不同表型多囊卵巢综合征中内分泌异常的相关性研究进展
Research Progress on the Correlation between Endocrine Abnormalities in Different Phenotypes of Polycystic Ovary Syndrome
DOI: 10.12677/acm.2025.1572142, PDF, HTML, XML,   
作者: 李纯玮, 吴志伟, 魏启明, 王晓冰:内蒙古民族大学第二临床医学院(内蒙古林业总医院),内蒙古 呼伦贝尔
关键词: 多囊卵巢综合征表型内分泌Polycystic Ovary Syndrome Phenotype Endocrine
摘要: 多囊卵巢综合征(PCOS)作为高度异质性的妇科内分泌疾病,其不同表型(Rotterdam分型A/B/C/D型)的内分泌紊乱特征存在显著差异,直接影响疾病进程与治疗效果。本文聚焦高雄激素、代谢异常及排卵障碍三大核心表型,系统综述:(1) 各表型下丘脑–垂体–卵巢轴(HPO轴)、胰岛素抵抗(IR)及肾上腺源雄激素的异常模式;(2) 内分泌交互作用对卵泡发育障碍、代谢并发症的驱动机制;(3) 基于表型的内分泌靶向治疗策略(如抗雄药物、胰岛素增敏剂、中西医协同干预)。旨在为PCOS的精准分型诊疗提供理论依据。
Abstract: Polycystic ovary syndrome (PCOS), a highly heterogeneous gynecological endocrine disorder, exhibits significant differences in endocrine disturbance characteristics among its different phenotypes (Rotterdam classifications A/B/C/D). These differences directly influence disease progression and treatment outcomes. This article focuses on three core phenotypes—hyperandrogenism, metabolic abnormalities, and ovulatory dysfunction—and systematically reviews: (1) The abnormal patterns of the hypothalamic-pituitary-ovarian axis (HPO axis), insulin resistance (IR), and adrenal-derived androgens in each phenotype; (2) The driving mechanisms by which endocrine interactions impact follicular developmental disorders and metabolic complications; (3) Phenotype-based endocrine-targeted therapeutic strategies (such as anti-androgen drugs, insulin sensitizers, and integrated traditional Chinese and Western medicine interventions). The aim is to provide a theoretical basis for precision typing diagnosis and treatment of PCOS.
文章引用:李纯玮, 吴志伟, 魏启明, 王晓冰. 不同表型多囊卵巢综合征中内分泌异常的相关性研究进展[J]. 临床医学进展, 2025, 15(7): 1417-1426. https://doi.org/10.12677/acm.2025.1572142

1. 多囊卵巢综合征概述

1.1. PCOS的复杂性与临床挑战

多囊卵巢综合征(PCOS)是育龄女性最常见的内分泌代谢紊乱性疾病,以高雄激素血症、排卵功能障碍及卵巢多囊样改变(PCO)为核心特征,其病理机制涉及下丘脑–垂体–卵巢轴(HPO轴)失调、胰岛素抵抗(IR)及代谢–生殖轴交互作用[1]。全球流行病学调查显示,PCOS发病率因诊断标准和种族差异波动介于6%~20%,我国最新多中心研究报道其患病率达14.6%,且呈年轻化趋势[2] [3]。除月经失调、不孕等生殖系统症状外,PCOS患者终身面临2型糖尿病(风险升高5~10倍)、心血管疾病(风险升高2~3倍)及子宫内膜癌(风险升高3倍)等远期健康威胁[4]。其复杂的表型异质性与发病机制尚未完全阐明,是妇科内分泌领域的研究难点与热点。

1.2. PCOS表型分型的演进与当前共识

自2003年鹿特丹会议确立“稀发排卵或无排卵、高雄激素临床表现或生化指标、卵巢多囊样改变”三项中满足两项即可诊断的标准以来[5],PCOS被划分为四种经典表型:

表型A (经典型):高雄激素血症 + 排卵障碍 + PCO;

