Image text: "The practice of testing drugs mainly in male animals means that there may be treatments that would work well in females that never make it to market because they are only tested in males"

By: Sara Curnow Wilson

Did you know that until recently, almost all scientific testing was performed on male animals? This was the case even when the studies investigated disorders that seemed to occur most commonly in women. Steps have been taken recently to address this imbalance. The National Institutes of Health (NIH) now requires that testing be performed on both male and female animals in order to provide a better idea of how sex works as a biological variable.

Psychology and neuroscience professor Debra Bangasser explains this development and its significance in a recent issue of Scientific American Mind. She took some time to talk to us about the piece, the related work happening in her lab, and why the new NIH requirement has the potential to make a big change.

Why has the historical tendency been to study male animals?

It was conventional to study male animals, so it probably never occurred to some researchers to study female animals. Another reason is that many researchers feared that fluctuating ovarian hormones would complicate their studies, muddy their data, and create a need for more subjects or more time at greater expense. Recent investigations have discredited this line of reasoning because data collected from female animals are no more variable than those from males.

Why is it important to study both male and female animals?

We use animal models to understand processes that occur in neurological and psychiatric disorders. These disorders often differ in men and women. For example, autism is more often diagnosed in boys, while depression is more often diagnosed in women. While these differences in part may be due to social and cultural factors, there is a lot of evidence to suggest that sex differences in biological processes also contribute to sex differences in the rates and presentation of diseases.

How may studying almost exclusively male animals have limited our understanding of female stress responses?

Women are more likely than men to suffer from stress-related disorders, such as depression and PTSD. Yet our knowledge of the stress response is based mainly on research conducted in male animals. When female animals are included, we find that in some cases males and females respond similarly to stress, but in other females are more sensitive to stress hormones. Thus, by only studying males we are not fully understanding the female stress response and missing processes that may be linked to the higher rates of stress-related disorders in women.

In your lab at Temple, you're looking into the link between hormones and stress by studying compulsive grooming in rodents. What have you found so far? 

Rats engage in excessive grooming when they are anxious, perhaps as a form of self-soothing. In response to a stress hormone called corticotrophin releasing factor (CRF), female rats groom more than males, suggesting that CRF increases this particular anxiety-related behavior more in females than in males. We have found that this sex difference is linked to the activation of different circuits in the brain in male versus female rats.

You've noticed a difference not just between male and female rodents, but also at different parts of the hormonal cycle. Is that right?

In this case, we found that CRF caused the biggest effect on grooming in female rats when they were in the stage of their cycle with the highest levels of ovarian hormones. This suggests that ovarian hormones can interact with stress hormones to increase anxiety.

Would you say that your research suggests we should be looking into treatment plans for stress disorders that take the hormonal cycle into account? 

Currently, only the sleep drug Ambien, known generically as Zolpidem, is prescribed differently in men and women. However, animal studies suggest that many drugs, including drugs being tested as new antidepressants and antianxiety medications, work optimally at different doses in males and females. These findings, in addition to our, data suggest that treatment plans for stress disorders should first consider the sex of the patient and then potentially the hormonal cycle in women.

At the end of your piece, you mention other conditions, like attention-deficit/hyperactivity disorder, that are more commonly diagnosed in men but might not necessarily be more common in men. You also make the point that women report more adverse side effects to medicine than men. Do you think the NIH's new requirement has the potential to bring about a sea change in how we understand women's health?  

Currently, only a small portion of animal studies in neuroscience include females. This means that most of our medications are tested in male animals and therefore optimized for male biology. Thus, it is not surprising that women have more adverse drug reactions than men.

Additionally, the practice of testing drugs mainly in male animals means that there may be treatments that would work well in females that never make it to market because they are only tested in males. That the NIH is now requiring animal researchers to include sex as a biological variable will improve our understanding of basic biological processes in females. Additionally, by studying both sexes we can identify factors that increase risk or resilience for disorders, such as factors in females less likely to develop autism. This information can be used improve the diagnosis and treatment of brain disorders in both men and women.