高丽虹,孙爱军
(中国医学科学院 北京协和医学院 北京协和医院妇产科,北京 100730)
近年来,代谢综合征正成为全球主要公共卫生问题[1]。它的实质是多种心血管疾病危险因素的聚集,包括中心性肥胖合并血压、血糖、甘油三酯升高和/或高密度脂蛋白降低[2]。代谢综合征有多个诊断标准,现多采用国际糖尿病联盟(IDF)2005年推荐的定义[3]。绝经后女性代谢综合征患病率增加[4],目前研究较多的是雌、雄激素与之的关系[5-7],却一直忽略了另一个重要的内分泌紊乱因素:卵泡刺激素(FSH)。2006年,Sun等[8]发现FSH 能刺激破骨细胞表面的卵泡刺激素受体(FSHR),促使破骨细胞活动增强从而引起骨质疏松,而雌激素并不能纠正这一作用。该论文的发表引起了医学界的广泛关注,也使得研究者开始探索绝经后FSH水平和多种老年性疾病的关系。现就绝经后女性卵泡刺激素水平和代谢综合征的关系作一综述。
代谢综合征在不同人群中的发病率均较高,既往研究认为一般成年人患病率为20%~30%[4,9-11],而绝经后女性患病率明显增高,约为31%~55%[12-14],也有研究提示绝经后女性患病率是绝经前的3.3倍[15]。MORGAM项目数据提示,60~78岁女性患病率较19~39岁增加5倍,男性则增加2倍[10]。国内一项31省150个监测点104 098 名18岁以上成年人代谢综合征(采用中华医学会糖尿病分会诊断标准)流行情况的研究显示,我国成年人代谢综合征患病率为11.0%,城市高于农村,50岁前男性患病率高于女性,50岁时男女性患病率曲线出现交叉,50~70岁女性患病率继续增加,而男性患病率在50岁以后处于平稳状态[16],这和既往研究相似[11,17]。
FSH是由垂体前叶嗜碱性细胞分泌的一种糖蛋白激素,因最早发现其能刺激女性卵泡成熟而得名,其分泌和释放受下丘脑促性腺激素释放激素调控,并受外周雌激素反馈调控。绝经后女性卵巢功能衰竭,雌激素下降,失去对FSH的负反馈,形成了绝经后的高FSH状态。研究显示,FSH在绝经前6.10年开始上升,绝经前2.05年迅速上升,绝经前0.20年上升幅度减慢,绝经2年后基本处于稳定状态[18-19]。FSH变化模式和绝经年龄、吸烟等无关,而与肥胖和种族有关[19]。绝经后肥胖妇女FSH较瘦者低(45.5 U/L vs. 64.1 U/L)[20],部分原因可能是脂肪组织的间叶细胞产生雌激素,并对FSH产生负反馈[21]。超重妇女减重后FSH水平有所回升[22]。
卵泡刺激素受体(FSHR)属于G蛋白偶联受体,分胞外区、7个跨膜区和胞内区三个结构域[23]。FSH结合FSHR,经由G蛋白激活的多种信号通路对细胞的功能产生作用。FSHR除了在生殖细胞表达外,还存在于血管[24]、肝脏[25]、脂肪[26]以及其他,FSHR的存在为FSH发挥广泛的功能提供了生物学基础。
最近两项研究提示,绝经后代谢综合征女性FSH低于无代谢综合征女性,并认为FSH是很好的预测代谢综合征发生的指标,预测价值与瘦素/脂联素相似,优于性激素结合球蛋白(SHBG),超敏C反应蛋白(CRP)和瘦素[27-28]。Wang等[29]发现绝经后女性高FSH水平和动脉粥样硬化性心血管疾病风险下降有关。以上研究均提示绝经后女性高FSH水平可能是代谢综合征的保护性因子,但在代谢综合征各病理状态中,FSH的作用却不总是表现为有利的作用。
1.与肥胖的关系:肥胖是代谢综合征发生的关键因素[20]。代谢综合征采用腰围作为评价肥胖的指标,而腰围的增加会导致女性心血管疾病发病风险和总体死亡率的增加[30]。有学者对543例42~52岁绝经前和围绝经期女性进行长达了6年的随访,发现6年后女性脂肪量增加3.4 kg,腰围增加5.7 cm,FSH和脂肪量两者变化的对数呈正相关[31]。但也有研究发现绝经后糖尿病女性低水平FSH和高体质指数有关[32]。Liu等[33]在人和小鼠脂肪组织和细胞中都发现存在FSHR表达,FSH直接参与3T3-L1细胞的成脂分化,其对成脂的调控呈浓度依赖效应。该调控可能是通过上调过氧化物酶体增殖物激活受体-γ(PPARγ)等基因表达而发挥作用,并提出FSH通过Gai/Ca(2+)/CREB信号通路来调节脂肪堆积和分布。近期Nature上发表了一项研究成果,阻断实验小鼠FSH作用后会出现骨量增加和脂肪堆积减缓,研究还发现FSH作用被阻断后,解偶联蛋白1(UCP1)蛋白表达量增加,白色脂肪细胞米色化[34]。该项研究具有重要的意义,揭示了FSH在绝经后女性肥胖和骨质疏松中的作用,并揭示了FSH在低雌激素下引致肥胖和骨质疏松的机制,并为将来研究提供了新的靶点和理论基础[35-36]。
