group compared to NA and control subjects. TGFBR2 protein level was significantly decreased in HA patients compared to controls. Free testosterone and free androgen index were positively correlated with expression of miR-93 and miR-21 in GCs of PCOS group. Our findings show distinct molecular signature of different subtypes of PCOS. Intermediary position of miRNAs as androgen responsive factors may play critical role in the pathogenesis of PCOS in hyperandrogenic condition.

/pdf/differential-expression-of-mir-93-and-mir-21-in-granulosa-2vh0qvbhf4.pdf

Differential Expression of miR-93 and miR-21 in Granulosa Cells and Follicular Fluid of Polycystic Ovary Syndrome Associating with Different Phenotypes.

main results: The gene expression profile of CCs from patients with PCOS was significantly different from that of CCs from non-PCOS patients. Specifically, CCs from women with PCOS were characterized by abnormal expression of many growth factors, including members of the epidermal growth factor-like (EGFR, EREG and AREG) and IGF-like families (IGF1R, IGF2R, IGF2BP2 and IGFBP2), that are known to play a role in oocyte competence. In addition, mRNA transcripts of factors involved in steroid metabolism, such as CYP11A1, CYP1B1, CYP19A1 and CYP2B7P1, were deregulated in PCOS CCs, and this could explain the abnormal steroidogenesis observed in these women. Functional annotation of the differentially expressed genes suggests that defects in the transforming growth factor b and estrogen receptors signalling cascades may contribute to the reduced oocyte developmental competence in patients with PCOS. limitations and reasons for caution: Owing to the strict selection criteria (similar age, weight and reasons for ART), this study included a small sample size (six cases and six controls), and thus, further investigations using a large cohort of patients are needed to confirm these results. wider implications of the findings: This study opens a new perspective for understanding the pathogenesis of PCOS. study funding/competing interests: This work was partially supported by a grant from the Ferring Pharmaceutical. The authors of the study have no competing interests to report. trial registration number: Not applicable.

Altered gene expression profile in cumulus cells of mature MII oocytes from patients with polycystic ovary syndrome

Resume Objectif Preserver la fertilite doit aujourd’hui faire partie integrante de la prise en charge du cancer. L’objectif de notre etude est d’evaluer notre activite de preservation de la fertilite feminine au sein du CHU de Montpellier mis en place depuis 2011. Patientes et methodes etat de lieu de la pratique d’oncofertilite au CHRU de Montpellier sur 2 ans, de septembre 2011 a septembre 2013. Resultats Soixante et onze patientes ont ete adressees en consultation de preservation de la fertilite. Quarante-deux patientes (59,1 %) etaient eligibles pour la preservation de la fertilite. Vingt-deux patientes (31 %) se sont vues proposer une congelation d’ovocytes matures, 8 patientes (11,3 %) une cryoconservation de tissu ovarien, 7 patientes (9,9 %) des injections d’analogues de la GnRH, 3 patientes (4,2 %) une transposition ovarienne et seulement 2 patientes (2,8 %) une congelation embryonnaire. Sur les 42 indications de preservation de la fertilite, seulement 18 auront finalement eu lieu. Conclusion La preservation de la fertilite doit etre integree dans le programme de soins du cancer, menee par une equipe pluridisciplinaire. Il est essentiel d’ameliorer la diffusion de l’information aupres des patientes mais aussi des oncologues impliques dans la prise en charge de ces patientes.

Programme de préservation de la fertilité féminine au CHRU de Montpellier 2 ans après

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Altered gene expression profile in cumulus cells of mature MII oocytes from patients with polycystic ovary syndrome

Programme de préservation de la fertilité féminine au CHRU de Montpellier 2 ans après