Research progress in effects of hyperandrogenin and insulin resistance on placental pathology of polycystic ovary syndrome
-
摘要:
多囊卵巢综合征(PCOS)是育龄期女性常见的内分泌疾病，可影响患者的生殖、代谢等。胎盘是影响妊娠和分娩结局及子代发育状况的关键介质, PCOS患者产前高雄激素和胰岛素抵抗所致糖脂代谢异常引起的胎盘结构和功能异常，可能是其子代出现低体质量出生儿、巨大儿甚至成年后发生内分泌及代谢系统疾病的主要原因。本文综述高雄激素和胰岛素抵抗对PCOS患者胎盘的病理影响，总结PCOS相关胎盘功能障碍的研究现状，探讨PCOS患者妊娠期胎盘结构和功能异常的原因及相应胎盘病理学特征，以期为预防PCOS相关妊娠并发症以及PCOS患者子代相关疾病的发生提供参考依据。
Abstract:Polycystic ovary syndrome (PCOS) is the most common endocrine disease in women of childbearing age, affecting women′s reproduction, metabolism and other aspect of patients. The placenta is a key medium that affects the outcome of pregnancy and childbirth and the development of the offspring. The abnormal placental structure and function caused by prenatal hyperandrogenism and abnormal glucose and lipid metabolism environment may be the main reason for the low birth weight, macrosomia, and even endocrine and metabolic system diseases after adulthood in the offspring of PCOS. This article reviewed the pathological effects of hyperandrogenin and insulin resistance on the placenta of PCOS, summarized the research results of PCOS related placental dysfunction, explored the causes of placental structure and function abnormalities in PCOS pregnancy and the corresponding placental pathological characteristics, so as to provide a reference for targeted treatment to prevent PCOS related pregnancy complications and PCOS related diseases in the offspring.
-
Keywords:
- polycystic ovary syndrome /
- placenta /
- hyperandrogen /
- insulin resistance /
- pregnancy /
- neonates with low body mass /
- macrosomia
-
多囊卵巢综合征(PCOS)是育龄期女性常见的内分泌疾病，发病率为5%~15%[1], 对患者的生殖、代谢等方面均有不良影响[2-3]。PCOS患者发生异常子宫出血、不孕、抑郁、胰岛素抵抗(IR)、2型糖尿病、高脂血症、心血管疾病和子宫内膜癌等疾病的风险均较健康女性显著增加[4-5]。胎盘是影响妊娠过程、分娩结局和子代发育状况的重要介质[6], 但PCOS特有的胎盘病理学特征目前尚未阐明。PCOS表型具有多样性，可能混杂并发症，且PCOS相关胎盘功能障碍的研究对伦理学及方法学提出了挑战，因此目前很难确定PCOS患者胎盘受损的精确机制。PCOS与不良妊娠结局存在着密切关联，其发病原因可否追溯至胚胎发育甚至妊娠宫内环境改变已成为很多研究者的关注焦点。越来越多的证据表明，雄激素过多和IR可能对胎盘功能产生负面影响。根据“巴克假说”，即“健康和疾病发展起源学说”，子宫内营养、内分泌、代谢和炎症环境的改变可能会改变胎儿发育过程中的基因表达，并易引发非传染性疾病[7]。本文综述高雄激素和IR对PCOS患者胎盘的病理影响，总结PCOS相关胎盘功能障碍的研究现状，以期为预防PCOS相关妊娠并发症以及PCOS患者子代相关疾病的发生提供参考依据。
