Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, 21999, Republic of Korea.
Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, 406-840, Republic of Korea.
Cell Death Dis. 2018 Aug 1;9(8):828. doi: 10.1038/s41419-018-0892-3.
Gonadotropin-releasing hormone (GnRH) stimulates the synthesis and release of gonadotropins, which induce estrogen production and subsequent ovulation. Therefore, long-term GnRH exposure to regulate ovarian hyperstimulation is recognized as the gold standard for most in vitro fertilization (IVF) strategies. However, one of the most disappointing aspects of current IVF technology is relatively low rate (between 35 and 50%) of positive pregnancy outcomes, and the major reason for this high cancellation rate has not yet been revealed. Previous studies have demonstrated that resident stem cell deficiency limits the cyclic regenerative capacity of the endometrium and subsequently increases pregnancy failure rates. Therefore, we hypothesized that long-term GnRH exposure directly damages endometrial stem cells and consequently negatively affects pregnancy outcomes in GnRH-based IVF. In addition to their well-known roles in regulating the hypothalamus-pituitary-gonadal axis, GnRH and its receptors also localize in the extra-hypothalamic endometrium, suggesting a possible non-canonical role in endometrial stem cells. Consistent with our hypothesis, we show for the first time that GnRH suppresses the multiple beneficial functions of endometrial stem cells via the PI3K/Akt signaling pathway in vitro and in vivo. To the best of our knowledge, this is the first study to focus on the direct effects of GnRH on the regenerative potential of stem cells, and the findings will facilitate the development of more promising IVF strategies.
促性腺激素释放激素（GnRH）刺激促性腺激素的合成和释放，促性腺激素诱导雌激素的产生和随后的排卵。因此，长期 GnRH 暴露以调节卵巢过度刺激被认为是大多数体外受精（IVF）策略的金标准。然而，目前 IVF 技术最令人失望的方面之一是阳性妊娠结局的相对较低率（在 35%至 50%之间），而导致高取消率的主要原因尚未揭示。先前的研究表明，常驻干细胞缺陷限制了子宫内膜的周期性再生能力，随后增加了妊娠失败的风险。因此，我们假设长期 GnRH 暴露会直接损害子宫内膜干细胞，从而对基于 GnRH 的 IVF 中的妊娠结局产生负面影响。除了在调节下丘脑-垂体-性腺轴方面的众所周知的作用外，GnRH 及其受体还定位于下丘脑外的子宫内膜中，这表明它们在子宫内膜干细胞中可能具有非典型作用。与我们的假设一致，我们首次证明 GnRH 通过体外和体内的 PI3K/Akt 信号通路抑制子宫内膜干细胞的多种有益功能。据我们所知，这是第一项专注于 GnRH 对干细胞再生潜力的直接影响的研究，这些发现将有助于开发更有前途的 IVF 策略。
