Department of Neuroendocrinology, ICMR- National Institute for Research in Reproductive and Child Health, Mumbai, India.
Andrology. 2022 Nov;10(8):1463-1483. doi: 10.1111/andr.13278. Epub 2022 Sep 12.
Varicocoele is a common risk factor associated with reduced male fertility potential. The current understanding of varicocoele pathophysiology does not completely explain the clinical manifestation of infertility. The present treatment options such as antioxidant supplementation and varicocoelectomy only help ≈35% of men to achieve spontaneous pregnancy.
This review aims to summarize the available knowledge on cellular and molecular alterations implicated to varicocoele-associated male infertility and also highlights the new knowledge generated by "omics" technologies.
PubMed, MEDLINE, Cochrane and Google Scholar databases are searched using different combinations of keywords (varicocoele, infertile/fertile men with varicocoele, cellular changes, molecular mechanisms, proteome, epigenome, transcriptome and metabolome). A total of 229 relevant human and animal studies published till 2021 were included in this review.
Current understanding advocates oxidative stress (OS) as a major contributory factor to varicocoele-associated male infertility. Excessive OS causes alteration in testicular microenvironment and sperm DNA fragmentation, which further contributes to infertility. Molecular and omics studies have identified several promising biomarkers such as AAMP, SPINT1, MKI67 (genetic markers), sperm quality and function related protein markers, global sperm DNA methylation level (epigenetic marker), Hspa2, Protamine, Gadd7, Dynlt1 and Beclin1 (mRNA markers), PRDX2, HSPA, APOA2, YKL40 (seminal protein markers), total choline and PHGDH (metabolic markers).
Mature spermatozoa harbours a plethora of molecular information in form of proteome, epigenome and transcriptome, which could provide very important clues regarding pathophysiology of varicocoele-associated infertility. Recent molecular and omics studies in infertile men with varicocoele have identified several promising biomarkers. Upon further validation with larger and well-defined studies, some of these biomarkers could aid in varicocoele management.
The present evidences suggest that inclusion of OS and sperm DNA fragmentation tests could be useful to the diagnostic workup for men with varicocoele. Furthermore, including precise molecular markers may assist in diagnostics and prognostics of varicocoele-associated male infertility.
精索静脉曲张是男性生育能力降低的常见危险因素。目前对精索静脉曲张病理生理学的理解尚不能完全解释不育的临床表现。目前的治疗选择，如抗氧化剂补充和精索静脉结扎术，仅帮助 ≈35%的男性实现自然妊娠。
本综述旨在总结与精索静脉曲张相关的男性不育症相关的细胞和分子变化的现有知识，并强调“组学”技术所带来的新知识。
使用不同的关键词组合在 PubMed、MEDLINE、Cochrane 和 Google Scholar 数据库中进行搜索（精索静脉曲张、有精索静脉曲张的不育/可育男性、细胞变化、分子机制、蛋白质组、表观基因组、转录组和代谢组）。本综述共纳入了 2021 年前发表的 229 项人类和动物相关研究。
目前的认识认为氧化应激（OS）是精索静脉曲张相关男性不育的主要致病因素。过多的 OS 导致睾丸微环境和精子 DNA 碎片化的改变，进一步导致不育。分子和组学研究已经确定了一些有前途的生物标志物，如 AAMP、SPINT1、MKI67（遗传标志物）、与精子质量和功能相关的蛋白标志物、全球精子 DNA 甲基化水平（表观遗传标志物）、Hspa2、Protamine、Gadd7、Dynlt1 和 Beclin1（mRNA 标志物）、PRDX2、HSPA、APOA2、YKL40（精液蛋白标志物）、总胆碱和 PHGDH（代谢标志物）。
成熟的精子具有大量的分子信息，包括蛋白质组、表观基因组和转录组，这些信息可以为精索静脉曲张相关不育症的病理生理学提供非常重要的线索。最近对精索静脉曲张的不育男性进行的分子和组学研究已经确定了一些有前途的生物标志物。通过进一步与更大、更明确的研究进行验证，其中一些生物标志物可能有助于精索静脉曲张的管理。
目前的证据表明，纳入 OS 和精子 DNA 碎片化测试可能有助于精索静脉曲张男性的诊断。此外，包括精确的分子标志物可能有助于精索静脉曲张相关男性不育症的诊断和预后。