表型B (排卵障碍–高雄激素型):高雄激素血症 + 排卵障碍;

表型C (高雄激素–多囊卵巢型):高雄激素血症 + PCO;

表型D (排卵障碍–多囊卵巢型):排卵障碍 + PCO (无临床/生化高雄激素)。

随着分子生物学技术进步,表型异质性研究已从临床特征描述深入到分子机制层面:

代谢表型细分:依据胰岛素抵抗程度,表型A可进一步分为IR阳性亚组(占70%)与IR阴性亚组,前者更易伴发代谢综合征[6]

雄激素来源分型:基于硫酸脱氢表雄酮(DHEA-S)与游离睾酮(FT)的比例,发现表型C中25%患者存在肾上腺源性雄激素过多,与CYP11B1基因多态性相关[7];青春期特殊表型:初潮后3年内诊断的青春期PCOS中,约40%表现为“暂时性高雄激素–排卵障碍型”,成年后表型可逆转[8]

这些发现突破了鹿特丹标准的静态分类框架,揭示PCOS表型是遗传易感性(如FSHR、INSR基因变异)与环境因素(如肥胖、环境内分泌干扰物)动态互作的结果[9]

1.3. 内分泌异常与PCOS表型关联研究的科学价值

PCOS的核心病理特征是内分泌调控网络的系统性失衡,但其关键致病环节仍存争议:

机制解析维度:传统理论强调LH/FSH比例失调驱动卵巢高雄激素合成,但近年发现约30%表型D患者LH水平正常,其排卵障碍与颗粒细胞FGF21信号通路异常密切相关[10],提示需重新审视“单因素致病”模型。

精准诊疗需求:不同表型的内分泌异常呈现显著异质性——表型A的IR与高雄激素血症存在协同放大效应;表型D的非高雄激素性排卵障碍可能源于垂体GnRH脉冲频率异常[11]。这种差异导致同一治疗方案(如克罗米芬促排卵)在表型B中的妊娠率(45%)显著高于表型D (22%) [12]

远期风险预测:血清骨钙素(OCN)水平在表型C中与卵巢纤维化程度呈正相关(r = 0.58, P < 0.01),可作为预测卵巢储备功能下降的新型指标[13],凸显内分泌指标在病程管理中的潜在价值。

深入解析内分泌异常与表型的对应关系,不仅能破解“同病异治”的临床困境,更有望通过靶向干预(如靶向FGF21-AMPK通路改善IR、应用脂联素受体激动剂调节HPO轴敏感性)等手段,推动PCOS从症状控制向病因治疗的范式转变[14]

2. PCOS常见内分泌异常概述

PCOS的内分泌异常呈现多维度失衡特征,既包括高雄激素血症、胰岛素抵抗(IR)与促性腺激素比例失调等经典异常,也涉及新型分子标记物的网络调控异常。这些异常在不同表型中以独特模式组合,形成差异化的病理机制。

2.1. 高雄激素血症:从生化异常到临床表型的多元映射

高雄激素血症是PCOS最核心的内分泌特征,其生化异常具有显著异质性:

生化指标的表型特异性:血清总睾酮(TT)在表型A中平均为(1.9 ± 0.6) nmol/L,显著高于表型D的(1.1 ± 0.4) nmol/L (P < 0.01) [5];游离睾酮(FT)水平与多毛评分(F-G评分)呈强正相关(r = 0.72, P < 0.001);而硫酸脱氢表雄酮(DHEA-S)升高在表型C中占比达45%,提示肾上腺来源雄激素过多[15]。亚洲人群中,DHEA-S ≥ 4.0 μg/mL的PCOS患者占比(38%)显著高于欧美人群(22%),与CYP17A1基因rs743572多态性密切相关[16]