1. 高雄激素对PCOS患者胎盘功能的影响
妊娠期间，女性的雄激素水平会生理性增高[8]。流行病学研究[9]表明，产前暴露于过量雄激素可能导致后代出现PCOS样表型和生殖、代谢、心血管及行为功能障碍。研究[10]显示, PCOS患者妊娠晚期表现出睾酮、硫酸脱氢表雄酮、雄烯二酮高水平状态，且此现象与胎儿性别无关。由此提示，即使未观察到女性胎儿的男性化改变，母体PCOS本身也可能造成雄激素过高的不利于胎儿宫内生长发育的环境。母体雄激素不能直接穿过胎盘[11], 可能通过对胎盘或胎儿类固醇激素的生成产生编程效应而改变胎儿-胎盘组织内的雄激素水平[12], MALIQUEO M等[13]证实了此种假设。然而，妊娠期母体雄激素水平是否与胎儿-胎盘组织中的雄激素水平相关仍存在争议。相关研究[14]认为，无论胎儿性别, PCOS孕妇分娩的新生儿脐带血中睾酮和雄烯二酮水平均升高，但亦有研究[15-17], PCOS孕妇分娩的女婴脐带血中雄激素水平与对照组相比并无显著差异，甚至雄烯二酮水平降低，这些差异可能是由研究设计、病例纳入和脐带血采集方法不同等引起的。
研究[18]证实，雄激素受体在人和动物的胎盘中表达。PCOS动物模型研究[19-20]显示，产前高雄激素状态与胎儿生长受限和出生低体质量相关，表明妊娠期间高雄激素水平可能对胎盘功能产生影响。SUN M等[21]研究发现，妊娠晚期雄激素干预会增高胎盘组织中雌激素受体-α、雌激素受体-β、雄激素受体和17 β-羟基类固醇脱氢酶-2表达水平，且循环雄激素水平与雌激素水平呈正相关。胎盘组织宏观测量结果显示，雄激素干预会使胎盘质量(PW)和胎儿体质量(BW)降低，但BW/PW值未显著改善(BW/PW值可推断胎盘适应胎儿生长需求的效率，是衡量胎盘功能不全和胎儿宫内生长受限的常用指标)[22-23]。值得注意的是, SUN M等[21]随后观察发现，妊娠期间高雄激素状态的雌鼠后代在发育成熟后出现代谢功能障碍，验证了雄激素过量在代谢性疾病发生中的作用。另有研究[24]发现，妊娠晚期的雄激素干预可通过降低胎盘氨基酸转运蛋白表达水平而降低BW和PW, 但BW/PW值无显著变化。GOPALAKRISHNAN K等[25]进行啮齿类动物模型研究发现，妊娠期雄激素表达水平增高可以减少子宫动脉血流量，增加低氧诱导因子-1α表达，降低BW和PW。妊娠期高雄激素血症动物模型通常基于母体雄激素干预而构建[26-28], 且构建啮齿类动物PCOS模型通常选择妊娠晚期作为雄激素干预时间，故这些发现不能解释早期胎儿-胎盘发育时间点潜在的雄激素效应机制。BECKETT E M等[12]基于绵羊模型发现，妊娠65 d时的高雄激素水平就会引起胎盘结构分化的差异，导致宫内生长受限和胎儿低BW，为阐明妊娠期间胎盘的分化发育过程提供了一定的参考依据。
研究[29-31]显示，产前雄激素暴露与胎盘血管病变的发生有关。妊娠大鼠相关研究[32]发现，雄激素升高会损害妊娠期子宫血液供应状态，并增加缺氧反应因子的表达。此外，基于大鼠模型，妊娠期高雄激素血症已被证实可降低胎盘促血管生成因子的表达[33]。子痫前期主要表现为母体高血压、蛋白尿和血管损害，与雄激素过多存在相关性[34]。流行病学研究[35]表明，与对照组相比，子痫前期孕妇血清中雄烯二酮和睾酮水平更高。子痫前期发病部位涉及母体和胎儿，常被认为由早期胎盘发育异常引起。PCOS患者妊娠期肥胖发生率、妊娠期糖尿病(GDM)患病率和辅助生殖技术应用率均偏高，而这些因素均为子痫前期的已知危险因素[36]。研究[34]表明，异常的滋养细胞侵袭和母体螺旋动脉重构受损是子痫前期的易感因素。PALOMBA S等[37]研究表明，与非PCOS对照组相比，妊娠早期的终末阶段时(妊娠第12周末)PCOS患者胎盘血管内滋养层细胞浸润存在缺陷，这为雄激素过量与子宫螺旋动脉重构损伤的关联提供了证据支持。SOTO E等[38]证实，妊娠晚期子痫前期患者的胎盘绒毛病变发生率和炎症标志物表达水平较对照组(无先兆子痫并发症)更高，且抗血管生成因子的比例高于促血管生成因子。此外有研究[39-40]基于组学技术发现，子痫前期孕妇的胎盘较正常对照组(无先兆子痫)具有更高的脂质含量和氧化应激标志物水平。由此提示，抗氧化剂、抗炎剂、血管扩张剂，甚至二甲双胍等降糖药可能会在预防子痫前期中发挥一定效果[41-42]。尽管相关分子靶点尚未在PCOS胎盘病理中得到实验验证，但雄激素过量依然可能是PCOS和子痫前期发生的共同病理基础，2种疾病可能存在相似的预防或治疗策略。
