Abstract
There are several reasons why gender matters in biomedical research. I will outline here why it is important to use both sexes in research and in scientific publishing. Recent developments suggest that the use of males in preclinical research may affect the use of medication with the female gender. A recent publication of Sorge and colleagues, 1 on differences in the regulation of chronic pain hypersensitivity, pointed out that in male mice microglia-to-neuron signaling is essential, while in female mice this mechanism is not required and hypersensitivity is achieved by adaptive immune cells. This surprising sexual dimorphism may explain why some clinical trials of pain drugs have failed and highlights shortcomings in the way that many researchers design their experiments. 2 Female mammals have long been neglected in biomedical research and a literature survey shows that male studies outnumber those of females by 5.5 to 1. 3
The National Institutes of Health (NIH) policy attempts to balance sex in cell and animal studies, mainly future preclinical studies. 4 From January 2016, in order to get NIH funding researchers will need to take into consideration the role of sex as a biological variable and to strongly justify why research will only be carried out with one sex. 5 Much data has shown, that by using only male animals in preclinical studies, the health risks for females remain unknown and may lead to a subsequent withdrawal of prescription drugs. 6 For example, of the 10 prescription drugs withdrawn from the US market between 1997 and 2000, eight were found to pose greater health risks for women. 7 It is therefore not only essential to include both sexes in preclinical research but also to address sex differences in basic research.
Two other important points arise as to why both genders should be used in research: an economical one and an ethical one. Breeding animals is costly and when only one gender is used, the other half of the litter has to be sacrificed. This raises the ethical point: in respecting the 3Rs (replacement, reduction, refinement), it is essential to use both sexes whenever possible for animal experimentation, and the use of only one sex needs to be justified. This is even more important when transgenic animals are being bred and used, i.e. from animals that carry several transgenes, or homo- or heterozygous transgenes, only a small part of the littermates exhibit the desired genotype and become useful for research.
In the literature, reporting gender is quite inconsistent; 3 in general biology and immunology journals the gender of animals used is mostly not specified, while the use of either male or females are stipulated in journals of reproduction and endocrinology, and the use of both sexes is more frequent in behavior and zoology journals.
For the last two years, Laboratory Animals has implemented the ARRIVE guidelines 8 for reporting animal research. These guidelines are quite helpful when it comes to the preparation of manuscripts, i.e. reminding authors to mention important points, such as the strain and sex of animals. It also improves the quality of manuscripts for peer review. Beery and Zucker 3 have recommended that when only one sex is studied, this should be mentioned in article titles. Here, we would like to propose that in cases where only one sex is used in animal experimentation, this should also be justified in the text. This is especially important when different disease models are studied and information on gender may provide valuable indications for the planning of preclinical studies.