2.与血脂的关系:绝经后女性多有血脂代谢紊乱[37-39]。2003年,Chu等[40]发现即使月经规律,FSH≥7 U/L女性总胆固醇(TC)和低密度脂蛋白(LDL)较FSH<7 U/L组高,高密度脂蛋白(HDL)和甘油三酯(TG)在两组间没有统计学差异。SWAN研究分析了绝经过渡期女性FSH水平和血脂的关系,发现高FSH组TC、LDL、TG、HDL等指标均更高[41]。FSH与绝经后女性血脂代谢的研究较少。近年来,有学者开始探讨绝经后女性FSH如何在低雌激素水平下影响血脂。Song等[25]研究了400例绝经后妇女FSH和血脂的关系,发现高FSH组TC和LDL更高,给予激素补充治疗后FSH下降明显者TC和LDL改善程度也更大。我们推测,导致各个研究结论不同的部分原因可能和绝经阶段有关,但以上研究均提示高FSH参与了TC、LDL等血脂紊乱的发生。另外,是否可以通过监测FSH下降幅度来预测血脂改善效果,值得进一步研究。
绝经后FSH和血脂关系的基础研究在过去几年也取得一定进展。Cui等[26]发现 FSH可以通过上调鸡的腹部脂肪组织中的FSHR mRNA表达来刺激脂质生物合成。体外实验也发现FSH可通过浓度依赖性及时间依赖性抑制LDL受体的表达而影响LDL代谢。当通过SiRNA敲除FSHR之后,FSH对LDLR的作用被完全抑制[25]。
3.与血糖的关系:绝经后血糖较绝经前上升4.64 mg/dL[38],高血糖和代谢综合征关系密切[42]。我国华东地区代谢性疾病和危险因素患病率调查首次探讨了55岁以上绝经后糖尿病妇女FSH水平与血糖的关系。根据FSH四分位数分为四组,低FSH四分位数组与高FSH四分位数组相比,空腹血糖、空腹胰岛素、胰岛素抵抗指数(HOMA-IR)明显升高。低FSH引起糖尿病前期和糖尿病的OR值分别为1.93和3.02,而这一作用在调整雌激素作用后仍然存在[32],提示低FSH和高血糖、糖尿病前期以及糖尿病有关,推测高FSH可能是绝经后妇女血糖代谢的保护性因子。低FSH引起血糖升高的部分原因可由肥胖和胰岛素抵抗来解释[32],另外,炎症因子可能也参与了FSH导致糖尿病的发生。炎症标记物CRP、肿瘤坏死因子-α(TNF-α)、白介素-1β(IL-1β)等不仅与雌激素水平正相关[43],而且在动物实验中也证实其可抑制促性腺激素释放激素的释放[44],从而产生低FSH,引起血糖的升高。这些还需要进一步研究证实。
4.与血压的关系:高血压是导致女性心血管疾病发生率和死亡率增加的主要风险因素,65以上女性患病率为60%[45]。绝经后女性收缩压和舒张压均升高,分别上升6.11 mmHg和3.54 mmHg[39]。有研究提示,低FSH组和血压升高有关[29,32]。但是,也有学者认为绝经后女性FSH的升高与血压上升有关,它可能通过上调儿茶酚胺水平发挥作用,并进一步通过动物和体外实验证实并探讨FSH促进儿茶酚胺合成和分泌的细胞内机制[46]。
综上所述,绝经后女性高FSH似乎是代谢综合征的保护因素,但是相关临床和机制研究不足,FSH对代谢综合征各组分作用亦存在矛盾。高FSH不利于LDL和TC代谢,在激素补充治疗过程中血脂改善程度和FSH下降幅度是否相关,这得进一步研究和验证。绝经后FSH水平与代谢综合征的关系是一个全新的研究切入点,相关研究和发现必将为衰老病理和老年相关疾病诊疗开辟一个全新的视野和领域。
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