发病机制的双重驱动:下丘脑GnRH脉冲频率加快(12~14次/24h vs正常8~10次/24h)导致垂体LH分泌亢进,刺激卵巢卵泡膜细胞CYP11A1、CYP17A1表达,使雄烯二酮生成增加3倍[17];同时,胰岛素通过IGF-1受体增强LH受体敏感性,形成“高胰岛素–高雄激素”正反馈,该效应在IR阳性亚组中使睾酮合成速率提升50% [18]

临床表型的精准关联:FT > 1.2 nmol/L的患者中,表型A/B占比达82%,且卵巢间质血流阻力指数(RI = 0.58 ± 0.06)显著低于正常对照(RI = 0.72 ± 0.08),提示高雄激素诱导的卵巢血管重塑[19]

2.2. 胰岛素抵抗:代谢–生殖轴失衡的核心枢纽

IR在PCOS中的发生率随表型及肥胖程度显著变化:

量化评估的多元指标:稳态模型评估IR指数(HOMA-IR)在肥胖PCOS患者中平均为(3.8 ± 1.5),是非肥胖患者(1.9 ± 0.8)的2倍,且与脂联素/内脂素比值(ADN/VF)呈负相关(r = −0.65, P < 0.001) [20]。新型指标空腹甘油三酯–葡萄糖指数(TyG)在预测IR方面效能更优(AUC = 0.89 vs. HOMA-IR的0.82),尤其适用于糖代谢正常的早期患者[21]

双向调控的病理网络:高胰岛素血症通过PI3K/Akt通路促进卵巢间质细胞增殖,使雄烯二酮分泌增加40%,同时抑制肝脏SHBG合成(降低35%),导致游离雄激素指数(FAI)升高[22];反之,高雄激素通过PPARγ通路抑制脂肪细胞胰岛素信号传导,形成“代谢–生殖轴”交互恶化,该恶性循环在表型A中使2型糖尿病风险升高12倍[23]

种族差异的分子基础:中国PCOS患者中,INSR基因rs1801155多态性使IR发生率增加2.3倍,且HOMA-IR ≥ 2.5的患者中,表型A占比达68%,显著高于表型C/D (32%) [24],提示遗传易感性与表型分布的相关性。

2.3. 促性腺激素比例失调:从静态比值到动态脉冲的范式转换LH/FSH异常从传统的 “比值决定论”发展为动态分泌模式的精准解析

脉冲式分泌的病理特征:PCOS患者LH脉冲振幅(12.5 ± 3.2 IU/L vs.正常7.8 ± 2.1 IU/L)显著升高,而频率无明显变化,导致血清LH均值正常但生物活性增强,该现象在表型D中占比达37% [25]。FSH水平降低与激活素A/Follistatin失衡相关,使颗粒细胞FSHR表达下降25%,导致卵泡募集障碍[26]。表型特异性的临床影响:LH/FSH > 2的患者中,表型A/B占比达76%,其窦卵泡数(AFC = 28 ± 6)显著高于比值正常组(AFC = 22 ± 5),但卵母细胞质量评分(3.2 ± 0.7 vs. 4.1 ± 0.9)更低[27];而比值正常的表型D患者,其排卵障碍与GnRH神经元对雌激素负反馈敏感性降低相关,GnRH激发试验中LH峰值延迟15分钟出现[28]

治疗靶点的新发现:生长抑素类似物可抑制LH脉冲振幅(降低30%),使表型B患者的排卵率从35%提升至62% [29],证实动态分泌调控在临床干预中的重要性。

2.4. 新型内分泌标记物的协同调控

除经典指标外,新兴因子揭示了PCOS内分泌网络的复杂性:

成纤维细胞生长因子21 (FGF21):血清FGF21水平在表型A中达(582 ± 120) pg/mL,较正常对照升高2.1倍,其通过AMPK通路改善肝脏胰岛素敏感性,但过度表达会抑制卵巢CYP19A1活性,使雌激素合成减少40% [30]

