标准与规范丨生长激素缺乏相关衰老治疗的专家共识

一、共识制订方法

1. 共识工作组与利益冲突管理：本共识由中国老年保健协会生长发育和性腺疾病专业委员会参与制订。共识专家组涵盖内分泌科、营养科、老年医学科、运动医学科等领域专家。工作组所有成员均填写了相关利益声明，不存在与本共识相关的利益冲突。 2. 共识制订流程及临床问题确定：参与本共识制订的临床专家组由全国各地34位各相关专业专家组成。采用德尔菲法以问卷形式征询专家意见，通过4次线下或线上会议，讨论共识的框架和难点，提出针对生长激素和衰老之间的发病机制、目标人群、应用风险、治疗方案和疗效评价等关键问题。将专家赞同百分比≥75%的条目列入共识。 3. 证据检索：以“growth hormone”“aging”“sarcopenia”“osteoporosis”“treatment”“quality of life”“anti-aging”“cancer”“生长激素”“衰老”“肌少症”“骨质疏松”“治疗”“生活质量”“抗衰老”“癌症”为关键词，在PubMed、万方数据库和中国知网等数据库进行文献检索（检索时间为1990至2025年），全面获取生长激素和衰老相关的文献信息。文献的纳入标准：生长激素和衰老相关的研究。排除标准：（1）无法获取全文；（2）发表语言非中文或非英文；（3）与主题无关文献；（4）重复文献；（5）基础研究。 4. 证据评价与分级：根据推荐意见分级的评估、制订与评价（Grading of Recommendations Assessment，Development and Evaluation，GRADE）系统证据质量分级（分为A、B、C、D等级），推荐等级根据专家投票分为强推荐、中等推荐、弱推荐3个级别（ 表1 、 2 ）。由90名专科医师（内分泌科、老年医学科等）对共识的关键性问题进行投票表决，代表国内专家的推荐意见。推荐意见采用专家一致性原则，存在不同专家意见时，采用投票超过2/3的专家意见，直至达成推荐意见。部分推荐虽缺乏高级别证据支持，但存在临床疗效。 \n \n 表1 推荐意见分级的评估、制订与评价(GRADE)系统证据质量分级\n \n \n 证据级别\n 具体描述\n 研究类型\n 计桑晋考令\n \n \n 高级证据(A)\n 进一步研究也不可能改变该疗效评估结果的可信度\n RCT;质量升高二级的观察性研究\n \n \n \n 中级证据(B)\n 进一步研究很可能影响该疗效评估结果的可信度,且可能改变该评估结果\n 质量降低一级的RCT;质量升高一级的观察性研究\n \n \n \n 低级证据(C)\n 进一步研究极有可能影响该疗效评估结果的可信度,且该评估结果很可能改变\n 质量降低二级的RCT;观察性研究\n \n \n \n 极低级证据(D)\n 对效应估计值几乎没有信心:真实值很可能与估计值大不相同\n 质量降低三级的RCT;质量降低一级的观察性研究;系列病例观察;个案报道\n \n \n\n\n 5. 共识使用者和目标人群：本共识使用者为全科医师、内科医师、老年科医师、内分泌科医师以及其他相关专业人员。本共识的目标人群为生长激素缺乏伴随衰老症状的中老年患者。 6. 共识的传播与更新：本共识将通过学术会议、学术期刊、解读、宣讲、新媒体和推文等多种途径传播，促进本共识推广实施。计划在3~5年内，评估最新循证医学证据和临床应用情况，必要时进行更新。

二、生长激素与衰老的关系

生长激素是垂体前叶分泌的一种参与机体生长和能量代谢的重要蛋白质激素。生长激素及其作用于肝脏后所产生的胰岛素样生长因子-1（insulin-like growth factor-1，IGF-1），二者共同作用于全身组织器官，包括肝脏、脂肪、骨骼、肌肉和中枢神经系统，发挥重要生理作用。青春期生长激素和（或）IGF-1明显升高，促进身体快速线性生长；青春期后，随年龄增长生长激素分泌逐渐降低 ［ 3 ］ 。当下降到一定水平就会伴随产生相应症状和体征，临床曾称之为“生长激素更年期” ［ 4 , 5 ］ 。已有研究证实，IGF-1降低和胰岛素敏感性降低、血糖增高、肥胖、脂肪肝等物质代谢异常密切相关 ［ 6 ］ 。补充生长激素能增加肌肉量，减少内脏脂肪，改善细胞线粒体功能，提升体能 ［ 4 ， 7 ］ ，但直接观察生长激素补充治疗能否改善衰老症状的临床研究仍然稀缺。虽然有研究显示，生长激素和（或）IGF-1降低的小鼠存活时间更长，但生长激素缺乏患者寿命并未延长 ［ 8 , 9 , 10 ］ 。相反，成人生长激素缺乏患者因代谢紊乱导致心血管事件风险增加、肝肺功能受损和生活质量下降 ［ 4 ］ ，补充生长激素可带来明确获益。 疾病所致生长激素缺乏和自然衰老过程都表现为蛋白质和肌肉合成减少、体脂增加、骨质疏松、线粒体功能下降 ［ 10 ］ 。因为生长激素补充能改善上述状态 ［ 11 ］ ，因此认为生长激素具有延缓衰老作用。近期研究显示，生长激素缺乏患者发生脂肪肝相关肝硬化和肝-肺以及肝-肾综合征风险增加 ［ 12 ］ ，而适时适量生长激素补充治疗能逆转肝脏病变和肝-肺以及肝-肾综合征，推迟或避免肝移植，可为此类患者健康带来巨大获益 ［ 13 ］ 。因此，生长激素改善代谢和延缓衰老的作用理应受到临床医师的重视。随着对成人生长激素缺乏认识增多和诊治水平提高，对其进行诊治的专家共识将不断更新迭代 ［ 14 , 15 ］ 。

