Department of Obstetrics and Gynecology, CHA Bundang Medical Center, CHA University, Seongnam, Korea.
Department of Medicine, The Graduate School of Yonsei University, Seoul, Korea.
Reprod Sci. 2020 Aug;27(8):1637-1647. doi: 10.1007/s43032-020-00194-7.
Subfertility associated with polycystic ovary syndrome (PCOS) mainly originates from oligoovulation/anovulation. Although insulin resistance and androgen excess are known to cause PCOS-associated implantation failure, the consequences of PCOS on endometrial homeostasis and pathophysiology have not been comprehensively understood. In this study, we examined whether the pathophysiologic milieu of PCOS intrinsically affects expression profiles of genes related to insulin signaling and facilitative glucose transporters (GLUTs) in the human endometrium and/or during in vitro decidualization.
Seven healthy women with regular menstrual cycles and 13 patients with PCOS were recruited for this study. To mimic the hyperandrogenic or hyperinsulinemic milieu in the endometrium of patient with PCOS (PCOSE) in vitro, human endometrial stromal cells (hESCs) were treated with dihydrotestosterone (DHT) or insulin, respectively.
In PCOSE, messenger RNA (mRNA) levels of insulin receptor (IR), IR substrate (IRS) 1, and IRS2 were significantly increased. Furthermore, GLUT1 and GLUT12 were aberrantly increased. Chronic exposure to insulin or DHT aberrantly increased IRS1/IRS2 phosphorylation and protein levels of GLUT1 and GLUT12 in hESCs, suggesting that not only hyperinsulinemic but also hyperandrogenic conditions affect insulin signaling and glucose metabolism. The mRNA microarrays demonstrated that DHT dysregulates various gene sets, including cell cycle and glucose metabolism, in hESCs. Furthermore, DHT suppressed the expression of GLUT1 and GLUT12 as well as decidualization markers, IGFBP1 and prolactin, during in vitro decidualization.
The hyperandrogenic milieu affects gene expression profiles, including gene sets associated with insulin signaling, cell cycle, glucose metabolism, and/or glucose transport, in human endometrium and during in vitro decidualization.
多囊卵巢综合征（PCOS）相关的不孕主要源于排卵障碍/无排卵。尽管胰岛素抵抗和雄激素过多会导致 PCOS 相关的着床失败，但 PCOS 对子宫内膜稳态和病理生理学的影响尚未被全面理解。在这项研究中，我们研究了 PCOS 的病理生理环境是否会内在地影响人子宫内膜中与胰岛素信号和葡萄糖转运（GLUTs）相关的基因的表达谱，以及在体外蜕膜化过程中这些基因的表达谱。
本研究招募了 7 名月经周期规律的健康女性和 13 名 PCOS 患者。为了模拟 PCOS 患者子宫内膜的高雄激素或高胰岛素环境，分别用人子宫内膜基质细胞（hESCs）处理二氢睾酮（DHT）或胰岛素。
在 PCOSE 中，胰岛素受体（IR）、IR 底物（IRS）1 和 IRS2 的信使 RNA（mRNA）水平显著增加。此外，GLUT1 和 GLUT12 也异常增加。慢性暴露于胰岛素或 DHT 会异常增加 hESCs 中 IRS1/IRS2 的磷酸化和 GLUT1 和 GLUT12 的蛋白水平，这表明不仅高胰岛素血症，而且高雄激素血症也会影响胰岛素信号和葡萄糖代谢。mRNA 微阵列显示，DHT 会使 hESCs 中的各种基因簇失调，包括细胞周期和葡萄糖代谢。此外，DHT 会抑制 GLUT1 和 GLUT12 以及体外蜕膜化过程中的蜕膜化标志物 IGFBP1 和催乳素的表达。
高雄激素环境会影响人子宫内膜和体外蜕膜化过程中的基因表达谱，包括与胰岛素信号、细胞周期、葡萄糖代谢和/或葡萄糖转运相关的基因簇。