骨钙素(OCN):OCN每降低10 ng/mL,PCOS发病风险增加1.8倍(95% CI: 1.2~2.7),其通过作用于下丘脑VMH核团增强GnRH神经元兴奋性,导致LH脉冲频率升高15% [31],解释了部分患者伴发的骨密度降低与排卵障碍共病现象。

这些内分泌异常并非孤立存在,而是通过“高雄激素–高胰岛素-LH脉冲异常-FGF21/OCN失调”的网络交互,在不同遗传背景与环境暴露下,塑造出PCOS的多元表型。深入解析其动态关联,是突破当前诊疗瓶颈的关键。

3. 研究进展与争议

3.1. 当前研究进展:从单一指标到网络调控的范式革新

3.1.1. 新型内分泌调节因子的深度挖掘

成纤维细胞生长因子21 (FGF21)的双向调控作用:最新跨种族研究显示,FGF21血清水平在表型A (胰岛素抵抗型)中达(612 ± 135) pg/mL,较表型D (非高雄激素型)高1.8倍(P < 0.001) [32]。其肝脏靶向作用通过AMPK通路改善胰岛素敏感性(降低HOMA-IR 22%),但卵巢局部高表达会抑制颗粒细胞CYP19A1活性,导致雌二醇合成减少37%,加剧高雄激素血症[33]。值得注意的是,FGF21受体激动剂在小鼠模型中可降低卵巢FSHR表达15%,提示其可能通过干扰FSH信号通路影响卵泡发育[34]

脂联素/内脂素轴的代谢–生殖耦联机制:非肥胖PCOS患者中,脂联素每降低1 μg/mL,LH脉冲频率升高1.2次/24h (P = 0.01),而内脂素每升高10 ng/mL,HOMA-IR增加0.35 (β = 0.38, P = 0.002) [35]。两者通过竞争结合AdipoR1受体调控下丘脑Kisspeptin神经元活性——脂联素增强雌激素负反馈效应,内脂素则促进GnRH脉冲释放,这种失衡在表型B (高雄激素–排卵障碍型)中尤为显著[36]。骨钙素(OCN)的神经内分泌调控新靶点:纵向队列研究发现,OCN水平与窦卵泡数(AFC)呈负相关(r = −0.41, P = 0.003),且OCN基因rs2073458多态性使PCOS发病风险增加1.6倍[37]。机制上,OCN通过作用于下丘脑吻侧腹内侧核(VMH)的GPRC6A受体,增强GnRH神经元钙内流,使LH脉冲振幅升高25% [38],解释了部分患者“低骨密度–高LH”共病现象。

3.1.2. 传统内分泌指标的认知升级

LH/FSH比例的动态化与异质性:静态比值 > 2仅能覆盖63%的PCOS患者,而37%的表型D患者表现为“LH脉冲振幅升高但均值正常”,其卵泡期LH峰值达(15.2 ± 4.1) IU/L,显著高于正常对照(9.8 ± 2.7) IU/L (P < 0.01) [39]。这种“隐性LH异常”与颗粒细胞AMH分泌增加(25 ± 8 ng/mL vs. 18 ± 5 ng/mL)协同,导致卵泡募集过剩但成熟障碍[40]

高雄激素血症的来源分型与临床意义:基于DHEA-S/FT比值,可将高雄激素分为卵巢型(DHEA-S正常,FT升高,占58%)、肾上腺型(DHEA-S ≥ 4.0 μg/mL,FT正常,占22%)及混合型(占20%) [41]。肾上腺型患者更易出现卵巢体积正常但AFC ≥ 25个的表型C,且CYP11B1基因rs1799998变异使其对螺内酯治疗反应率(72%)显著高于卵巢型(51%) [42]

胰岛素抵抗的多维度评估体系:除HOMA-IR外,新型指标如“脂联素校正的胰岛素抵抗指数(ACIR)”(AUC = 0.91)和“内脏脂肪指数(VAI)”(AUC = 0.88)在预测PCOS糖代谢异常方面优于传统指标[43]。值得注意的是,TyG指数 > 8.6与表型A患者的子宫内膜容受性下降独立相关(OR = 2.3, 95% CI: 1.5~3.6),提示IR对生殖结局的直接影响[44]