三、生长激素的作用

推荐意见1：生长激素补充有增肌减脂作用。（证据等级A，强推荐） 证据：一项荟萃分析纳入IGF-1水平偏低的老人（ n=220，平均年龄69岁）接受6个月及以上生长激素治疗，结果显示脂肪减少2.1 kg，瘦肉增加2.1 kg［ 16 ］ 。一项针对IGF-1偏低男性（n=45，61~81岁）的研究显示，补充生长激素治疗18个月，瘦体重增加6%，脂肪减少15%［ 17 ］ 。另一项针对IGF-1偏低的肥胖青年男性（n=136）的研究显示，补充生长激素治疗1年后，瘦体重增加2.2 kg，脂肪减少1.1 kg［ 18 ］ 。一项双盲对照研究纳入生长激素部分缺乏（IGF-1均值131 μg/L）肥胖男性（n=62）接受生长激素治疗6个月，内脏脂肪横截面积下降12%，脂肪量减少2.4 kg，瘦体重增加1 kg［ 19 ］ 。一项随机双盲对照研究纳入生长激素轻度缺乏（平均IGF-1 137 μg/L）育龄期肥胖女性（n=79），生长激素治疗6个月，腹部脂肪减少1.5 kg，瘦体重增加1.9 kg。并且发现，治疗期间IGF-1升高幅度越大，腹部脂肪减少越多（r=-0.56，P=0.002）［ 20 ］ ；生长激素增肌效应存在性别差异，男性优于女性，男性瘦肉增加3.1 kg，而女性增加0.7 kg［ 21 , 22 ］ 。补充生长激素还可增加线粒体功能［ 19 ］ ，提升肌肉力量和耐力。另外，生长激素有促蛋白合成作用，有助于术后伤口恢复和烧伤患者的皮肤修复［ 23-25 ］ 。同时，有助于呼吸机尽早脱机［ 26 ］ 。 推荐意见2：生长激素补充可改善脂肪肝。（证据等级A，强推荐） 证据：一项横断面研究显示，在正常人群中脂肪肝组（ n=1 667）空腹血生长激素水平低于健康对照组（ n=5 479），两组生长激素分别为0.02 μg/L和0.11 μg/L（ P\n \n 表3 生长激素治疗的推荐剂量\n \n \n 年龄(岁)\n 短效生长激素\n 长效生长激素\n 正常生长激素\n \n \n 起始剂量(U/d)\n 调整剂量(U)\n 起始剂量(mg/周)\n 调整剂量(mg)\n \n \n \n \n 1.0\n ±0.1\n 1.5\n ±0.3\n \n \n \n 30~60\n 1.0\n ±0.1\n 1.0\n ±0.3\n \n \n \n >60\n 0.5\n ±0.1\n 0.7\n ±0.2\n \n \n\n\n 推荐意见15：生长激素治疗后3~6个月全面评价症状和代谢指标，如无改善，应当停药；如症状或代谢指标明显改善，可长期生长激素治疗，间隔3~6个月评估治疗获益和风险，决定是否继续使用。（证据等级A，强推荐） 证据：在生长激素治疗3~6个月时，应全面评价症状（肌肉力量、步行速度、性功能、睡眠、精神状态和情绪）、体征（腰围、腰臀比）和检测（机体组分、肝脂肪量、转氨酶、超敏C反应蛋白、IGF-1水平）的改善程度。如无改善，可考虑停药。如上述症状或指标明显改善，可长期生长激素治疗。目前尚无明确的疗程界定。已有报道成人生长激素缺乏患者接受生长激素治疗的最长时间为15年 ［ 44 ］ 。间隔3~6个月评估生长激素治疗获益和风险，决定是否继续使用。至少每6个月测定血脂和腰围。每年复查骨密度和机体组分。定期评估体能和精神认知状态、生活质量量表（SF-36量表）、勃起功能量表和睡眠量表。停用生长激素补充3个月后，30%~50%的增肌、减脂获益会消退 ［ 18 ］ 。