2. IR对PCOS患者胎盘功能的影响
正常妊娠过程中，胰岛素敏感性会随着孕周的增加而降低，其原因是机体通过胎盘优先输送葡萄糖至胎儿，这有助于为发育中的胎儿提供足够的营养支持[43-44]。此时，母体胰岛β细胞需要有良好的适应能力，如增加数量或提高胰岛素分泌量，以应对机体可能出现的IR状态。若胰岛β细胞不能充分适应和调节妊娠期间增加的代谢需求，将引发机体葡萄糖耐受不良、高血糖和GDM。对妊娠早期人类胎盘组织的体外研究[45]表明，妊娠早期高血糖可能会升高流产、宫内生长受限和子痫前期的发生率，而滋养层侵袭受损可能是主要原因。与非妊娠PCOS患者相比，妊娠PCOS患者表现出高血糖、高胰岛素血症和脂质异常[37]。孕前IR是PCOS的临床表现之一，大约1/3的PCOS肥胖妇女表现出糖耐量受损，且与肥胖无关[46]。胎盘作为妊娠期间重要的内分泌器官，可分泌多种胎盘肽，如胎盘催乳素、肝细胞生长因子及脂肪因子等，在调控母体胰岛β细胞功能方面发挥作用，这对于维持正常妊娠过程必不可少[47]。因此，关注并探究妊娠期间IR与PCOS患者胎盘功能相关的病理机制，可能是解决PCOS妊娠相关问题的关键。
胎盘会表达大量胰岛素受体和胰岛素样生长因子受体，其与胎盘的发育和功能的调节具有密切联系[48]。在妊娠早期，胰岛素受体主要表达于面向母体循环的合体滋养细胞，而在妊娠晚期，胰岛素受体主要表达于面向胎儿循环的胎盘内皮细胞[49]。胰岛素受体在妊娠中的不同作用和影响主要受母体血浆胰岛素水平的调节，但在妊娠晚期其可能主要由胎儿血浆胰岛素水平决定。相关研究[48-50]发现, 1型糖尿病和GDM孕妇胰岛素/胰岛素样生长因子受体系统是失调的，这些改变影响着胎盘营养物质向胎儿的释放。此外，IR可能对早期胎盘形成具有负面影响，由于IR可减弱胰岛素生长因子-Ⅰ信号的传导，而胰岛素生长因子-Ⅰ信号对母体螺旋动脉滋养层的侵袭非常重要。反之，添加胰岛素增敏剂可以恢复正常信号传导并促进滋养层细胞迁移和侵袭[51]。研究[52]表明, PCOS女性在妊娠早期显示出较低的胰岛素生长因子-Ⅰ水平，这可能是由IR造成的。
PCOS是GDM的已知危险因素之一，但GDM通常在孕中期才确诊，如何早期发现并控制GDM的发生与发展一直是临床医师关注的问题。IR是判断及预测GDM发生的良好临床指标[53], 故在孕早期定期检测PCOS妊娠患者血清葡萄糖、胰岛素代谢水平很有必要。MENG Q等[54]探讨GDM患者胎盘血管病变机制发现，胎盘组织中血管内皮生长因子和血管内皮生长因子受体-2表达减少，末端绒毛血管发生退行性改变，故GDM是影响胎盘血管病变的重要因素之一。ZHOU J等[55]以GDM患者胎盘内皮细胞和人脐静脉内皮细胞系为双重验证研究模型，发现GDM和高血糖状态均会抑制胎盘内皮细胞的增殖、迁移和成管能力，且丝裂原活化蛋白激酶1/2-细胞外调节蛋白激酶1/2通路受抑制很可能是介导此现象的机制。另有研究[56-57]表明, GDM孕妇胎盘产生和释放的脂肪因子如瘦素、脂联素、抵抗素可能发生改变，而这可能与胎盘氧化应激和炎症有关。脂肪因子除了调控胰岛素敏感性外，还可能参与胎儿生长调节，其在PCOS患者妊娠过程中的作用值得进一步研究[58]。
3. 小结
PCOS患者妊娠期间，母体和胎儿的疾病发生率均较高，而胎盘是影响妊娠和分娩结局的关键介质，提示PCOS患者妊娠期间发生胎盘功能障碍存在可能性。产前高雄激素及糖脂代谢异常引起的胎盘结构和功能异常，可能是PCOS患者胎儿糖脂代谢异常和子代出现低体质量出生儿、巨大儿甚至成年后发生内分泌及代谢系统疾病的主要原因。阐明PCOS患者妊娠期胎盘结构和功能异常的原因及相应胎盘病理学特征，能够为有效防治由PCOS患者异常宫内环境引起的子代PCOS及其他内分泌系统疾病提供依据，尽可能明确“胎源性疾病”可能的致病因素，从而降低PCOS患者子代的PCOS及代谢系统疾病发生风险。但由于诸多动物的胎盘在解剖结构特征及妊娠期发育周期方面均与人类的胎盘存在较大差异，未来亟需开展更多基于人类胎盘的研究以制订干预策略，从而更好地改善PCOS患者及其子代的身体状况与生活质量。
-
[1] GOODMAN N F, COBIN R H, FUTTERWEIT W, et al. Guide to the best practices in the evaluation and treatment of polycystic ovary syndrome[J]. Endocr Pract, 2015, 21(12): 1415-1426. doi: 10.4158/EP15748.DSCPT2
