Table_2_Considerations for Studying Sex as a Biological Variable in Spinal Cord Injury.DOCX

In response to NIH initiatives to investigate sex as a biological variable in preclinical animal studies, researchers have increased their focus on male and female differences in neurotrauma. Inclusion of both sexes when modeling neurotrauma is leading to the identification of novel areas for therapeutic and scientific exploitation. Here, we review the organizational and activational effects of sex hormones on recovery from injury and how these changes impact the long-term health of spinal cord injury (SCI) patients. When determining how sex affects SCI it remains imperative to expand outcomes beyond locomotor recovery and consider other complications plaguing the quality of life of patients with SCI. Interestingly, the SCI field predominately utilizes female rodents for basic science research which contrasts most other male-biased research fields. We discuss the unique caveats this creates to the translatability of preclinical research in the SCI field. We also review current clinical and preclinical data examining sex as biological variable in SCI. Further, we report how technical considerations such as housing, size, care management, and age, confound the interpretation of sex-specific effects in animal studies of SCI. We have uncovered novel findings regarding how age differentially affects mortality and injury-induced anemia in males and females after SCI, and further identified estrus cycle dysfunction in mice after injury. Emerging concepts underlying sexually dimorphic responses to therapy are also discussed. Through a combination of literature review and primary research observations we present a practical guide for considering and incorporating sex as biological variable in preclinical neurotrauma studies.

为响应美国国立卫生研究院（National Institutes of Health, NIH）关于在临床前动物研究中将性别作为生物学变量开展研究的倡议，研究者愈发关注神经创伤中雌雄个体的差异。在神经创伤建模过程中纳入雌雄两性受试对象，正推动识别出可用于治疗开发与科学探索的全新领域。本文综述了性激素对损伤后恢复的组织性与激活性功能，以及这些变化如何影响脊髓损伤（spinal cord injury, SCI）患者的长期健康状况。在探究性别对脊髓损伤的影响时，仍需将评估范围拓展至运动功能恢复之外，并兼顾其他严重影响脊髓损伤患者生活质量的并发症。有趣的是，脊髓损伤领域的基础科学研究主要使用雌性啮齿类动物，这与其他大多偏向雄性的研究领域形成鲜明对比。本文讨论了这一现状给脊髓损伤领域临床前研究的临床转化可行性带来的独特局限。我们还综述了当前将性别作为生物学变量开展研究的脊髓损伤临床与临床前相关数据。此外，本文阐述了饲养环境、体型大小、护理管理与年龄等技术层面的考量因素，是如何干扰脊髓损伤动物研究中性别特异性效应解读的。我们的原创研究揭示了年龄对脊髓损伤后雌雄个体死亡率与损伤诱导性贫血的差异化影响，并进一步发现了损伤后小鼠的动情周期功能障碍。本文还讨论了治疗应答中性二态性反应背后的新兴研究理念。通过结合文献综述与原创研究观察结果，本文为在临床前神经创伤研究中考虑并纳入「性别作为生物学变量」这一原则提供了实用指南。