Research progress of complications of polycystic ovary syndrome in obstetric department and mechanisms
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摘要: 多囊卵巢综合征(PCOS)是体内激素水平改变导致的一种内分泌疾病, 困扰PCOS患者多年的不孕难题现已逐渐得到解决，但相关产科并发症的发生也随之逐渐增多。目前, PCOS患者妊娠高血压综合征、妊娠糖尿病、先兆流产等产科并发症方面的研究已取得一定进展。本文对PCOS产科并发症及其机制的研究进展进行系统性综述，以期为PCOS的临床诊治提供参考。Abstract: Polycystic ovary syndrome (PCOS) is an endocrine disease caused by changes in hormone levels in the body. The problem of infertility in PCOS patients that has been plagued for many years is gradually solved, and the obstetric complications are gradually increasing. some progress has made in researches for PCOS patients with gestational hypertension, gestational diabetes, and threatened abortion research. The article made a systematic review of the latest researches on obstetric complications of PCOS and its mechanism in order to provide reference for clinical diagnosis and treatment of PCOS.
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多囊卵巢综合征(PCOS)是一种以高雄激素血症(HA)、卵巢功能障碍和多囊卵巢形态(PCOM)为特征的异质性疾病[1]。PCOS不仅是一种生殖障碍性疾病，而且是一种具有代谢障碍的综合征，可在产前和产后的不同阶段影响孕妇的健康[2]。与此同时, PCOS带来的经济负担是巨大的，美国医疗系统预计2032年用于检测和治疗PCOS的成本将达到40亿美元，这其中还不包括与PCOS相关的严重疾病(如不孕症、2型糖尿病和心血管疾病)的治疗费用[3]。不同PCOS患者之间的激素水平和代谢能力存在差异，导致其产科并发症的发生也有显著区别[4-5]。相关研究[6]显示，肥胖和(或)胰岛素抵抗(IR)和(或)代谢异常等在PCOS患者之间的差异也对不同并发症的发生起到一定作用。本文对PCOS产科并发症及其作用机制的研究进展进行综述，旨在为PCOS及其产科并发症的临床诊治提供相关理论依据，进而减少不良妊娠结局的发生。
1. PCOS产科并发症
1.1 妊娠高血压综合征(PIH)、先兆子痫(PE)
荟萃分析[7-9]显示, PCOS孕妇发生PIH、PE的风险是健康孕妇的4~5倍。NAVER K V等[10]研究发现, PCOS女性发生PE的风险增加，但这种影响会在其体质量指数得到调整后消失，此外还发现PCOS合并HA女性发生PE的风险显著增加。PALOMBA S等[11]的病例对照研究结果显示, PCOS患者人群的PIH、PE发生风险显著增加。一项前瞻性研究[12]分析了22例PCOS孕妇的24 h动态血压水平和颈动脉超声结果，评估其妊娠期不同时点的动脉血管弹性，发现PCOS孕妇基线动态血压较高且动脉弹性受损，提示PCSO孕妇伴有血管功能适应性紊乱。此外有研究[13]表明，妊娠早期存在的IR与PE风险增加有关，在多变量分析中调整体质量指数后，这种关联性仍然显著。相关研究[14]比较了PCOS孕妇与非PCOS孕妇的PE发生率，发现PCOS孕妇的PE发生率显著高于非PCOS孕妇，且调查结果显示患有PE的孕妇常伴有PCOS。