[2] 董亚光, 朱琳, 陈浩暘. 多囊卵巢综合征产科并发症及其机制的研究进展[J]. 实用临床医药杂志, 2022, 26(9): 112-116. doi: 10.7619/jcmp.20214639 [3] 江波. 代谢相关性多囊卵巢综合征及其理论基础[J]. 实用临床医药杂志, 2021, 25(2): 1-4, 9. doi: 10.7619/jcmp.20210388 [4] 栗凤霞, 王艳硕, 史艳想, 等. 维生素E联合二甲双胍治疗对多囊卵巢综合征不孕症患者的影响[J]. 实用临床医药杂志, 2022, 26(14): 97-100, 104. doi: 10.7619/jcmp.20220640 [5] AVERSA A, VIGNERA S L, RAGO R, et al. Fundamental concepts and novel aspects of polycystic ovarian syndrome: expert consensus resolutions[J]. Front Endocrinol, 2020, 11: 516. doi: 10.3389/fendo.2020.00516
[6] KELLEY A S, SMITH Y R, PADMANABHAN V. A narrative review of placental contribution to adverse pregnancy outcomes in women with polycystic ovary syndrome[J]. J Clin Endocrinol Metab, 2019, 104(11): 5299-5315. doi: 10.1210/jc.2019-00383
[7] PADMANABHAN V, CARDOSO R C, PUTTABYATAPPA M. Developmental programming, a pathway to disease[J]. Endocrinology, 2016, 157(4): 1328-1340. doi: 10.1210/en.2016-1003
[8] MEAKIN A S, CLIFTON V L. Review: understanding the role of androgens and placental AR variants: insight into steroid-dependent fetal-placental growth and development[J]. Placenta, 2019, 84: 63-68. doi: 10.1016/j.placenta.2019.03.006
[9] FILIPPOU P, HOMBURG R. Is foetal hyperexposure to androgens a cause of PCOS?[J]. Hum Reprod Update, 2017, 23(4): 421-432. doi: 10.1093/humupd/dmx013
[10] GLINTBORG D, JENSEN R C, BENTSEN K, et al. Testosterone levels in third trimester in polycystic ovary syndrome: Odense child cohort[J]. J Clin Endocrinol Metab, 2018, 103(10): 3819-3827. doi: 10.1210/jc.2018-00889
[11] 王园林, 张青, 张方芳, 等. 宫内高雄环境对多囊卵巢综合征子代的影响[J]. 华中科技大学学报: 医学版, 2019, 48(6): 742-746. https://www.cnki.com.cn/Article/CJFDTOTAL-TJYX201906023.htm [12] BECKETT E M, ASTAPOVA O, STECKLER T L, et al. Developmental programing: impact of testosterone on placental differentiation[J]. Reproduction, 2014, 148(2): 199-209. doi: 10.1530/REP-14-0055
[13] MALIQUEO M, LARA H E, S?NCHEZ F, et al. Placental steroidogenesis in pregnant women with polycystic ovary syndrome[J]. Eur J Obstet Gynecol Reprod Biol, 2013, 166(2): 151-155. doi: 10.1016/j.ejogrb.2012.10.015
