Advanced glycation end products alter steroidogenic gene expression by granulosa cells: An effect partially reversible by vitamin D

Z. Merhi, E. Buyuk, M. J. Cipolla

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


STUDY QUESTION: Does vitamin D attenuate the adverse effects of advanced glycation end products (AGEs) on steroidogenesis by human granulosa cells (GCs)? SUMMARY ANSWER: AGEs alter the expression of genes important in steroidogenesis while 1,25-dihydroxyvitamin D3 (vit D3) in vitro attenuates some of the actions of AGEs on steroidogenic gene expression, possibly by downregulating the expression of the pro-inflammatory cell membrane receptor for AGEs (RAGE). WHAT IS KNOWN ALREADY: Vitamin D attenuates the pro-inflammatory effects of AGEs in non-ovarian tissues. STUDY DESIGN, SIZE, DURATION: Women who were undergoing IVF were enrolled. Follicular fluid samples (n = 71) were collected and cumulus GCs (n = 12) were treated in culture. PARTICIPANTS/MATERIALS, SETTING, METHODS: Follicular fluid levels of the anti-inflammatory soluble RAGE (sRAGE), AGEs and 25-hydroxyvitamin D (25-OHD) were quantified for possible correlations. GCs of each participant were split equally and treated with either media alone (control) or with human glycated albumin (HGA as a precursor for AGEs) with or without vit D3 after which RT-PCR and immunofluorescence were performed and cell culture media estradiol (E2) levels were compared. MAIN RESULTS AND THE ROLE OF CHANCE: In follicular fluid, sRAGE levels were positively correlated with 25-OHD levels. HGA treatment (i) increased CYP11A1 (by 48%), 3β-HSD (by 38%), StAR (by 42%), CYP17A1 (by 30%) and LHR (by 37%) mRNA expression levels (P < 0.05 for all) but did not alter CYP19A1 or FSHR mRNA expression levels; and (ii) increased E2 release in cell culture media (P = 0.02). Vit D3 treatment (i) downregulated RAGE mRNA expression by 33% and RAGE protein levels by 44% (P < 0.05); (ii) inhibited the HGA-induced increase in CYP11A1, StAR, CYP17A1 and LHR mRNA levels, but not the increase in 3β-HSD mRNA levels; and (iii) did not inhibit the HGAinduced E2 release in cell culture media. LIMITATIONS REASONS FOR CAUTION: This study used luteinized GCs that were collected from women who received gonadotropins thus the results obtained may not fully extrapolate to non-luteinized GCs in vivo. WIDER IMPLICATIONS OF THE FINDINGS: This study suggests that there is a relationship between AGEs and their receptors (RAGE and sRAGE) with vitamin D. Understanding the interaction between AGEs and vitamin D in ovarian physiology could lead to a more targeted therapy for the treatment of ovarian dysfunction. STUDY FUNDING/COMPETING INTEREST(S): Funding was received from NIH (R01 NS045940), American Society for Reproductive Medicine, Ferring Pharmaceuticals Inc., and University of Vermont College of Medicine Bridge Funds. All authors have nothing to disclose.

Original languageEnglish (US)
Pages (from-to)318-326
Number of pages9
JournalMolecular Human Reproduction
Issue number6
StatePublished - Jun 1 2018


  • Advanced glycation end products
  • RAGE
  • follicular fluid
  • granulosa
  • sRAGE
  • steroidogenesis
  • vitamin D

ASJC Scopus subject areas

  • Reproductive Medicine
  • Embryology
  • Molecular Biology
  • Genetics
  • Obstetrics and Gynecology
  • Developmental Biology
  • Cell Biology


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