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Sex Differences in Research: Painfully Evident

Robert Ungard

PhD Candidate McMaster University 
Twitter: @rungard

posted May 29, 2018

Preclinical medical research has a history of neglecting to account for sex as an experimental variable. Despite this readily observable and fundamental difference within humans and many model species, experiments are regularly conducted on cell lines or animals of a single sex, with results then extrapolated to both sexes. 

In many cases, this may not be of concern – there seems to be little reason to expect that medical imaging technologies, for example, would produce different results in males or females. But in other cases, this uncollected data may result in misunderstood mechanisms and ineffective medicines. 

An illustrative example of this is found in pain research. As in much of neuroscience, preclinical pain research was largely conducted on male animals, with conclusions applied to both male and female humans. The clinical reality of pain, however, is also not uniform between the sexes, with women making up the majority of chronic pain patients, and also showing greater sensitivity to experimental painful stimuli (1). The field of pain has also famously suffered from a lack of mechanistic research translation from the lab to the clinic, prompting a search for answers.

Evidence of sexual dimorphism in pain has been accumulating. One particularly fertile area of investigation has been into differential actions of the female and male neuroimmune systems. Microglia – the resident macrophages and only dedicated immune cells of the central nervous system – have been shown to perpetuate chronic neuropathic and inflammatory pain states in male rats and mice, but not in females. Indeed, these pain states can be reversed in males by drugs that target microglia, but this cannot be done in females. Instead, it may be the case that pain states in females are maintained by other immune cells: peripheral T-Cells that have infiltrated the spinal cord (2). It is the influence of these immune cells on neurons that ultimately impacts the sensation of pain.

To some extent the motivation for this neglect of sex in research is understandable: less complicated experiments with half the number of subjects – this saves time, energy and resources, all of which are scarce. However, acknowledging sex as a variable at the preclinical stage could dramatically save time and resources in a scenario where the alternative is discovering a sexual dimorphism at the clinical research or post-market approval stages. Hormonal variability has also been cited as a reason to avoid female animals in research, however the actual extent of this variability in pain research and the necessity of estrous cycle monitoring has been convincingly called into question (3).

As medicine becomes more and more tailored to individuals, sex is a prominent variable in need of further delineation. In response to this, the NIH and CIHR now require an indication of the sex of research animals in applications for funding, with justifications included for omitting one sex or the other. As is the case with pain, fascinating new differences – and therapeutics – may be the outcome.

 

References

1.     Fillingim RB, King CD, Ribeiro-Dasilva MC, Rahim-Williams B, Riley JL. Sex, Gender, and Pain: A Review of Recent Clinical and Experimental Findings. J Pain. 2009 May;10(5):447–85. 
2.     Sorge RE, Mapplebeck JCS, Rosen S, Beggs S, Taves S, Alexander JK, et al. Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nat Neurosci. 2015 Aug 29;18(8):1081–3. 
3.     Mogil JS, Chanda ML. The case for the inclusion of female subjects in basic science studies of pain. Pain. 2005 Sep;117(1):1–5.