[14] DAAN N M, KOSTER M P, STEEGERS-THEUNISSEN R P, et al. Endocrine and cardiometabolic cord blood characteristics of offspring born to mothers with and without polycystic ovary syndrome[J]. Fertil Steril, 2017, 107(1): 261-268. doi: 10.1016/j.fertnstert.2016.09.042
[15] CAANEN M R, KUIJPER E A, HOMPES P G, et al. Mass spectrometry methods measured androgen and estrogen concentrations during pregnancy and in newborns of mothers with polycystic ovary syndrome[J]. Eur J Endocrinol, 2016, 174(1): 25-32. doi: 10.1530/EJE-15-0699
[16] ANDERSON H, FOGEL N, GREBE S K, et al. Infants of women with polycystic ovary syndrome have lower cord blood androstenedione and estradiol levels[J]. J Clin Endocrinol Metab, 2010, 95(5): 2180-2186. doi: 10.1210/jc.2009-2651
[17] DUAN C L, PEI T J, LI Y J, et al. Androgen levels in the fetal cord blood of children born to women with polycystic ovary syndrome: a meta-analysis[J]. Reprod Biol Endocrinol, 2020, 18(1): 81. doi: 10.1186/s12958-020-00634-8
[18] PARSONS A M, BOUMA G J. A potential role and contribution of androgens in placental development and pregnancy[J]. Life, 2021, 11(7): 644. doi: 10.3390/life11070644
[19] STENER-VICTORIN E, PADMANABHAN V, WALTERS K A, et al. Animal models to understand the etiology and pathophysiology of polycystic ovary syndrome[J]. Endocr Rev, 2020, 41(4): bnaa010. doi: 10.1210/endrev/bnaa010
[20] ABBOTT D H, DUMESIC D A, LEVINE J E. Hyperandrogenic origins of polycystic ovary syndrome -implications for pathophysiology and therapy[J]. Expert Rev Endocrinol Metab, 2019, 14(2): 131-143. doi: 10.1080/17446651.2019.1576522
[21] SUN M, MALIQUEO M, BENRICK A, et al. Maternal androgen excess reduces placental and fetal weights, increases placental steroidogenesis, and leads to long-term health effects in their female offspring[J]. Am J Physiol Endocrinol Metab, 2012, 303(11): E1373-E1385. doi: 10.1152/ajpendo.00421.2012
[22] SILVA J F, SERAKIDES R. Intrauterine trophoblast migration: a comparative view of humans and rodents[J]. Cell Adh Migr, 2016, 10(1/2): 88-110.
