title: Ovarian reserve status in young women is associated with altered gene expression in membrana granulosa cells.
abstract: Diminished ovarian reserve (DOR) is a challenging diagnosis of infertility, as there are currently no tests to predict who may become affected with this condition, or at what age. We designed the present study to compare the gene expression profile of membrana granulosa cells from young women affected with DOR with those from egg donors of similar age and to determine if distinct genetic patterns could be identified to provide insight into the etiology of DOR. Young women with DOR were identified based on FSH level in conjunction with poor follicular development during an IVF cycle (n = 13). Egg donors with normal ovarian reserve (NOR) comprised the control group (n = 13). Granulosa cells were collected following retrieval, RNA was extracted and microarray analysis was conducted to evaluate genetic differences between the groups. Confirmatory studies were undertaken with quantitative RT-PCR (qRT-PCR). Multiple significant differences in gene expression were observed between the DOR patients and egg donors. Two genes linked with ovarian function, anti-Mullerian hormone (AMH) and luteinizing hormone receptor (LHCGR), were further analyzed with qRT-PCR in all patients. The average expression of AMH was significantly higher in egg donors (adjusted P-value = 0.01), and the average expression of LHCGR was significantly higher in DOR patients (adjusted P-value = 0.005). Expression levels for four additional genes, progesterone receptor membrane component 2 (PGRMC2), prostaglandin E receptor 3 (subtype EP3) (PTGER3), steroidogenic acute regulatory protein (StAR), and StAR-related lipid transfer domain containing 4 (StarD4), were validated in a group consisting of five NOR and five DOR patients. We conclude that gene expression analysis has substantial potential to determine which young women may be affected with DOR. More importantly, our analysis suggests that DOR patients fall into two distinct subgroups based on gene expression profiles, indicating that different mechanisms may be involved during development of this pathology.
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
authors.forename: Christine C
authors.initials: CC
authors.lastname: Skiadas
authors.forename: Shenghua
authors.initials: S
authors.lastname: Duan
authors.forename: Mick
authors.initials: M
authors.lastname: Correll
authors.forename: Renee
authors.initials: R
authors.lastname: Rubio
authors.forename: Nilay
authors.initials: N
authors.lastname: Karaca
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Ginsburg
authors.forename: John
authors.initials: J
authors.lastname: Quackenbush
authors.forename: Catherine
authors.initials: C
authors.lastname: Racowsky
mesh_terms: D000328:Adult; D054304:Anti-Mullerian Hormone / Q000235:genetics; D019295:Computational Biology; D005260:Female; D005640:Follicle Stimulating Hormone / Q000378:metabolism; D006107:Granulosa Cells / Q000378:metabolism*; D006801:Humans; D007247:Infertility, Female / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D026901:Membrane Transport Proteins / Q000235:genetics; D046228:Microarray Analysis; D009865:Oocytes / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011974:Receptors, LH / Q000235:genetics; D011980:Receptors, Progesterone / Q000235:genetics; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000235:genetics
chemical_list: D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C115297:PGRMC2 protein, human; C545647:PTGER3 protein, human; D011974:Receptors, LH; D011980:Receptors, Progesterone; D058308:Receptors, Prostaglandin E, EP3 Subtype; C456544:STARD4 protein, human; D054304:Anti-Mullerian Hormone; D005640:Follicle Stimulating Hormone