Scientists don’t really get the female brain

Science tells us that female and male brains are different yet biomedical research is largely conducted on males, as if they’re a neutral stand-in for the human population as a whole.

The problem is, female brains can have starkly different neuroimmune responses from males. And our lack of basic understanding is having a very real impact on women and their health.

For example, of a sample of 10 drugs withdrawn in the US between 1997 and 2001, eight affected women more severely due to differing impacts of the drugs on female bodies or usage differences between men and women.

And even though older women are more at risk of suffering cognitive impairments like Alzheimer’s and dementia, the vast majority of research in this field is done on males.

Now a comprehensive international review on the neuroimmunology of the female brain has been published in Brain, Behaviour and Immunity.

Associate Professor Sarah Spencer and co-authors from the US and UK examined what we know about the unique aspects of the female brain.

“While it’s an under-researched field, we were happy to find that it is growing, as scientists realise its importance – not just to female health but human health overall,” she says.

Spencer – a Principal Research Fellow at RMIT and Head, Neuroendocrinology of the Obese Brain Research Group – breaks down the key findings.

The resilient female brain

The female brain is remarkably dynamic, responding uniquely to the early life environment, aging and various life stages in between.

In early life, the female immune response seems to have a special protective effect that’s missing, or at least very different, in males.

For example, prenatal diesel particulate exposure coupled with early life stress leads to an elevated inflammatory response in the male brain. But in the female brain, the same double-hit has an opposite effect, leading to elevations in anti-inflammatory cytokines.

Spencer says this suggests the immune system response in the female brain may actually buffer against later behavioral effects by activating anti-inflammatory pathways.

Early life inflammation is a risk factor for neurodevelopmental disorders, such as autism spectrum disorders, schizophrenia, attention deficit hyperactivity disorder (ADHD), and Tourette’s syndrome. But most of these disorders affect females at a much lower rate than males.

So what do girls have that boys lack?

“If we were able to pinpoint this, and understand the factors that contribute to female resilience to early life inflammatory events, it would be a major breakthrough for neurodevelopmental disorder prevention and treatment across both sexes,” Spencer says.

Ageing and adverse effects

While the female brain in early life shows greater resilience, ageing seems to bring a harder hit, Spencer says.

Women with mild cognitive impairments show deteriorating cognitive function at a rate twice as fast as men. Older women are also twice as likely as men to exhibit long-lasting post-operative cognitive dysfunction; have poorer outcomes following stroke than men and are more likely to suffer from Alzheimer’s disease and other dementias.

But although over half of the aging population is comprised of females, the vast majority of basic research on aging, neuroinflammation, and cognitive decline has been conducted using only male subjects.

“This disproportionate focus on the male brain is unjustified and troubling because women are more at risk of suffering cognitive impairments – and we don’t really understand why,” Spencer says.

“There is growing evidence this vulnerability is markedly influenced by changes in sex steroid hormone levels associated with advanced age, but we know little about the mechanisms underlying these sex differences.”

Hormone cycles and pregnancy

The female brain is highly sensitive to hormonal fluctuations across the ovarian cycle and at life stages of hormone withdrawal. This can affect the efficacy of treatments.

There is also still a lot we do not understand about the neuroimmune adaptations that occur in pregnancy, the authors say. Of particular interest is the potential for these adaptations to go wrong, potentially predisposing women to postpartum mood disorders.

“Enhancing our understanding of the impact of neuroimmunological adaptations in pregnancy and post-partum on mood is critical for strategies to prevent and treat pregnancy-related mood disorders,” Spencer says.

Female cancer effects on brain

Later life stages can also change the female brain in specific ways. As a woman ages she has increased risk of developing sex hormone-dependent diseases like cancer, including breast cancer, the most common malignancy in women.

Overall, the authors find there’s a lack of understanding of how menopause and long-term endocrine, chemotherapy, and radiation treatments may influence the brain to cause anxiety or depression in cancer patients.

Female-specific sex hormones influence cancer development and the cognitive consequences that ensue, yet our understanding of those neuroimmune interactions remains poor.

Even when scientists are looking at female-specific cancer effects on the brain, the research models aren’t perfectly suited to the job. For example, most breast cancer patients are post-menopausal and middle aged, whereas most neurobiological work in this field is performed in young adult rodents with functioning ovaries.

Better research, better outcomes

Until very recently, there has been a conspicuous paucity of research focusing solely on females. For example, with the exception of reproductive topics, female-only studies accounted for 20% or fewer of the papers published in 2009.

“This blinkered approach to research has resulted in a fundamental limitation in our understanding of the female brain, with problematic health and economic consequences,” Spencer says.

As our understanding of female psychoneuroimmunology progresses, so will our capacity to:

• tailor drug delivery systems to accommodate monthly and even circadian sex hormone fluctuations;
• prevent pre-term birth by strategically enhancing a woman’s adaptive neuroimmune responses to pregnancy;
• identify and mimic how females are relatively protected against early life challenges.

While the authors acknowledge that studying the female brain may pose some additional challenges to researchers – especially those associated with hormonal cycles and behavioral variability – they argue that these are not insurmountable.

“Understanding something as dynamic, vulnerable, and resilient as the female brain presents one of the next great frontiers for science.”

This article was first published on Australia’s Science Channel, the original news platform of The Royal Institution of Australia.