Mauro Cozzolino1,2,3,4, Sonia Herraiz5, Yigit Cakiroglu6,7, Juan Antonio Garcia-Velasco8,9, Bulent Tiras6,7, Alberto Pacheco9, Susana Rabadan9, Graciela Kohls9, Ana Isabel Barrio9, Antonio Pellicer10,5, Emre Seli11,12. 1. Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA. mauro.cozzolino@ivirma.com. 2. IVIRMA, Roma, Italy. mauro.cozzolino@ivirma.com. 3. Universidad Rey Juan Carlos, Madrid, Spain. mauro.cozzolino@ivirma.com. 4. Grupo de investigación en Medicina Reproductiva, Fundación IVI-Instituto de Investigación Sanitaria La Fe (IISLAFE), Valencia, Spain. mauro.cozzolino@ivirma.com. 5. Grupo de investigación en Medicina Reproductiva, Fundación IVI-Instituto de Investigación Sanitaria La Fe (IISLAFE), Valencia, Spain. 6. Acibadem Maslak Hospital Assisted Reproductive Technologies Unit, Istanbul, Turkey. 7. Department of Obstetrics and Gynecology, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey. 8. Universidad Rey Juan Carlos, Madrid, Spain. 9. IVIRMA, Madrid, Spain. 10. IVIRMA, Roma, Italy. 11. Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA. 12. IVIRMA New Jersey, Basking Ridge, NJ, USA.
Abstract
PURPOSE: In this study, we investigated whether metabolic dysfunction in women with Polycystic ovarian syndrome (PCOS) induces granulosa cell (GC) stress and activates in the endoplamatic reticulum and the mitochondria (UPRer and UPRmt, respectively). METHODS: Women who were diagnosed with PCOS (based on the Rotterdam criteria), were divided into two groups, PCOS with insulin resistance (PCOS-IR; n = 20) and PCOS with no insulin resistance (PCOS-nIR; n = 20), and compared to healthy oocyte donors (CONT; n = 20). Insulin resistance (IR) was assessed on the results of homeostasis model assessment (HOMA) that determines IR using the concentration of fasting plasma glucose and fasting insuline. Expression of UPRer genes (i.e., IRE1, ATF4, ATF6, XBP1, BIP, and CHOP), and UPRmt genes (i.e., HSP60, HSP10, CLPP, and HSP40) was assessed in cumulus GCs by qRT-PCR. RESULTS: We found that several genes involved in UPRer and UPRmt were overexpressed in the GCs of PCOS-IR and PCOS-nIR compared to CONT. IRE1, ATF4 and XBP1, that are activated by ER stress, were significantly overexpressed in PCOS-IR compared to CONT. BIP and CHOP were overexpressed in PCOS groups compared to CONT. HSP10 and HSP40 were upregulated in PCOS-IR and PCOS-nIR groups compared to the CONT. HSP60 and CLPP showed no statistical different expression in PCOS-IR and PCOS-nIR compared to CONT group. CONCLUSION: Our findings suggest that the GCs of women with PCOS (with or without IR) are metabolically distressed and upregulate UPRer and UPRmt genes. Our study contributes to the understanding of the molecular mechanisms underlying the pathological changes that occur in the follicular microenvironment of women with PCOS.
PURPOSE: In this study, we investigated whether metabolic dysfunction in women with Polycystic ovarian syndrome (PCOS) induces granulosa cell (GC) stress and activates in the endoplamatic reticulum and the mitochondria (UPRer and UPRmt, respectively). METHODS: Women who were diagnosed with PCOS (based on the Rotterdam criteria), were divided into two groups, PCOS with insulin resistance (PCOS-IR; n = 20) and PCOS with no insulin resistance (PCOS-nIR; n = 20), and compared to healthy oocyte donors (CONT; n = 20). Insulin resistance (IR) was assessed on the results of homeostasis model assessment (HOMA) that determines IR using the concentration of fasting plasma glucose and fasting insuline. Expression of UPRer genes (i.e., IRE1, ATF4, ATF6, XBP1, BIP, and CHOP), and UPRmt genes (i.e., HSP60, HSP10, CLPP, and HSP40) was assessed in cumulus GCs by qRT-PCR. RESULTS: We found that several genes involved in UPRer and UPRmt were overexpressed in the GCs of PCOS-IR and PCOS-nIR compared to CONT. IRE1, ATF4 and XBP1, that are activated by ER stress, were significantly overexpressed in PCOS-IR compared to CONT. BIP and CHOP were overexpressed in PCOS groups compared to CONT. HSP10 and HSP40 were upregulated in PCOS-IR and PCOS-nIR groups compared to the CONT. HSP60 and CLPP showed no statistical different expression in PCOS-IR and PCOS-nIR compared to CONT group. CONCLUSION: Our findings suggest that the GCs of women with PCOS (with or without IR) are metabolically distressed and upregulate UPRer and UPRmt genes. Our study contributes to the understanding of the molecular mechanisms underlying the pathological changes that occur in the follicular microenvironment of women with PCOS.
Authors: Daniel A Dumesic; Sharon E Oberfield; Elisabet Stener-Victorin; John C Marshall; Joop S Laven; Richard S Legro Journal: Endocr Rev Date: 2015-10 Impact factor: 19.871
Authors: Ricardo Azziz; Enrico Carmina; Didier Dewailly; Evanthia Diamanti-Kandarakis; Héctor F Escobar-Morreale; Walter Futterweit; Onno E Janssen; Richard S Legro; Robert J Norman; Ann E Taylor; Selma F Witchel Journal: Fertil Steril Date: 2008-10-23 Impact factor: 7.329