Stressed Out

by Mind Over Matter V 14:

Does Sex Make a Difference?

Stress is a normal response to situational pressures or demands, especially if they are perceived as threatening or dangerous. Our bodies are hard-wired to react to stress in ways that are meant to protect us from predators and other aggressors. Although such threats are rare today, that does not mean that life is free of stress. On the contrary, stress is commonplace in modern life. 

Typical sources of stress include a person's physical environment (e.g., noisy streets or an unsafe living space), work, relationships, and major life changes (e.g., experiencing financial difficulties, falling ill, or caring for a sick loved one). While stress can be brief and even a motivating force, if experienced over an extended period of time it can become chronic stress, which adversely impacts our overall health and well-being.

Chronic Stress

Chronic stress is defined as a stressor that is “long-term, something that persists days, weeks, and even years,” explained Dr. Tracey Shors, Distinguished Professor in Behavioral and Systems Neuroscience at Rutgers University and the author of the 2021 book entitled Everyday Trauma: Remapping the Brain’s Response to Stress, Anxiety, and Painful Memories for a Better Life. 

“A chronic stressor is, in addition to being persistent, also unpredictable and uncertain. Part of the stress comes from not knowing what’s going to happen in the future.”  

A chronic stressor can have physical, chemical, environmental, or psychological roots, but “the basic definition is the physiological response to these with the production of a stress hormone called cortisol,” added Dr. Jill M. Goldstein, Professor of Psychiatry and Medicine at Harvard Medical School and Founder and Executive Director of the Innovation Center on Sex Differences in Medicine at Massachusetts General Hospital. 

Cortisol is created via a pathway in the brain called the “hypothalamic-pituitary-adrenal axis” (or the HPA axis) and this axis in the brain is what regulates how we respond to stress. 

Some acute (or short-term) stress can help us make necessary changes, learn something new, or, in the case of exercise, create stronger muscles, heart, and brain function. However, when stress is negative and chronic, it is problematic. “It affects every chronic disease we know,” said Dr. Goldstein, including psychiatric and neurological conditions. 

Sex Differences 

Women and men both experience chronic stress, but the impact of it can differ in the way that it presents itself behaviourally, in the onset of particular diseases, or how resilient individuals are to its effects. Over the last 30 years, researchers have begun to examine how the differences in women’s and men’s brains affect long-term brain health outcomes, including anxiety and depression (which women are twice as likely to be diagnosed with during the lifespan), and dementia and Alzheimer’s disease (where two-thirds of those with Alzheimer’s are female). 

While women’s and men’s brains are largely similar in composition, researchers have found that the small differences in how the brain develops and functions could be contributing to why women are more susceptible. 

Brain regions such as the hypothalamus and the amygdala – which are activated during chronic stress – are highly sexually dimorphic, and “these brain regions develop differently in the male and female brain and, in part, function differently across our lifespan,” explained Dr. Goldstein. “These modest differences are associated with substantial disease risk differences,” and getting to the crux of why this occurs is part of the reason Dr. Goldstein founded the Innovation Center on Sex Differences in Medicine.

One avenue of research that is beginning to gain traction is how individuals respond to chronic negative stress and how women and men respond differently. In January of 2021, Dr. Goldstein and her colleagues published a call-to-arms article in JAMA Psychiatry that stressed the importance of studying sex differences in brain and heart diseases (such as depression, cardiovascular, and Alzheimer’s disease) that co-occur frequently and for which women are at higher risk. In fact, the origins of these co-occurrences and the sex differences therein may begin in prenatal development.

In a recent study published by Dr. Goldstein and her colleagues in the April 2021 issue of Proceedings of the National Academy of Sciences of the United States of America, the researchers found that maternal prenatal negative stress was significantly associated with sex differences in the offspring’s response to negative stress over 40 years later, with women affected more severely, regardless of diagnosis.

What else is currently known about how chronic stress affects the brains of women and men differently? Like most things to do with our intricate bodies, the answer is not simple. “There is no one factor. It’s X, Y, Z, and a few other things,” said Dr. Shors. Hormones do play a part. 

“We know that many of the stress-related mental conditions – like depression, anxiety, and post-traumatic stress disorder – arise as women start to menstruate.” 

We also know that the reduction of certain hormones like estradiol (the primary form of estrogen that works in the brain) during menopause sometimes has “implications for our memory performance,” said Dr. Goldstein.

Chronic stress can impact brain function and structure over the course of our lifespan. The regions in the brain that regulate stress are some of the same regions that are involved in our immune and cardiovascular systems implicated in chronic diseases. Also, some of the same HPA axis regions regulate the release of our sex hormones (estrogens, progesterone, and testosterone). So, chronic stress affects hormonal, immune, and cardiovascular regulation. 

