Abstract
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.
Highlights
In most areas of scientific study, knowledge gained from both pre-clinical and clinical research is based upon a disproportionate inclusion of male subjects
Both clinical and pre-clinical reports find that females recover more locomotor abilities after spinal cord injury (SCI)
Sex-differences in acute inflammation have been reported following traumatic brain injury (TBI) and similar effects are likely to be found following SCI. It remains to be determined if sex differences in acute inflammation are causal to a greater frequency of SCIinduced pain that is reported in females
Summary
In most areas of scientific study, knowledge gained from both pre-clinical and clinical research is based upon a disproportionate inclusion of male subjects. Modeling medical practice on such limited demographics and failure to advance our understanding of disease, injury, and treatment in the context of sex-based differences have manifested into practices that are emerging as not just ineffective, but sometimes dangerous, to the health of women. Likely owing to this mandate, findings from animal models of many neurological conditions have begun exposing exactly how important sex-dependent effects in medicine can be. This manuscript evaluates work that has considered sex as a biological variable in neurotrauma with specific emphasis on spinal cord injury (SCI). Methodological considerations for assimilating sex as a biological variable in SCI studies are discussed owing to a substantial increase in the complexity of study design and interpretation
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