Lee Mee-Hwa, Yoon Jung-Ah, Kim Hye-Ryun, Kim Yeon Sun, Lyu Sang Woo, Lee Byung Seok, Song Haengseok, Choi Dong Hee
1 Department of Obstetrics and Gynecology, CHA Bundang Medical Center, CHA University, Seongnam, Korea.
2 Department of Medicine, The Graduate School of Yonsei University, Seoul, Korea.
Reprod Sci. 2019 Mar 4:1933719119833487. doi: 10.1177/1933719119833487.
: 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）相关的生育力低下主要源于排卵稀少/无排卵。尽管已知胰岛素抵抗和雄激素过多会导致PCOS相关的着床失败，但PCOS对子宫内膜内环境稳定和病理生理学的影响尚未得到全面了解。在本研究中，我们研究了PCOS的病理生理环境是否内在地影响人子宫内膜中与胰岛素信号传导和易化性葡萄糖转运蛋白（GLUTs）相关的基因表达谱，以及体外蜕膜化过程中的相关情况。
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。为了在体外模拟PCOS患者（PCOSE）子宫内膜中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）与二氢睾酮（DHT）或胰岛素进行处理。
在PCOSE中，胰岛素受体（IR）、IR底物（IRS）1和IRS2的信使核糖核酸（mRNA）水平显著升高。此外，GLUT1和GLUT12异常增加。长期暴露于胰岛素或DHT会异常增加hESCs中IRS1/IRS2的磷酸化以及GLUT1和GLUT12的蛋白水平，这表明不仅高胰岛素环境，而且高雄激素环境也会影响胰岛素信号传导和葡萄糖代谢。mRNA微阵列显示，DHT会使hESCs中的各种基因集失调，包括细胞周期和葡萄糖代谢相关基因集。此外，在体外蜕膜化过程中，DHT抑制了GLUT1和GLUT12以及蜕膜化标志物胰岛素样生长因子结合蛋白1（IGFBP1）和催乳素的表达。
高雄激素环境会影响人子宫内膜以及体外蜕膜化过程中的基因表达谱，包括与胰岛素信号传导、细胞周期、葡萄糖代谢和/或葡萄糖转运相关的基因集。
