“阻滞型”精子发生障碍：一分为三，分型治疗

撰文：白昊威 许俊伟 李铮

“阻滞型”精子发生障碍:一分为三,分型治疗

一、精子发生

精子发生是指精原干细胞经过一系列复杂有规律的分化过程变形成为精子的过程，主要分为三个连续阶段： 精原干细胞的自我更新和增殖分化、精母细胞减数分裂与精子形成 ，其中 任何一个环节出现严重异常均会导致精子发生障碍，从而引发男性不育。

精子发生模式图

二、精子发生障碍

1985年，英国布里斯托大学HULL等提出精子发生障碍，简称生精障碍。这是一种严重的生育障碍临床疾病。1993 年，“WHO 男性不育标准化检查与诊疗手册”指出生精障碍存在显著异质性，即生精障碍患者睾丸内少数生精小管可有“局灶型”正常精子发生。2007年，美国康奈尔大学 Peter N Schlegel 提出生精障碍“阻滞型”的概念，这类患者临床特征为“均一性睾丸生精阻滞”，且 FSH 水平正常，多与遗传变异相关。

2022-2023 年李铮团队提出生精障碍是一种临床综合征，即精子发生障碍（生精障碍）是由环境、遗传、内分泌、炎症、免疫、不良生活方式等因素独立或交互影响，损伤生精细胞与生精微环境，导致生精细胞自我更新、增殖与分化障碍的临床综合征，临床表现为非梗阻性无精子症、隐匿精子症或严重少弱畸精子症 （其精子浓度一般小于 5×10⁶/ml，伴有弱精子症或畸形精子症)。目前我国已有高达500万生精障碍患者，这些患者仍面临诊断困难、病因不明、治疗效果欠佳、尚无规范统一的临床分型诊疗体系等一系列问题，严重影响男性生殖健康，一直是男科学领域的热点和难点。亟需通过临床表型不同将生精障碍患者分型细化，建立针对性临床诊疗体系，取得更好的治疗效果。

近期，上海交通大学医学院附属第一人民医院李铮教授团队针对“阻滞型”精子发生障碍的遗传学及其诊疗研究进展的述评发表于中文核心期刊《陆军军医大学学报》

李铮团队基于9615例生精障碍患者临床样本库及504例家系样本库，综合考虑患者的生精情况，从临床表型、发病原因、发病过程、治疗及预后五个维度创新性提出将生精障碍分为3种亚型：①生精小管形态各异，多数小管无精子仅孤立小管有精子的“局灶型”；②生精小管形态相近，生精细胞分化阻滞于精母细胞与精子细胞的“阻滞型”；③生精小管破坏或萎缩，仅存支持细胞或偶见精原细胞的“衰竭型”。

三、“阻滞型”精子发生障碍

在临床工作中有一类特殊的生精障碍患者：其精液中往往未见精子，睾丸体积及性激素检查相对正常，回顾病史无明显导致无精子症的病因，常规药物治疗效果欠佳。该类患者最终接受显微取精手术治疗，术中切开睾丸发现其生精小管粗细均一，无明显生精灶存在。术后睾丸组织病理学表现为生精小管管周细胞、间质细胞、管腔内支持细胞及精原细胞均正常，但未见精子。管腔内可见大量精母或精子细胞，生精过程停滞。该类生精障碍患者目前临床尚无规范统一的分类，无法进行系统性诊疗。

因此，根据该类患者精子发生过程停滞的特点，本团队从临床表型提出“阻滞型”精子发生障碍的概念：“阻滞型”生精障碍患者病史排除腮腺炎睾丸炎、疝气手术史等既往能够导致无精子症的病因、体格检查睾丸体积12～15 mL、性激素检查结果均处于参考值范围内、术中可见粗细均一的生精小管，术中镜检所获睾丸组织未见精子，可见较多生精细胞。术后病理学检查睾丸组织染色后未见精子，可见较多生精细胞，术后病理Johnsen评分4～7分。