1.2 妊娠糖尿病(GDM)
GDM是PCOS孕妇最常见的妊娠并发症之一[15-16]。GDM的早期诊断和早期治疗至关重要，可大大降低相关母婴并发症的发生率[17]。研究[18]显示, PCOS孕妇发生GDM的风险大约比健康孕妇高3倍。50%的PCOS患者伴有肥胖, 20%~40%的PCOS患者伴有高胰岛素血症和组织特异性IR[19]。二甲双胍是一种性价比高、效果显著的糖尿病治疗药物，可用于改善PCOS患者的IR，增强胰岛素敏感性，具有良好的临床效果。相关研究[20]指出，二甲双胍可通过胎盘屏障，但尚无证据表明服用二甲双胍会致畸。一项多中心随机对照试验[21]评估了二甲双胍对274例PCOS孕妇妊娠并发症的疗效，发现二甲双胍组和安慰剂组的GDM发病率分别为17.6%和16.9%, 提示二甲双胍对PCOS孕妇GDM的疗效并不显著，故不推荐常规服用二甲双胍。NATHALIE R等[22]在瑞典开展了一项大型多中心研究，调整混杂因素后，结果显示PCOS孕妇GDM的发生增加了2倍以上。一项针对社区育龄妇女的队列研究[23]结果显示，调整年龄、体质量指数、高血压、吸烟和人口因素后, PCOS与GDM风险增加独立相关。
1.3 流产
相关研究[24]报道, PCOS患者的流产风险增加，达到30%~50%, 是健康女性的3倍。而前瞻性随机试验[25-26]结果显示, PCOS患者的流产发生率为15%~25%, 与一般人群的流产概率相当。受反复流产影响的孕妇中，有82%可发现PCOS的超声特征[27]。同时, 30%的PCOS孕妇有流产史[28]。许多研究[29-31]认为，血清促性腺激素浓度升高与反复流产有关。卵泡期促性腺激素浓度升高可能导致卵母细胞过早发育，而黄体期促性腺激素浓度过高可能导致胎盘植入期间子宫内膜功能异常[32]。与无生育障碍女性相比, PCOS患者是否有更高的流产风险仍存在争议[33]。一项关于有或无PCOS的妇女接受体外受精治疗的荟萃分析[25]结果表明，两者流产率无显著差异。澳大利亚一项大型研究[34]结果表明, PCOS患者的流产率高于对照组，但PCOS不是流产发生的独立危险因素，值得注意的是流产率受到体质量指数的强烈影响。PCOS孕妇早孕流产风险的增加与促性腺激素水平升高、雄激素水平升高、IR和肥胖有关[35]。REGAN L等[36]调查了193名月经周期规律的妇女孕前卵泡期血清促性腺激素浓度与流产率的关系，发现高促性腺激素组中65%妇女的妊娠结局为流产，而促性腺激素正常组仅12%妇女发生流产。PCOS患者常伴有肥胖，而肥胖的发生也与流产有关。WANG Y H等[37]研究发现, PCOS孕妇接受体外受精治疗的流产率(28%)显著高于非PCOS孕妇(18%)。
1.4 胎儿/新生儿相关并发症
PCOS本身带来的危险可能会与妊娠期并发症相互作用，导致胎儿和新生儿不良结局[38]。目前观点[39]认为，胎儿和新生儿出现的相关并发症可能是母体本身并发症不断发展和恶化的结果。由于各中心的实验设计不完全相同，目前关于PCOS孕妇胎儿/新生儿并发症的研究结果也并不一致。WANG Y H等[37]研究发现，在年龄、体质量指数相当的孕妇中, PCOS孕妇的胎儿出现宫内生长受限的风险更高。PALOMBA S等[11]对PCOS孕妇和非PCOS孕妇进行调查，发现PCOS孕妇中小于胎龄儿和大于胎龄儿的发生率均显著高于后者。PCOS孕妇如果合并GDM, 则发生巨大儿的风险更高。此外, PCOS产妇的新生儿转入重症监护病房的风险是健康产妇的2.3倍，其原因多为早产引发的呼吸窘迫综合征[40]。多胎妊娠是辅助生育治疗后患者围产期发病率增高的最重要原因，特别是PCOS无排卵性不孕症患者[41]。PCOS患者的多胎妊娠发生率较高，而双胎妊娠可使小于胎龄儿的发生风险增加10倍，早产风险增加6倍[42]。一项荟萃分析显示, PCOS孕妇与对照组孕妇的多胎妊娠率没有差异，但纳入的研究对象缺乏分层，故并不能将PCOS孕妇的多胎妊娠结局与对照组进行比较。一项针对20 965例双胎妊娠孕妇的队列研究[43]结果显示, PCOS孕妇发生早产和新生儿低出生体质量的风险较高。
