⬇️ Prefer to listen instead? ⬇️
- 🧠 Estrogen in men, specifically via estrogen receptor beta (ERβ), plays a critical role in stress resilience.
- ⚠️ Loss of ERβ in male mice leads to depression-like behaviors after mild stress, while females remain unaffected.
- 💊 DHED, a brain-specific estrogen compound, restored stress resilience without feminizing side effects in male mice.
- 💡 Testosterone’s antidepressant effects may stem from its conversion into estrogen, not from testosterone itself.
- 🧬 Future antidepressants may target ERβ to address depression in men with fewer systemic risks.
Estrogen’s Unexpected Role in Men’s Mental Health
For a long time, testosterone has been the main focus in men’s mental health. People often assume it protects men from depression, seen in talks about “low T” and hormone therapies sold as mood boosters. But a new study suggests this idea might be wrong. Research in Molecular Psychiatry shows that estrogen, specifically 17β-estradiol working through estrogen receptor beta, may be very important for men to handle stress well. This finding helps us understand how hormones affect the brain. It also points to new ways to treat depression in men that could be safer and more specific.
Estrogen in Men: Not Just a “Female Hormone”
People usually think of estrogen as a hormone for female reproduction. But this idea is too limited and old. Men also make estrogen. Even though their levels are much lower than in women, estrogen is very important, especially in the brain. In men, most testosterone that moves through the body changes into 17β-estradiol. This happens locally by an enzyme called aromatase, mainly in the brain’s limbic areas. These areas handle emotion, memory, and how we feel rewarded.
This chemical change has strong effects on feelings and thinking. Research shows that estrogen in the male brain helps with brain changes, mood control, and how brain connections work. It also helps reshape brain pathways for memory and learning. Estrogen in men is not just a side product of testosterone. It is an important chemical that affects how men deal with their surroundings, including stress.
Trouble with this testosterone-to-estrogen change may cause mood problems. This helps explain things about male mental health that we did not understand before.
Estrogen Receptor Beta (ERβ): The Molecular Gatekeeper
How estrogen works in the brain largely depends on how it attaches to its receptors. Estrogen receptor beta (ERβ) is very important here. This receptor shows how estrogen signals turn into brain activity. ERβ is found in many brain areas, like the amygdala, hippocampus, and prefrontal cortex. These areas do a lot of work in controlling emotions and reacting to stress.
The recent Molecular Psychiatry study found that male mice without ERβ were much more prone to mild social stress. These mice showed clear signs like depression, such as avoiding others and not enjoying things. This connects ERβ directly to how well male subjects handle stress. Surprisingly, female mice without ERβ did not show these changes. This showed an interesting difference in how hormone receptors work between sexes. It means males and females might manage stress in different ways that developed over time.
This has a big meaning for human health. Standard antidepressants might not deal with these sex-specific ways the body works. This could explain why some treatments do not work as well for men or women, depending on their symptoms and hormone levels.
The Two-Hit Model: Hormone Loss + Social Stress
To understand how complicated mental health problems are in the real world, researchers used what they call the “two-hit” model in their studies. Depression in real life often comes from a mix of inner weaknesses and outside stresses. This model shows that well.
First hit: The researchers took out the testes from adult male mice (orchiectomy). This removed their testosterone and, so, the estrogen made from it.
Second hit: These mice, now without hormones, then faced mild social defeat stress. This stress usually would not cause lasting behavior changes in healthy animals, but here it was the important second blow.
The results were strong. Only mice that had both hormone loss and mild stress showed clear signs of depression. These signs included avoiding social contact, having less interest in female mice, and not looking for rewards. These behaviors were like human symptoms such as pulling away from others and not feeling pleasure.
This two-hit model clearly shows how inner factors (like hormones) and outer factors (like the environment) combine. They affect how likely men are to get depression. It shows how important estrogen is in men.
Key Brain Circuitry: From Amygdala to Accumbens
Looking closely at the brain’s structure, the study found a key brain pathway that helps with stress resilience. This pathway goes from the basolateral amygdala (BLA) to the nucleus accumbens (NAc). Both of these areas are very important for handling emotions. The BLA deals with things that threaten or stress us, and the NAc controls motivation and reward. These are main parts that often do not work right in depression.
What is interesting is that ERβ is found a lot within this BLA→NAc circuit. Using methods like optogenetics (controlling brain cells with light) and viral tracing, scientists turned on this brain pathway. They saw that male mice showed more reward-seeking behavior. Simply put, making this circuit active made the experience enjoyable. It also kept the mice safe from depression-like signs caused by stress.
But if they blocked or turned off this pathway, especially in mice without hormones, this natural protection was gone. This made the mice more at risk for stress.
This gives important information about how brain pathways specific to males, linked to estrogen, can either lessen or make mental health risks worse. Knowing about these circuits could lead to new therapies that target specific circuits. It could also lead to imaging methods that predict or find depression.
From Mice to Men: What’s the Clinical Potential?
These studies were done in mice, but what they mean for human males is very important. The basic ways hormones work and brain circuits operate, like how testosterone changes to estrogen and how estrogen receptors appear, are similar across all mammals, including humans.
Men with low testosterone, maybe from getting older, medical treatments, or hormone problems, might have low estrogen levels in their brains without knowing it. This lack could make them more prone to mental health problems caused by stress, like major depression.