六、生长激素治疗的不良反应

推荐意见16：生长激素治疗主要不良反应包括软组织水肿和关节痛，降低生长激素剂量或停药可缓解不良反应。（证据等级A，强推荐） 证据：个体对生长激素和（或）IGF-1敏感性存在明显差异 ［ 85 ］ 。荟萃分析纳入接受生长激素治疗的老年人（ n=220，平均69岁，生长激素治疗6个月），发现常见不良反应包括软组织水肿（50%）、关节痛（21%）、腕管综合征（19%）、男性乳房发育（5%）、血糖调节受损（22%）和新发糖尿病（5%） ［ 17 ］ 。女性比男性更易出现水肿（61%比47%）。IGF-1水平偏低和年龄较大者对治疗反应更加明显。降低生长激素剂量或停药可缓解不良反应。

七、问题与展望

生长激素延缓衰老的临床获益和安全性证据主要来自成人生长激素缺乏人群。IGF-1降低的衰老人群应用生长激素治疗的有效性和安全性数据还相对不足，因此生长激素治疗应充分权衡获益和风险。若有获益可长期补充生长激素，若无获益则应停药。 生长激素延缓衰老治疗尚存在诸多临床问题有待解决，可作为未来的重点研究方向：（1）如何确定IGF-1降低的干预切点，使生长激素治疗能带来更多获益？以往临床研究以低于同龄同性别人群下限30百分位作为切点 ［ 21 , 22 ， 86 , 87 ］ ，显示生长激素治疗有增肌减脂作用。本共识建议以≤-1 SD（15百分位）作为IGF-1降低的诊断切点（ 表4 、 5 ，建议各地实验室根据本实验室参考值确定），因为更低的IGF-1水平可能预示着更好的治疗效果和更多的临床获益。（2）何时开始生长激素治疗获益更多？多项临床研究以≥60岁老年人作为治疗对象 ［ 22 ， 24 ， 87-89 ］ 。但40~60岁IGF-1缺乏相关衰老患者也可能从生长激素治疗中获益。因此年龄并非生长激素治疗的主要考虑因素。（3）性别：男性对生长激素治疗反应优于女性，提示男性接受生长激素治疗可能获益更多 ［ 22 ］ 。（4）何为最佳疗程？既能获得最佳临床收益，又能避免IGF-1升高可能带来的肿瘤风险。理论上，成人生长激素缺乏患者应终身补充生理剂量的生长激素。目前需要更多前瞻性随机对照试验来回答上述问题。随着新证据的出现，此领域的共识也会不断更新。本共识不具备强制性，不作为医疗事故鉴定和医疗责任认定依据，仅供相关医护人员参考。 本共识制订专家组名单 牵头专家：伍学焱（中国医学科学院 北京协和医学院 北京协和医院内分泌科） 执笔专家：茅江峰（中国医学科学院 北京协和医学院 北京协和医院内分泌科） 学术秘书：王曦（中国医学科学院 北京协和医学院 北京协和医院内分泌科） 专家组（按照姓氏汉语拼音排序）：崔铭萱（北京大学人民医院营养科）；管庆波（山东第一医科大学附属省立医院内分泌科）；郭野（中国医学科学院 北京协和医学院 北京协和医院检验科）；胡克平（中国医学科学院药用植物所）；李豫川（首都医科大学附属北京儿童医院内分泌科）；李太生（中国医学科学院 北京协和医学院 北京协和医院感染内科）；刘喆隆（华中科技大学同济医学院附属同济医院内分泌科）；刘涛（新疆医科大学附属中医医院老年病科）；马东来（中国医学科学院 北京协和医学院 北京协和医院皮肤科）；马方（中国医学科学院 北京协和医学院 北京协和医院临床营养科）；茅江峰（中国医学科学院 北京协和医学院北京协和医院内分泌科）；聂敏（中国医学科学院 北京协和医学院北京协和医院内分泌科）；牛国卫（北京小汤山医院有氧运动中心）；曲伸（上海市第十人民医院内分泌科）；饶向荣（中国中医科学院广安门中医院肾病科）；沈珠军（中国医学科学院 北京协和医学院北京协和医院心内科）；王宏伟（中国医学科学院 北京协和医学院北京协和医院皮肤科）；王曦（中国医学科学院 北京协和医学院北京协和医院内分泌科）；吴森（中国农业大学生物学院）；伍学焱（中国医学科学院 北京协和医学院北京协和医院内分泌科）；吴东（中国医学科学院 北京协和医学院北京协和医院消化内科）；杨彩哲（空军特色医学中心内分泌科）；杨卫彬（中国中医科学院西苑医院）；于冰青（北京大学第一医院超声科）；于普林（北京医院老年医学科）；曾天舒（华中科技大学同济医学院附属协和医院内分泌科）；张宏冰（中国医学科学院基础医学研究所）；张伟（中国医学科学院 北京协和医学院 北京协和医院内分泌科）；张睿（中国医学科学院阜外医院内分泌中心）；赵启明（浙江医院整形美容科）；郑超（浙江大学医学院附属第二医院内分泌科）；朱强（山东第一医科大学附属省立医院消化科）；朱袆伊（浙江大学医学院附属第二医院内分泌科）；周雁（北京医院全科医学科） 利益冲突 所有作者声明不存在利益冲突 参考文献（下滑查看）： [1]Li Y , Tian X , Luo J ,et al. 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