[23] CHRISTIANS J K, GRYNSPAN D, GREENWOOD S L, et al. The problem with using the birthweight: placental weight ratio as a measure of placental efficiency[J]. Placenta, 2018, 68: 52-58. doi: 10.1016/j.placenta.2018.06.311
[24] PADMANABHAN V, VEIGA-LOPEZ A. Animal models of the polycystic ovary syndrome phenotype[J]. Steroids, 2013, 78(8): 734-740. doi: 10.1016/j.steroids.2013.05.004
[25] GOPALAKRISHNAN K, MISHRA J S, CHINNATHAMBI V, et al. Elevated testosterone reduces uterine blood flow, spiral artery elongation, and placental oxygenation in pregnant rats[J]. Hypertension, 2016, 67(3): 630-639. doi: 10.1161/HYPERTENSIONAHA.115.06946
[26] SHAH A B, NIVAR I, SPEELMAN D L. Elevated androstenedione in young adult but not early adolescent prenatally androgenized female rats[J]. PLoS One, 2018, 13(5): e0196862. doi: 10.1371/journal.pone.0196862
[27] DOMONKOS E, BORBÉLYOVÁ V, KOLÁTOROVÁ L, et al. Sex differences in the effect of prenatal testosterone exposure on steroid hormone production in adult rats[J]. Physiol Res, 2017, 66(Suppl 3): S367-S374.
[28] STENER-VICTORIN E. Update on animal models of polycystic ovary syndrome[J]. Endocrinology, 2022, 163(12): bqac164. doi: 10.1210/endocr/bqac164
[29] KUMAR S, GORDON G H, ABBOTT D H, et al. Androgens in maternal vascular and placental function: implications for preeclampsia pathogenesis[J]. Reproduction, 2018, 156(5): R155-R167.
[30] METZLER V M, BROT S D, ROBINSON R S, et al. Androgen dependent mechanisms of pro-angiogenic networks in placental and tumor development[J]. Placenta, 2017, 56: 79-85. doi: 10.1016/j.placenta.2017.02.018
[31] WILLIAMS C J, CHU A, JEFFERSON W N, et al. Epithelial membrane protein 2 (EMP2) deficiency alters placental angiogenesis, mimicking features of human placental insufficiency[J]. J Pathol, 2017, 242(2): 246-259. doi: 10.1002/path.4893
[32] FURUKAWA S, TSUJI N, HAYASHI S, et al. Effects of testosterone on rat placental development[J]. J Toxicol Pathol, 2022, 35(1): 37-44. doi: 10.1293/tox.2021-0035
[33] HU M, ZHANG Y H, GUO X Z, et al. Hyperandrogenism and insulin resistance induce gravid uterine defects in association with mitochondrial dysfunction and aberrant reactive oxygen species production[J]. Am J Physiol Endocrinol Metab, 2019, 316(5): E794-E809. doi: 10.1152/ajpendo.00359.2018
[34] BROWN S H, EATHER S R, FREEMAN D J, et al. A lipidomic analysis of placenta in preeclampsia: evidence for lipid storage[J]. PLoS One, 2016, 11(9): e0163972. doi: 10.1371/journal.pone.0163972
[35] SHARIFZADEH F, KASHANIAN M, FATEMI F. A comparison of serum androgens in pre-eclamptic and normotensive pregnant women during the third trimester of pregnancy[J]. Gynecol Endocrinol, 2012, 28(10): 834-836. doi: 10.3109/09513590.2012.683061