This animal model sets the stage for human studies that look at:
- Estrogen levels in men with depression
- Different gene types in ERβ receptors
- Brain scans of the BLA→NAc pathway when people do tasks that challenge their emotions
Also, this new way of thinking about hormones prompts mental health care to add to how we diagnose problems. Later, tests that check hormone levels could be as normal as checking for serotonin problems or doing gene tests to see if an antidepressant will work.
A Brain-Selective Solution: The Promise of DHED
An important step in treatment is finding DHED (10β,17β-Dihydroxyestra-1,4-dien-3-one). This is a type of drug that changes into 17β-estradiol only in the brain, not in other parts of the body.
Why does this matter? Standard estrogen treatments have risks. These include weight gain, breast growth (gynecomastia), heart problems, and even prostate issues in men. But DHED avoids changes outside the brain. It works only inside brain tissue. So, it may give the mood benefits of estrogen without unwanted female-like side effects or problems throughout the body.
In the study, giving DHED to male mice that lacked hormones helped them handle stress again. It also kept their behavior normal, even when they faced social stress. This approach gets us closer to making safe, tailored treatments for depression in men caused by hormone problems.
This looks especially good for:
- Older men with lower testosterone (and, because of that, lower brain estrogen) levels.
- Men with mood problems tied to hormone cancer treatments (like for prostate cancer).
- Young men with hypogonadism who want other options instead of risky testosterone therapy.
Testosterone Therapy: Risks Without Clear Mental Health Rewards
Testosterone replacement therapy (TRT) is a common choice for men with depression, tiredness, or irritability. But it also causes debate. The science behind how well it treats mood problems is not clear. Some patients say they feel better, but big studies and reviews show mixed results. They also cause serious worries about long-term safety.
TRT can cause:
- A higher risk of heart problems
- A larger prostate and pee problems
- Acne and changing moods
- Problems with being able to have children because of shrinking testicles
- Breast growth due to hormone imbalance
Here is an interesting point: the study showed that testosterone’s protection against stress in mice relied on it changing into estrogen. When researchers stopped aromatase, the enzyme that turns testosterone into 17β-estradiol, the good effects disappeared.
So, the true antidepressant might not be testosterone itself. It could be the estrogen made from it in the brain. This idea changes the main thinking behind TRT. It suggests we should look at treatments like ERβ modulators or DHED instead. These treatments more directly and safely use the real protective things that are at work.
Better Antidepressants for Men? ERβ Modulators on the Horizon
Standard antidepressants, like SSRIs and SNRIs, often do not work well for many men. This might be because they do not deal with how hormones and the brain work together differently for men and women. The ability to make drugs that work only on ERβ leads to new treatment possibilities.
By making molecules that turn on ERβ, but not ERα or other estrogen receptors outside the brain, we can:
- Lessen side effects like getting female-like traits or hormone problems throughout the body
- Aim at the emotional and motivation pathways that are specific to male depression
- Give a safe, hormone-based choice for men whose depression does not respond to other treatments
These medicines could eventually make antidepressant plans more personal. They could be based on hormone levels, how sensitive receptors are, or biological sex. This would bring about more exact mental health care.
Stress and Sex Differences in the Brain
We know that biological sex differences in how people react to stress are common, but doctors do not often deal with them in treatments. The study shows clearly that ERβ works differently depending on sex. In males, turning it on protects them. In females, not having ERβ actually made them stronger.
This means that treating depression with one method for everyone is not only old-fashioned but could also be bad. Some strategies may need to be made for specific sexes. They should consider differences in both how hormones work and brain structure.
Understanding why these differences came about over time is still something to research. But for now, this finding should prompt more studies that look at sex-specific issues in brain science and mental health.
Shifting the Hormonal Conversation
The false idea that estrogen does not do anything in male bodies has slowed down science. It has also added to the shame men feel. Many men link hormone problems with being weak or less masculine. This makes it harder for them to get help and talk openly.
New research shows that estrogen helps with important parts of male strength, drive, and even who they are. Thinking of estrogen as a hormone that supports male traits, instead of one that threatens masculinity, can do a lot of good. It can make health results better and remove the shame around men showing their feelings.
Mental health is not about stopping natural body processes. It is about working with them.
Toward a New Way of Thinking
These findings really question common ideas about hormones and mental health. Estrogen in men, once ignored, is now showing up as a strong controller of emotions and how well men handle stress. The finding that ERβ has a main part in male emotional health leads to new paths in mental health care, drug science, and how society understands things.
Future research may help create:
- Blood tests or brain scans to find depression linked to hormones
- Estrogen-like drugs that target the brain, like DHED
- Antidepressants that work only on ERβ. These would treat the main cause of stress risk in men.
With more knowledge and exact science, we are close to a new time in male mental health. This is a time where biology, not old ideas, guides how we treat problems.
Citations
Georgiou, P., Postle, A. F., Mou, T.-C. M., Potter, L. E., An, X., Zanos, P., Patton, M. S., Pultorak, K. J., Clark, S. M., Ngyuyen, V., Powels, C. F., Prokai-Tatrai, K., Kirmizis, A., Merchenthaler, I., Prokai, L., McCarthy, M. M., Mathur, B. N., & Gould, T. D. (2024). Estradiol, via estrogen receptor β signaling, mediates stress susceptibility in the male brain. Molecular Psychiatry. https://doi.org/10.1038/s41380-025-03027-8