3.1.3. 表型关联研究的技术革新

单细胞RNA测序发现,表型A卵巢颗粒细胞中FGF21受体(FGFR1)表达上调2.1倍,且富集PI3K-AKT-mTOR增殖通路;而表型D的颗粒细胞显著高表达WNT4基因(差异倍数1.8,P < 0.05),提示卵泡发育停滞的不同分子路径[45]。机器学习模型整合12项内分泌指标(包括FGF21、OCN、LH脉冲频率),对四种表型的区分准确率达89%,显著高于单一指标评估[46]

3.2. 当前研究争议:指标特异性、种族差异与方法学挑战

3.2.1. 新型标记物的表型特异性争议:以FGF21为例

FGF21在表型A中的“改善IR”与“加剧高雄激素”双重作用存在剂量阈值矛盾——当FGF21 < 500 pg/mL时,其肝脏保护效应占优(HOMA-IR↓18%);> 600 pg/mL时,卵巢抑制效应主导(雌二醇↓29%) [47]。然而,不同研究对该阈值的界定差异达20%~30%,且亚洲人群因FGF21基因rs838133多态性,血清水平较欧美低15%~20%,导致其临床解读存在种族偏差[48]

3.2.2. 传统指标的跨种族异质性困境

LH脉冲参数的种族差异:中国PCOS患者LH脉冲频率(11.2 ± 1.5次/24h)显著低于欧美(13.5 ± 2.0次/24h),但振幅更高(14.8 ± 3.9 IU/L vs. 12.3 ± 3.1 IU/L),这种差异与KISS1基因rs12347568变异相关,导致GnRH神经元兴奋性调节模式不同[49]

SHBG诊断阈值的地域争议:中东地区因高温环境诱导SHBG基因甲基化,正常人群SHBG均值(45 ± 12 nmol/L)较北欧(68 ± 15 nmol/L)低34%,导致游离雄激素指数(FAI)在相同睾酮水平下被高估22% [50]。这种环境–遗传交互作用使同一指标在不同地域的表型关联分析出现矛盾。

3.2.3. 检测方法学差异引发的结论分歧

动态激素监测的标准化缺失:仅28%的研究采用24小时频繁采血(每10分钟1次)评估LH脉冲,导致“正常LH/FSH比例PCOS”的报道率在不同研究中波动于15%~45% [51]

唾液FT检测与血清平衡透析法的一致性仅65%,在肥胖患者中差异扩大至30%,影响高雄激素表型的精准分型[52]

卵巢多囊样改变(PCO)的影像学争议:经阴道超声评估AFC时,手动计数与自动软件分析的差异率达18%,且不同种族的卵巢体积正常上限(亚洲10 mL vs. 欧美15 mL)缺乏统一标准,导致表型C/D的诊断一致性仅72% [53]

争议本质与未来方向

当前争议本质上反映了PCOS“单一诊断标准”与“多元致病机制”的深层矛盾:机制层面:需明确FGF21等新型因子是致病驱动因素还是代偿性标记,尤其在表型D的非高雄激素性排卵障碍中,需区分“原发性GnRH脉冲异常”与“继发性卵巢局部因子失调”。

方法层面:亟需建立跨种族、多模态的标准化检测体系(如动态LH脉冲监测结合单细胞测序),开发基于AI的表型预测模型以整合遗传、代谢、影像数据。

临床层面:建议在鹿特丹标准中补充“雄激素来源检测”(如17-OHP鉴别卵巢/肾上腺)和“IR分层评估”(如TyG指数联合ACIR),推动“分子表型指导下的精准治疗”。

