The School of Basic Medical Science, Heilongjiang University of Chinese Medicine, 150040 Harbin, China.
Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, 150040 Harbin, China.
Int J Biol Sci. 2019 Jan 24;15(3):714-725. doi: 10.7150/ijbs.31425. eCollection 2019.
The underlying mechanisms of polycystic ovarian syndrome (PCOS)-induced endometrial dysfunction are not fully understood, and although accumulating evidence shows that the use of metformin has beneficial effects in PCOS patients, the precise regulatory mechanisms of metformin on endometrial function under PCOS conditions have only been partially explored. To address these clinical challenges, this study aimed to assess the protein expression patterns of glycolytic enzymes, estrogen receptor (ER), and androgen receptor (AR) along with differences in mitochondria-dependent apoptosis in PCOS patients with and without endometrial hyperplasia and to investigate the effects of metformin in PCOS patients with endometrial hyperplasia . Here, we showed that compared to non-PCOS patients and PCOS patients without hyperplasia, the endometria from PCOS patients with hyperplasia had a distinct protein expression pattern of glycolytic enzymes, including pyruvate kinase isozyme M2 isoform (PKM2) and pyruvate dehydrogenase (PDH), and mitochondrial transcription factor A (TFAM). In PCOS patients with endometrial hyperplasia, increased glandular epithelial cell secretion and infiltrated stromal cells in the glands were associated with decreased PDH immunoreactivity in the epithelial cells. Using endometrial tissues from PCOS patients with hyperplasia, we found that in response to metformin treatment , hexokinase 2 (HK2) expression was decreased, whereas phosphofructokinase (PFK), PKM2, and lactate dehydrogenase A (LDHA) expression was increased compared to controls. Although there was no change in PDH expression, metformin treatment increased the expression of TFAM and cleaved caspase-3. Moreover, our study showed that while endometrial ERβ expression was no different between non-PCOS and PCOS patients regardless of whether or not hyperplasia was present, ERα and AR protein expression was gradually increased in women with PCOS following the onset of endometrial hyperplasia. Our study showed that treatment with metformin inhibited ERα expression without affecting ERβ expression. Our findings suggest that decreased glycolysis and increased mitochondrial activity might contribute to the onset of ERα-dependent endometrial hyperplasia and that metformin might directly reverse impaired glycolysis and normalize mitochondrial function in PCOS patients with endometrial hyperplasia.
多囊卵巢综合征（PCOS）引起的子宫内膜功能障碍的潜在机制尚不完全清楚，尽管越来越多的证据表明二甲双胍在 PCOS 患者中具有有益的作用，但二甲双胍在 PCOS 情况下对子宫内膜功能的确切调节机制仅部分得到了探索。为了解决这些临床挑战，本研究旨在评估患有和不患有子宫内膜增生的 PCOS 患者的糖酵解酶、雌激素受体（ER）和雄激素受体（AR）的蛋白表达模式以及线粒体依赖性细胞凋亡的差异，并研究二甲双胍对患有子宫内膜增生的 PCOS 患者的影响。在这里，我们表明，与非 PCOS 患者和不伴有增生的 PCOS 患者相比，增生的 PCOS 患者的子宫内膜具有明显不同的糖酵解酶蛋白表达模式，包括丙酮酸激酶同工酶 M2 同工型（PKM2）和丙酮酸脱氢酶（PDH）以及线粒体转录因子 A（TFAM）。在患有子宫内膜增生的 PCOS 患者中，腺体中腺上皮细胞的分泌增加和浸润的基质细胞与上皮细胞中 PDH 免疫反应性降低有关。使用增生的 PCOS 患者的子宫内膜组织，我们发现，与对照组相比，二甲双胍治疗后，己糖激酶 2（HK2）的表达降低，而磷酸果糖激酶（PFK）、PKM2 和乳酸脱氢酶 A（LDHA）的表达增加。虽然 PDH 的表达没有变化，但二甲双胍治疗增加了 TFAM 和 cleaved caspase-3 的表达。此外，我们的研究表明，尽管子宫内膜 ERβ 的表达在非 PCOS 和 PCOS 患者之间没有差异，无论是否存在增生，但随着子宫内膜增生的发生，PCOS 患者的 ERα 和 AR 蛋白表达逐渐增加。我们的研究表明，二甲双胍治疗抑制了 ERα 的表达而不影响 ERβ 的表达。我们的研究结果表明，糖酵解的减少和线粒体活性的增加可能导致 ERα 依赖性子宫内膜增生的发生，并且二甲双胍可能直接逆转 PCOS 患者子宫内膜增生中的糖酵解受损并使线粒体功能正常化。