2. PCOS引起不良妊娠结局的可能机制
研究[44]显示，葡萄糖代谢对于胚胎着床和早期妊娠状态维持特别是子宫内膜蜕膜化非常重要。IR被定义为对循环胰岛素的敏感性减弱，是肥胖和PCOS常见的代谢特征[45]。肥胖是一种以异常或过度脂肪积累为特征的疾病，是多种疾病的诱发因素，如糖尿病和心血管疾病[46-47]。由于IR, 肥胖患者更有可能患糖尿病。IR和代偿性高胰岛素血症会对子宫内膜正常代谢产生不利影响，导致子宫内膜敏感性降低和蜕膜化缺陷。研究[48-50]表明，IR可降低子宫内膜增生晚期患者的葡萄糖转运体如葡萄糖转运体4(GLUT-4)的表达水平，从而减少子宫内膜细胞的葡萄糖供应，导致子宫内膜发育障碍。此外, PCOS患者的子宫内膜也受到促炎环境的影响。促炎分子可通过增加肿瘤坏死因子-α(TNF-α)来干扰胰岛素信号通路，负调控PCOS女性子宫内膜基质细胞衍生因子1(SDF-1)的激活，并导致胰岛素信号通路破坏，特别是在患有PCOS的肥胖女性中[51]。相关研究[52]发现，跨膜黏附糖蛋白44-骨调素(CD44-OPN)黏附复合物与调节子宫内膜容受性的炎症因子通路之间存在交互关系，在不孕PCOS患者中，高水平的炎症细胞因子TNF-α、γ干扰素(IFN-γ)刺激核因子κB(NF-κB)和和转录激活因子1(STAT1)蛋白被募集到骨调素(OPN)和CD44启动子上，导致其在子宫内膜组织中过表达。胰岛素水平升高也可能影响妊娠早期蜕膜化，导致胎盘植入不良和流产率升高[53]。
除了IR外, PCOS的另一种典型表现是HA, 其特征是循环血液中的雄激素水平升高(生化HA)和/或临床表现为多毛症、脱发和/或痤疮。与IR一样, HA不仅是PCOS的主要临床表现，也是PCOS的核心病因。HA和IR在PCOS的发生发展过程中会相互作用，加重患者病情。IR可增加黄体生成素(LH)的释放，促进卵巢和肾上腺分泌雄激素，或抑制肝脏中性激素结合蛋白的合成，进而增高游离睾酮水平[54]。HA可直接影响子宫内膜功能，或造成高胰岛素血症; 同时，过高的雄激素水平还会抑制卵泡成熟，使卵巢不能形成优势卵泡，从而影响排卵[55]。HA可通过干扰胰岛素信号或葡萄糖代谢影响子宫内膜容受性。HA可影响人子宫内膜和体外蜕膜化过程中与胰岛素信号传导、葡萄糖代谢和/或葡萄糖转运相关的基因表达。高浓度的睾酮和二氢睾酮可抑制胰岛素受体底物-1(IRS-1)、胰岛素受体底物-2(IRS-2)、葡萄糖转运体1(GLUT-1)、GLUT-4和葡萄糖转运体12(GLUT-12)的表达，以及蜕膜化标志物胰岛素样生长因子结合蛋白1(IGFBP1)的表达。HA还可通过降低葡萄糖调节蛋白78的蛋白水平破坏葡萄糖代谢，研究[56-59]发现PCOS女性子宫内膜基质细胞的葡萄糖摄取减少。此外，雄激素对子宫内膜循环功能至关重要[60]。雄激素浓度会影响月经周期和妊娠早期子宫内膜雄激素受体(AR)及AR共激活因子的表达[61], PCOS患者子宫内膜AR表达升高。在HA诱导的PCOS小鼠模型中，氟他胺治疗可显著提高胚胎植入率，改善蜕膜化[62]。尽管越来越多的研究证明HA对PCOS女性的子宫内膜容受性有重要影响，但很难阐明哪些雄激素[去氢表雄酮(DHEA)、DHEA-硫酸盐或睾酮]作用于子宫内膜，且其潜在机制尚不清楚[63]。此外，有研究[64]发现, PCOS可引起241个基因变异，而基因缺陷引发的代谢途径改变可导致卵巢功能障碍。
3. 小结
综上所述, PCOS患者是潜在的高危妊娠人群，产前需接受密切监测和护理，以预防产科并发症的发生。保持合理的生活方式，控制体质量，有助于改善PCOS患者的不良妊娠结局。未来，临床研究人员还应着重于对PCOS患者孕前和孕期不良反应机制的研究，并积极探寻有效的干预措施(药物与非药物干预措施)，以减少PCOS患者相关产科并发症的发生，获得更好的子代生存质量。
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