title: Poor ovarian response in women undergoing in vitro fertilization is associated with altered microRNA expression in cumulus cells.
abstract: OBJECTIVE
  To analyze the association of micro-ribonucleic acid (miRNA) expression with the number of oocytes retrieved, in women undergoing in vitro fertilization (IVF).
  
  
  METHODS
  Experimental study.
  
  
  METHODS
  Academic medical center.
  
  
  METHODS
  A total of 189 women undergoing IVF-intracytoplasmic sperm injection (ICSI).
  
  
  METHODS
  Pooled cumulus cells were collected.
  
  
  METHODS
  Poor responders were identified as patients who produced fewer oocytes than the 25th percentile of their respective age group. MicroRNAs were extracted from cumulus cells, and an miRNA microarray was performed, comparing poor responders (n = 3) to non-poor responders (n = 3). Expression of miR-21-5p (active strand of miR-21) and miR-21-3p was tested in poor responders (n = 21) and non-poor responders (n = 29), using reverse transcription real-time polymerase chain reaction (qRT-PCR). Regulation of miR-21-5p and miR-21-3p, in human granulosa-like tumor (KGN) cells, by estradiol (E2), was tested in vitro.
  
  
  RESULTS
  MicroRNA microarray analysis showed up-regulation of 16 miRNAs and down-regulation of 88 miRNAs in poor responders. Notably, miR-21 was significantly up-regulated 5-fold in poor-responder samples. Analysis using qRT-PCR confirmed that miR-21-5p expression was significantly up-regulated in poor responders, whereas miR-21-3p expression was significantly lower, suggesting that elevated miR-21-5p expression in cumulus cells is not regulated at the pre-miR-21 level in poor responders. Both miR-21-5p and miR-21-3p were increased in KGN cells in response to higher doses of E2; their expression was not affected at lower E2 concentrations.
  
  
  CONCLUSIONS
  We found that poor response to IVF is associated with altered miRNA expression in cumulus cells, specifically with elevated expression of miR-21-5p, and that this elevated expression is independent of lower serum E2 levels in poor responders.
authors.affiliation: Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut; Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Gazi University School of Medicine, Ankara, Turkey.
authors.forename: Cengiz
authors.initials: C
authors.lastname: Karakaya
authors.affiliation: Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Ozlem
authors.initials: O
authors.lastname: Guzeloglu-Kayisli
authors.affiliation: Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut; Department of Computer Engineering, Okan University, Istanbul, Turkey.
authors.forename: Asli
authors.initials: A
authors.lastname: Uyar
authors.affiliation: Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Amanda N
authors.initials: AN
authors.lastname: Kallen
authors.affiliation: Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Elnur
authors.initials: E
authors.lastname: Babayev
authors.affiliation: Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Gazi University School of Medicine, Ankara, Turkey.
authors.forename: Nuray
authors.initials: N
authors.lastname: Bozkurt
authors.affiliation: Department of Histology and Embryology, Istanbul Bilim University School of Medicine, Istanbul, Turkey.
authors.forename: Evrim
authors.initials: E
authors.lastname: Unsal
authors.affiliation: Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Gazi University School of Medicine, Ankara, Turkey.
authors.forename: Onur
authors.initials: O
authors.lastname: Karabacak
authors.affiliation: Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut. Electronic address: emre.seli@yale.edu.
authors.forename: Emre
authors.initials: E
authors.lastname: Seli
mesh_terms: D002452:Cell Count; D002478:Cells, Cultured; D054885:Cumulus Cells / Q000166:cytology* / Q000502:physiology*; D005260:Female; D005307:Fertilization in Vitro; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006801:Humans; D007247:Infertility, Female / Q000235:genetics* / Q000628:therapy*; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D010060:Ovulation / Q000235:genetics*; D010062:Ovulation Induction / Q000379:methods; D011247:Pregnancy; D055815:Young Adult
chemical_list: C524940:MIRN21 microRNA, human; D035683:MicroRNAs
keywords: IVF; cumulus cells; miR-21; miRNA; poor ovarian response