Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
Mol Hum Reprod. 2012 Jul;18(7):362-71. doi: 10.1093/molehr/gas008. Epub 2012 Feb 20.
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.
卵巢储备功能降低（DOR）是一种具有挑战性的不孕诊断，因为目前尚无测试可以预测哪些人可能会出现这种情况，或者在什么年龄出现。我们设计了本研究，旨在比较年轻的 DOR 患者的颗粒细胞基因表达谱与年龄相似的卵子供者的基因表达谱，并确定是否可以识别出不同的遗传模式，以深入了解 DOR 的病因。根据 IVF 周期中 FSH 水平和卵泡发育不良情况，确定患有 DOR 的年轻女性（n = 13）。正常卵巢储备（NOR）的卵子供者为对照组（n = 13）。取卵后收集颗粒细胞，提取 RNA，进行微阵列分析，以评估两组之间的基因差异。采用定量 RT-PCR（qRT-PCR）进行验证研究。在 DOR 患者和卵子供者之间观察到多个基因表达的显著差异。进一步用 qRT-PCR 对与卵巢功能相关的两个基因，抗苗勒管激素（AMH）和促黄体生成素受体（LHCGR）进行分析。所有患者中，AMH 的平均表达在卵子供者中明显更高（调整后的 P 值= 0.01），而 LHCGR 的平均表达在 DOR 患者中明显更高（调整后的 P 值= 0.005）。在包括 5 名 NOR 和 5 名 DOR 患者的一组中，验证了另外四个基因的表达水平，即孕激素受体膜成分 2（PGRMC2）、前列腺素 E 受体 3（亚型 EP3）（PTGER3）、类固醇急性调节蛋白（StAR）和 StAR 相关脂质转移结构域包含蛋白 4（StarD4）。我们得出结论，基因表达分析具有很大的潜力来确定哪些年轻女性可能患有 DOR。更重要的是，我们的分析表明，根据基因表达谱，DOR 患者可分为两个不同的亚组，表明在该病理发生发展过程中可能涉及不同的机制。