[36] WRIGHT D, WRIGHT A, NICOLAIDES K H. The competing risk approach for prediction of preeclampsia[J]. Am J Obstet Gynecol, 2020, 223(1): 12-23. e7. doi: 10.1016/j.ajog.2019.11.1247
[37] PALOMBA S, FALBO A, CHIOSSI G, et al. Lipid profile in nonobese pregnant women with polycystic ovary syndrome: a prospective controlled clinical study[J]. Steroids, 2014, 88: 36-43. doi: 10.1016/j.steroids.2014.06.005
[38] SOTO E, ROMERO R, KUSANOVIC J P, et al. Late-onset preeclampsia is associated with an imbalance of angiogenic and anti-angiogenic factors in patients with and without placental lesions consistent with maternal underperfusion[J]. J Matern Fetal Neonatal Med, 2012, 25(5): 498-507. doi: 10.3109/14767058.2011.591461
[39] YANG Y, WANG Y X, LV Y, et al. Dissecting the roles of lipids in preeclampsia[J]. Metabolites, 2022, 12(7): 590. doi: 10.3390/metabo12070590
[40] HARAM K, MORTENSEN J H, MYKING O, et al. The role of oxidative stress, adhesion molecules and antioxidants in preeclampsia[J]. Curr Hypertens Rev, 2019, 15(2): 105-112. doi: 10.2174/1573402115666190119163942
[41] ROMERO R, EREZ O, HVTTEMANN M, et al. Metformin, the aspirin of the 21st century: itsrole in gestational diabetes mellitus, prevention of preeclampsia and cancer, andthe promotion of longevity[J]. Am J Obstet Gynecol, 2017, 217(3): 282-302. doi: 10.1016/j.ajog.2017.06.003
[42] TRAN H T, LIONG S, LIM R, et al. Resveratrol ameliorates the chemical and microbial induction of inflammation and insulin resistance in human placenta, adipose tissue and skeletal muscle[J]. PLoS One, 2017, 12(3): e0173373. doi: 10.1371/journal.pone.0173373
[43] LADYMAN S R, BROOKS V L. Central actions of insulin during pregnancy and lactation[J]. J Neuroendocrinol, 2021, 33(4): e12946.
[44] STERN C, SCHWARZ S, MOSER G, et al. Placental endocrine activity: adaptation and disruption of maternal glucose metabolism in pregnancy and the influence of fetal sex[J]. Int J Mol Sci, 2021, 22(23): 12722. doi: 10.3390/ijms222312722
[45] GABBAY-BENZIV R, BASCHAT A A. Gestational diabetes as one of the "great obstetrical syndromes": the maternal, placental, and fetal dialog[J]. Best Pract Res Clin Obstet Gynaecol, 2015, 29(2): 150-155. doi: 10.1016/j.bpobgyn.2014.04.025
[46] NADERPOOR N, SHORAKAE S, COURTEN B D, et al. Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis[J]. Hum Reprod Update, 2016, 22(3): 408-409. doi: 10.1093/humupd/dmv063
[47] SIMPSON S, SMITH L, BOWE J. Placental peptides regulating islet adaptation to pregnancy: clinical potential in gestational diabetes mellitus[J]. Curr Opin Pharmacol, 2018, 43: 59-65. doi: 10.1016/j.coph.2018.08.004
[48] TUMMINIA A, SCALISI N M, MILLUZZO A, et al. Maternal diabetes impairs insulin and IGF-1 receptor expression and signaling in human placenta[J]. Front Endocrinol, 2021, 12: 621680. doi: 10.3389/fendo.2021.621680