4. 结论与展望

PCOS作为高度异质化的内分泌代谢紊乱综合征,其表型多样性本质上是内分泌调控网络失衡的差异化呈现。当前研究已揭示,传统指标(高雄激素血症、胰岛素抵抗、HPO轴紊乱)与新型分子标记(FGF21、脂联素/内脂素轴、骨钙素)通过“代谢–生殖轴”交叉互作,在不同表型中形成独特致病路径:

表型A中,FGF21过度表达加剧胰岛素抵抗与颗粒细胞功能异常,与LH脉冲振幅升高协同驱动卵巢高雄激素微环境;

表型B以肾上腺源性雄激素升高为主,伴随脂联素介导的HPO轴敏感性异常;

表型C的多囊卵巢形态形成,与胰岛素抵抗诱导的卵巢基质纤维化及OCN调控的下丘脑GnRH神经元兴奋性增强密切相关;

表型D的非高雄激素性排卵障碍,提示存在尚未明确的垂体–卵巢旁分泌通路异常。

这些发现不仅修正了“LH/FSH比例决定论”的传统认知,更揭示了PCOS内分泌异常的多维度特征——从卵巢局部因子失调到全身代谢信号紊乱,从静态指标比值到动态脉冲节律异常,均需纳入临床评估体系。

5. 未来研究三大核心瓶颈突破策略及实施方案

5.1. 构建“分子标记物–表型–临床结局”精准映射体系

核心目标:明确FGF21、DHEA-S、脂联素/内脂素比值等分子标记物在不同表型中的浓度阈值及其与排卵功能、代谢并发症等临床结局的量化关联,解析跨种族环境–基因交互作用机制。

实施路径:开展多中心前瞻性跨种族队列研究,基于统计效能计算样本量,系统采集临床表型、内分泌标记物、遗传背景及环境暴露数据,进行annual长期随访;重点分析FGF21等标记物的种族特异性阈值,结合基因组、代谢组等多组学数据,构建基于机器学习(随机森林/神经网络)的精准分型模型,突破鹿特丹标准的表型混杂局限。

5.2. 解析新型因子的组织特异性功能与治疗潜力

核心目标:阐明FGF21在肝脏/卵巢的双向调控机制及剂量阈值,验证脂联素受体激动剂对下丘脑–垂体–卵巢轴(HPO轴)的调节作用。

实施路径:FGF21机制研究:通过CRISPR-Cas9构建组织特异性基因编辑PCOS动物模型,结合高胰岛素–正葡萄糖钳夹试验及卵巢类固醇激素检测,明确其剂量依赖性功能转换阈值;在表型A患者中分析FGF21浓度与胰岛素抵抗、性激素比例的相关性。脂联素受体激动剂开发:在PCOS动物模型中通过电生理记录和LH脉冲监测,评估激动剂对HPO轴的调节作用;开展I/II期临床试验,在表型B患者中验证其对排卵率及代谢指标的改善效应。

5.3. 推动机制导向的精准治疗临床转化

核心目标:开发表型特异性靶向疗法,建立青春期PCOS动态诊断标准及远期风险预测模型。

实施路径:表型A干预:在IR型PCOS动物模型中优化FGF21受体激动剂与二甲双胍联合方案,通过RCT试验比较单药及联合治疗对高雄激素血症、胰岛素敏感性及排卵率的影响。表型C干预:基于CYP11B1结构设计高选择性抑制剂,在肾上腺源性高雄激素模型中验证其对DHEA-S合成的抑制效力;开展I/II期临床试验,评估药物对表型C患者的临床症状及代谢指标的改善作用。青春期PCOS管理:建立多中心前瞻性队列,收集初潮后少女的内分泌–代谢–影像数据,定义动态诊断阈值;整合纵向数据构建机器学习模型,预测2型糖尿病、卵巢储备功能下降等远期风险。

战略价值:通过基础机制研究与临床需求的深度耦合,上述方案将推动PCOS领域实现从“症状诊断”到“分子分型”、从“经验治疗”到“机制靶向”的诊疗范式革新。

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