How "Female Hysteria" Hampered Biomedical Research

Victorian era notions may have excluded female animals from research.

Posted Jun 18, 2019

Wikimedia Commons
A selection from John Henry Fuseli's The Nightmare, 1781
Source: Wikimedia Commons

Hysteria was the first mental disorder attributed to women, dating back more than 4,000 years. It evolved from a mythical animalistic uterus-based evil to a mental state of unrest that could also occur in men, but the basic premise was the same: Women are emotionally volatile and unpredictable because they are ruled by their hormones.

The negative impact of this unquestioned assumption on the status of women is beyond measure, but an artfully written perspective piece in Science by Dr. Rebecca Shansky, Associate Professor of Psychology at Northeastern University, shines a light on a dark corner of unintended harm, the exclusion of female subjects in neuroscience research.  

 In 1993, in an effort to improve health across the board, Congress mandated that all NIH clinical trials include women or give darn good reasons why not. Did it work? Yes and no. The inclusion of women in clinical trials research increased, often to parity with men. But there were two simmering problems. First was the mandate did not include a provision that the data be analyzed for any influence of gender. Thus, while thousands of studies dutifully reported the percent of male and female subjects, that was often the end of it, with the tacit assumption that there was no difference in men and women in whatever parameter was being measured in response to whatever treatment. An egregious case of leaving data on the table, but at least women were in the mix. 

Far more insidious and unrecognized for more than 20 years is the fact that the fairness mandate had not trickled down to scientists working at the bench conducting research on animals and cell lines. Not only were bench scientists not getting the message, in the case of neuroscience there was a concerted effort to exclude female subjects, mostly rats and mice, from studies of the brain. Just how bad things had gotten was revealed in an impactful report by Irving Zucker, a Professor of the Graduate School in the departments of Psychology and Integrative Biology at UC-Berkley, who, working with a trainee at the time and now an Associate Professor of Psychology at Smith, Dr. Annaliesse Beery, analyzed publications that used animals for research across a wide range of fields (i.e. immunology, endocrinology, behavior etc.), and found there was a tremendous skewing in the representation of  the sexes in basic research but that neuroscience was the worst offender, with almost six times as many studies exclusively using male animals.

How can this happen! This is outrageous! Who could possibly think this was a good idea! are just some of the responses I heard when speaking with female reporters at major news outlets when this fact was brought to their attention. Shansky persuasively argues that the roots for excluding female rats and mice in pre-clinical research has its origins in Victorian era perceptions of women as flighty, overly emotional and most of all, unpredictable. Scientist seek to reduce variability, not increase it. Studies in the 1990s found impressive effects of gonadal hormones on cognitive tasks and associated brain regions in female rats. Rats do not have a menstrual cycle but instead a rapid four-to-five day estrous cycle during which hormone levels vary and female rats sometimes vary in their behavior and neural physiology as well. The timing of these publications, which received wide acclaim for their scientific rigor, corresponds with the active exclusion of females from most neuroscience research. Shansky suggests the variability seen in female rats across the estrous cycle was interpreted by scientists at the time as proof that females are unpredictable and should therefore not be the go-to animal for establishing first principles in understanding the brain.  

She may be right, we’ll never know what was in the mind of scientists. An equally plausible and possible contributing factor is that many scientists at that time were products of the ’60s and ’70s and believed that men and women are equal and the only differences are cultural, not biological. Thus, there was no reason to think there might be sex differences in brain or behavior. Yes, this is logically inconsistent, why not include females then? Perhaps just because it was another variable that could be controlled, and, well, there were those studies showing hormones really can have an effect…Here is where Shansky takes them to task, noting that no one ever thought to ask if hormones have effects on male brains too. Without any evidence, it was assumed that not only were males emancipated from their hormones, but there was also no variability between or within individuals either. This has since been resoundingly debunked, with multiple demonstrations that the dominance hierarchies males establish impact hormone levels as robustly as the estrous cycle and that the behavior and neural physiology are as variable, if not more so, in males than females. A follow-up study by Prendergast and Zucker found that male mice housed alone, and thus without dominance hierarchies, were less variable than group housed males and that singly housed males and females do not differ in variability. 

So, what did the NIH do about it? They passed another mandate, this one declaring that all preclinical research they fund must include sex as a biological variable, meaning not only must female animals be included, the data must be disaggregated and analyzed for an effect of sex. This means that when new drugs used in clinical trials they will have first been tested in both male and female animals. This means when we write the textbooks on how the brain works it will include things that are true for both males and females. This means that we are finally getting it right and recognizing that neither males nor females are slaves to their hormones. This means progress.