[49] JAMES-ALLAN L B, ARBET J, TEAL S B, et al. Insulin stimulates GLUT4 trafficking to the syncytiotrophoblast basal plasma membrane in the human placenta[J]. J Clin Endocrinol Metab, 2019, 104(9): 4225-4238. doi: 10.1210/jc.2018-02778
[50] RUIZ-PALACIOS M, PRIETO-SÁNCHEZ M T, RUIZ-ALCARAZ A J, et al. Insulin treatment may alter fatty acid carriers in placentas from gestational diabetes subjects[J]. Int J Mol Sci, 2017, 18(6): 1203. doi: 10.3390/ijms18061203
[51] MAYAMA R, IZAWA T, SAKAI K, et al. Improvement of insulin sensitivity promotes extravillous trophoblast cell migration stimulated by insulin-like growth factor-Ⅰ[J]. Endocr J, 2013, 60(3): 359-368. doi: 10.1507/endocrj.EJ12-0241
[52] JAKUBOWICZ D J, ESSAH P A, SEPPÄLÄ M, et al. Reduced serum glycodelin and insulin-like growth factor-binding protein-1 in women with polycystic ovary syndrome during first trimester of pregnancy[J]. J Clin Endocrinol Metab, 2004, 89(2): 833-839. doi: 10.1210/jc.2003-030975
[53] POWE C E. Early pregnancy biochemical predictors of gestational diabetes mellitus[J]. Curr Diab Rep, 2017, 17(2): 12. doi: 10.1007/s11892-017-0834-y
[54] MENG Q, SHAO L, LUO X C, et al. Expressions of VEGF-A and VEGFR-2 in placentae from GDM pregnancies[J]. Reprod Biol Endocrinol, 2016, 14(1): 61. doi: 10.1186/s12958-016-0191-8
[55] ZHOU J, NI X T, HUANG X J, et al. Potential role of hyperglycemia in fetoplacental endothelial dysfunction in gestational diabetes mellitus[J]. Cell Physiol Biochem, 2016, 39(4): 1317-1328. doi: 10.1159/000447836
[56] SCHANTON M, MAYMÓ J L, PÉREZ-PÉREZ A, et al. Involvement of leptin in the molecular physiology of the placenta[J]. Reproduction, 2018, 155(1): R1-R12. doi: 10.1530/REP-17-0512
[57] WU W, TAN Q Y, XI F F, et al. NLRP3 inflammasome activation in gestational diabetes mellitus placentas is associated with hydrogen sulfide synthetase deficiency[J]. Exp Ther Med, 2022, 23(1): 94.
[58] BONGRANI A, MELLOUK N, RAME C, et al. Ovarian expression of adipokines in polycystic ovary syndrome: a role for chemerin, omentin, and apelin in follicular growth arrest and ovulatory dysfunction[J]. Int J Mol Sci, 2019, 20(15): 3778. doi: 10.3390/ijms20153778
-
期刊类型引用(5)
1. 綦萍，王璇，刘钦文. PCOS孕妇血清AMH、LH/FSH、HOMA-IR水平及其对妊娠结局的影响. 中国计划生育学杂志. 2025(02): 468-472 . 
百度学术
2. 季东贤，徐扬. MDT管理模式对多囊卵巢综合征孕妇妊娠结局与内分泌代谢状态的影响. 中国医药指南. 2025(08): 98-100 . 百度学术
3. 潘静，热汗古丽·库尔班，吐松古·艾买尔，沈娟娟，薄晓莉. LncRNA LUCAT1调控miR-375/HMGB1轴对多囊卵巢综合征大鼠胰岛素抵抗的机制研究. 现代生物医学进展. 2024(08): 1439-1443 . 百度学术
4. 刘琼，陈蕾，刘流山. 绒促性素结合针灸对多囊卵巢综合征患者性激素水平及排卵率的影响. 中国医学创新. 2024(17): 75-80 . 百度学术
5. 王懿娴，张瑞瑞，武权生，潘文，许彩凤，石璇，师雪莲. 补肾化瘀方治疗多囊卵巢综合征肾虚血瘀证50例临床观察. 甘肃中医药大学学报. 2023(04): 44-48 . 百度学术
其他类型引用(0)
计量
- 文章访问数: 216
- HTML全文浏览量: 77
- PDF下载量: 17
- 被引次数: 5
下载:
苏公网安备 32100302010246号