本团队前期研究发现，约60%的“阻滞型”生精障碍患者可以发现其遗传学致病因素。目前，探究精子发生障碍遗传病因学的方法主要有染色体核型分析、全外显子测序及染色体微阵列等。主要涉及 DSB 重组修复相关基因（DMC1、SHOCI、TEX14、 MEIl、 MSH4、 MSH5 等）；联会复合体相关基因（SYCE1、 SIX6OS1、 SYCP2 等）；染色体动态变化相关基因（STAG3、 CCDC155、 TERB1、 TERB2 等）；此外，MAST2、MYRIP、 LRRC4C 杂合拷贝数变异和 SYCE1 的纯合拷贝数变异，也会导致精子发生障碍。染色体核型异常、AZFb 区和 AZFb+c 区完全缺失也可导致”阻滞型”精子发生障碍。总结如下（红色标注及下划线基因为本团队既往报道）。

目前，对大多数生精障碍患者仍缺乏有效治疗手段，即使依托睾丸取精和辅助生殖技术，多数患者往往助孕失败，只能借助捐献者的精子生育子代。究其根本原因，是由于当前仍缺少持续高效恢复精子发生的治疗方法。

四、“阻滞型”生精障碍新疗法

针对以上挑战，结合“阻滞型”生精障碍遗传病因学诊断率高的特点，本团队在阐明“阻滞型”生精障碍新致病机理的基础上，正在探究 芳香化酶抑制剂疗法和体内外复合靶向递送生精障碍治疗新技术 ，力求利用新型治疗技术恢复生精功能。

HPG轴

1、芳香化酶抑制剂疗法

芳香化酶抑制剂可以抑制雄激素向雌激素的转化，解除雌激素对下丘脑和垂体的过度抑制，增加卵泡刺激素和黄体生成素分泌，进而促进生精障碍患者精子发生 。针对“阻滞型”生精障碍患者，本中心目前已有一例患者接受芳香化酶抑制剂治疗后成功出现精子。因此，运用包括芳香化酶抑制剂在内的新辅助内分泌序贯疗法进行多中心有效性及安全性研究有望实现“阻滞型”生精障碍的治疗，突破治疗瓶颈。内分泌药物与芳香化酶抑制剂可以使部分阻滞型患者出现精子，经辅助生殖技术生育子代。对该类患者推荐实施显微小切口取精或切除组织送病理活检，术中必须注意严密止血。不推荐常规实施显微取精术。

芳香化酶抑制剂促进精子发生原理图

2、mRNA靶向递送疗法

模式动物表明，经CRISPR实施基因治疗，生精障碍大鼠恢复精子发生，可生育子代。2023年报道基于纳米脂质体颗粒（LNP）技术，递送 mRNA 模式动物恢复精子发生，为“阻滞型”生精障碍治疗带来曙光。结合“阻滞型”生精障碍遗传病因学诊断率高的特点，本团队在阐明“阻滞型”生精障碍 新致病机理的基础上，探究 体内外复合靶向递送生精障碍治疗新技术，通过 优化既有ｍＲＮＡ序列和元件的设计方法， 开发新型靶向递送模块，实现脂质纳米颗粒（ＬＮＰ）及外泌体为载体的ＲＮＡ体内外复合靶向递送， 结合本团队所特有的单根生精小管体外培养 以及输出小管显微注射技术实现体外生精小管靶向治疗，力求恢复生精功能获得精子。

靶向mRNA递送挽救精子发生障碍示意图

五、“阻滞型”生精障碍诊疗展望

为了完善“阻滞型”生精障碍的分型标准和治疗方案，本团队进一步收集病史、进行专科体检、辅助检查、手术资料、病理图片等数据，结合人工智能进行综合分析，建立一个精准的多元诊断技术体系。根据此诊断筛查“阻滞型”生精障碍患者，同时结合全外显子测序、染色体微阵列、染色体核型分析等技术从染色体异常、拷贝数变异和单核苷酸突变多个角度筛选和分析“阻滞型”生精障碍的遗传病因学因素，并建立遗传筛查组套，力争尽早进行明确的诊断，同时为临床治疗提供靶标，从而提出有效安全的治疗策略，制定完整的诊疗路径，最大限度地挽救“阻滞型“生精障碍患者的生育能力。

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