Sex bias in neuroscience and biomedical research

Abstract

Female mammals have long been neglected in biomedical research. The NIH mandated enrollment of women in human clinical trials in 1993, but no similar initiatives exist to foster research on female animals. We reviewed sex bias in research on mammals in 10 biological fields for 2009 and their historical precedents. Male bias was evident in 8 disciplines and most prominent in neuroscience, with single-sex studies of male animals outnumbering those of females 5.5 to 1. In the past half-century, male bias in non-human studies has increased while declining in human studies. Studies of both sexes frequently fail to analyze results by sex. Underrepresentation of females in animal models of disease is also commonplace, and our understanding of female biology is compromised by these deficiencies. The majority of articles in several journals are conducted on rats and mice to the exclusion of other useful animal models. The belief that non-human female mammals are intrinsically more variable than males and too troublesome for routine inclusion in research protocols is without foundation. We recommend that when only one sex is studied, this should be indicated in article titles, and that funding agencies favor proposals that investigate both sexes and analyze data by sex.

Sex effects on neurodevelopmental outcomes of innate immune activation during prenatal and neonatal life

“…The latter observation is in line with human studies that documented symptoms of schizophrenia are most severe during the late luteal and premenstrual phases, when estrogen levels are low (Angermeyer et al, 1998;Hafner et al, 1993). More importantly, since sex steroids play an important modulatory role in the regulation of immune function, and a variety of autoimmune (e.g., rheumatoid arthritis, Grave's disease) and neurological (e.g., anxiety, depression) disorders are more prevalent in females than males (reported in (Beery and Zucker, 2011;Gaillard and Spinedi, 1998), it is necessary to remove sex bias from neuroscience and biomedical sciences in general.…”

“…A survey of 2000 basic research papers in 2009 (Beery and Zucker, 2011) revealed a male bias in 8 out of 10 disciplines, most pronounced in neuroscience and pharmacology. What is more alarming is that many articles failed to report the sex of the subjects used and when both sexes were used in a study, about two-thirds of those studies did not analyze the data by sex (Beery and Zucker, 2011;Wald and Wu, 2010).…”

“…A survey of 2000 basic research papers in 2009 (Beery and Zucker, 2011) revealed a male bias in 8 out of 10 disciplines, most pronounced in neuroscience and pharmacology. What is more alarming is that many articles failed to report the sex of the subjects used and when both sexes were used in a study, about two-thirds of those studies did not analyze the data by sex (Beery and Zucker, 2011;Wald and Wu, 2010). Factors that continue to encourage male bias in basic research include the cyclic nature of reproductive hormones and the subsequent increased cost of using females in studies; more female subjects are necessary to account for cyclic hormone changes in the rodent's 4-day estrous cycle (Beery and Zucker, 2011;Wald and Wu, 2010).…”

“…What is more alarming is that many articles failed to report the sex of the subjects used and when both sexes were used in a study, about two-thirds of those studies did not analyze the data by sex (Beery and Zucker, 2011;Wald and Wu, 2010). Factors that continue to encourage male bias in basic research include the cyclic nature of reproductive hormones and the subsequent increased cost of using females in studies; more female subjects are necessary to account for cyclic hormone changes in the rodent's 4-day estrous cycle (Beery and Zucker, 2011;Wald and Wu, 2010). Furthermore, the majority of studies that evaluate sex differences covered in this review did not consider the rodents' estrous cycle (i.e., did not monitor cycle phase) in the analyses, nor did they attempt to test the females in a particular phase of the 4-day cycle.…”

“…This is problematic since sex differences are observed in a broad range of neuropsychiatric disorders such as autism, depression and schizophrenia (see Aleman et al, 2003;Beery and Zucker, 2011;Flor-Henry, 1990;Wald and Wu, 2010). The aim of this review is to provide a brief overview of studies that have examined the longterm effects of early life immune activation on brain development and behavior in both sexes, with particular emphasis on factors contributing to the broad variability in results.…”