Researchers at UF Health have identified fundamental differences in how males and females respond to stress. Their study could revolutionize treatment approaches for anxiety and depression, facilitating gender-specific therapies.
A new study led by University of Florida Health researchers has unveiled critical differences in how males and females respond to stress, offering pivotal insights that could shape future treatments for anxiety and depression.
The brain produces a neurosteroid known as allopregnanolone (AP) in response to acute stress, a brief yet intense reaction to sudden challenges or threats. Elevated levels of AP are essential for the body’s initial stress response, aiding in rapid adaptation and regulation of reactions during events such as imminent danger.
At the heart of this process is an enzyme called 5α-reductase (5αR), existing in two principal forms: 5αR1 and 5αR2.
The researchers used animal studies to explore how these enzymes operate, illuminating biological disparities between male and female stress responses.
“Men, in general, tend to have a greater propensity to display outward, aggressive reactions to acute stress, whereas women have a much greater tendency to internalize their responses,” senior author Marco Bortolato, a professor of pharmacodynamics in the University of Florida College of Pharmacy, said in a news release. “This distinction is believed to contribute to the higher female prevalence of anxiety and depression.”
Published in Science Advances, the study highlights that acute stress raises levels of 5αR2 — but not 5αR1 — in the frontal brain region of male laboratory rats. Female rats didn’t show similar changes, indicating a notable sex-specific difference in stress management at the molecular level.
The enzyme 5αR2 plays a crucial role in producing AP during stress, whereas 5αR1 helps maintain baseline levels of this neurosteroid.
The researchers found that reducing 5αR2 in male rats resulted in diminished engagement and slower responses to both stress and rewarding stimuli. However, administering AP restored their responsiveness, underscoring the enzyme’s importance.
“Our research sits at the intersection of stress response and sex differences, which have major potential implications for personalized medicine,” Bortolato added. “For instance, understanding why women are more susceptible to depression than men allows us to tailor more targeted treatments. Ultimately, these findings could help guide the development of drugs that specifically modulate stress responses.”
Bortolato expresses optimism about translating these findings into new medications, potentially creating a novel class of steroid-based compounds to treat depression resistant to current therapies.
“Depression is the leading cause of disability worldwide, largely due to increasing levels of chronic stress,” added Bortolato. “Conventional antidepressants often take two to four weeks to show initial results. Conversely, AP-based treatments could have much faster effects. Enhancing our ability to produce AP could transform the way we approach depression and other stress-related disorders.”