Better understanding these relationships will help researchers determine why chronic stress affects diseases of the brain and heart. In the future, the goal is to develop “sex-dependent therapeutics,” said Dr. Goldstein – whether that is pharmaceuticals, devices, and/or programs of action – that will be sensitive to the specific health concerns of women and men across the lifespan.

Beyond hormones, the negative effects of chronic stress (like depression and anxiety) are likely more detrimental for women than men, in part, due to the way “women experience society,” noted Dr. Shors. Women historically (and still today) have less control, whether it is over their own safety, housing, or finances. One in three women experience physical or sexual abuse. What’s more, women tend to ruminate more than men.

“Women tend to have repetitive, often negative, thoughts about what happened in the past or wishing things had been different.” 

Part of the reason Dr. Shors wrote her book was to educate people – especially women – that our brains are creating these thoughts, images, and memories. “I think people think their thoughts are these passive, supernatural events, but they’re not. They’re created by your brain,” explained Dr. Shors. These repetitive, negative thoughts can contribute to the prevalence of mental illness and actually change the brain. 

In one study of rumination (i.e., the process of continuously thinking about the same idea, event, or situation) conducted by Dr. Rebecca Cooney and colleagues, published in the December 2010 issue of Cognitive, Affective, & Behavioral Neuroscience, the researchers used functional magnetic resonance imaging (fMRI) scans in depressed and healthy individuals and gave them a ruminative task to focus on.

The depressed participants exhibited more activity in neural regions that are overactive in depression during the rumination task, suggesting that the brain does change through certain patterns of thinking. Social and behavioural factors, along with the biological differences previously noted, make women more vulnerable to particular forms of mental illness and brain diseases.

Readers of Mind Over Matter® will know that dementia and Alzheimer’s disease (AD) are complex issues, and that AD is a biological disease process that has a “specific profile under the microscope, the neurofibrillary plagues and tangles tau,” said Dr. Shors. While researchers have not yet established the cause(s) of AD, we do know that there are many risk factors – sex being one of them. There are also several hypotheses regarding the origin of AD, from one’s genes to quality of social interaction and certain other lifestyle factors. 

One group of researchers have hypothesized that the different biochemical responses to stress between women and men may contribute to the sex disparity in AD prevalence (this hypothesis was published in the February 2018 issue of Neurobiology of Stress). Dr. Hongxin Dong, Professor of Psychiatry and Behavioral Sciences and Neurology at Northwestern University’s Feinberg School of Medicine, and one of the co-authors of the paper, noted that “stress, anxiety, depression, and AD may have some intrinsic link,” and while hormones play a role, more research is needed to determine the exact mechanisms. Future study needs to focus on how to treat traumatic injuries early, for example, to curtail prolonged chronic stress responses in the brain and body.

What You Can Do to Counter Chronic Stress

No matter where you are in your life journey, research shows that taking action as soon as you can – especially in your forties and fifties – can improve brain health outcomes. Cardiovascular disease, diabetes, and depression, for example, are all major risk factors for AD. They can, in part, be modifiable with “diet, mindfulness strategies, psychological and pharmacological therapies, and exercise,” said Dr. Goldstein. 

Physical exercise, as well as brain training and activity, can also curtail negative brain outcomes and engaging in these activities early is critical.

“I’ve been adamant about training your brain for the future,” said Dr. Shors. To help do so, she developed a clinical intervention called “MAP Training” (or Mental and Physical Training), which combines mental training of the brain with physical training of the body. A number of studies conducted by Dr. Shors and her colleagues have demonstrated that individuals who engage in meditation practice, immediately followed by aerobic exercise, are less depressed, less anxious, and ruminate less. 

It is important to keep in mind, though, that consistency and effort are key. “Taking a walk is fine, but it is probably not going to change the brain demonstrably. You need to sweat. A little relaxation is fine, but if you really want to change your brain through mediation, you’re going to have to sit down and really work at it,” noted Dr. Shors. 

Dr. Shors also recommends engaging in what she refers to as “effortful learning.” Challenge yourself – “the brain really likes novelty,” observed Dr. Shors. “Learn new things, travel, take courses, meet new people. Work at it.” 

If you are approaching menopause or are early post-menopause, consider talking to your doctor about hormone replacement therapy (HRT). Although controversial in recent decades, the tide may be turning in favour of HRT during later perimenopause or early post-menopause to help maintain intact memory function (however, research about the timing and duration of HRT is still ongoing, cautioned Dr. Goldstein). While some women may not be good candidates for HRT, due in part to increases in certain kinds of hormone-dependant cancers, alternative strategies are being developed as well.

Like most things in medicine and science, research regarding chronic stress, sex differences, and brain health is still underway. In the meantime, learning techniques to reduce your stress levels can not only make you feel better in the short term, but may also help protect your physical and mental health and well-being in the long term.