A new study of nearly 125,000 women is one of the largest ever to examine menopause and HRT (hormone replacement therapy), looking at how both relate to mood, sleep, cognition, and brain structure. Published in Psychological Medicine in January 2026, the research is striking in scale — and careful in what it claims. It found an association between HRT use and mental health symptoms, but cannot infer cause and effect.
What the researchers did, and what they found
A University of Cambridge team, led by Katharina Zühlsdorff and Barbara Sahakian, analyzed UK Biobank data. They divided 124,780 women into three groups: pre-menopausal women, post-menopausal women who had never used hormone replacement therapy (HRT), and post-menopausal women who had used it. Participants answered questionnaires about mood, sleep, and health. Many completed cognitive tests. A subset of nearly 11,000 women also had brain MRI scans.
Post-menopausal women reported more anxiety and depression than pre-menopausal women. They were more likely to have seen a general practitioner (GP) or psychiatrist for these symptoms. They were also more likely to have a formal diagnosis of depression or anxiety. That tracks with existing research linking menopause to mood changes.
The unexpected finding: women taking HRT reported more mental health symptoms than post-menopausal women not on it. Sleep followed a similar pattern. Post-menopausal women generally slept less and reported more insomnia. The HRT group reported the most tiredness of all three groups.
Women taking HRT reported more mental health symptoms than post-menopausal women not on it.
Brain scans showed something parallel. Post-menopausal women had smaller volumes than pre-menopausal women in three regions:
- The hippocampus, key for memory
- The entorhinal cortex, which relays information to the hippocampus
- The anterior cingulate cortex, involved in emotion regulation
These reductions were largest in the HRT group. Memory test scores, though, barely differed between groups, and reaction times were only slightly slower in non-HRT women.
In short: the study found associations between menopause and HRT use, and several markers of brain and mental health. The group of women using HRT had more mental health symptoms and lower brain volumes.
Why the HRT group fared worse
The researchers anticipated an obvious objection: maybe HRT doesn’t worsen mental health, maybe women with worse mental health are simply more likely to be prescribed it. They tested this using a smaller group of women who started HRT between two assessment visits, years apart. Women who later started HRT had already reported more GP and psychiatrist visits for anxiety or depression before treatment began.
That finding suggests doctors may prescribe HRT in response to, or in anticipation of, mental health struggles already present. The study’s authors acknowledge this directly. They write that it remains uncertain whether HRT users’ symptoms would have been worse without treatment.
Because this is an observational study, not a clinical trial, the design can’t fully resolve that question. No one was randomly assigned to take HRT. The findings are associations, not causes.
What outside experts said
The UK-based Science Media Centre collected reactions from researchers not involved in the study. Professor Ciara McCabe of the University of Reading addressed the question of causation directly. The findings, she said, argue against the idea that HRT causes depression, since women with higher pre-existing symptoms appear more likely to receive a prescription. Longitudinal studies that track the same women over time are still needed, she added.
Professor Channa Jayasena of Imperial College London raised a related concern. Women who are prescribed HRT tend to be those with more severe menopause symptoms. That means the HRT and non-HRT groups are not comparable at the starting point. So even if HRT helped, the HRT group might still look worse on paper than women who never needed it in the first place. Jayasena’s point is that this makes it hard to draw conclusions about HRT’s effectiveness from this kind of data.
These concepts have support. While hot flashes and other vasomotor symptoms are common, menopause also brings memory and mood disturbances to some women. In fact, research has shown that the menopause transition is related to significant increases in depression and bipolar disorder in women. And longitudinal studies designed to determine whether HRT impacts mental health are being published. For example, two recent studies of the same women before and after taking modern hormone formulations reported significant improvements in mood and cognition (for details, see our post on menopause and mental health).
What this means if you’re weighing menopause and HRT
This study adds weight to the idea that menopause coincides with real changes in mood, sleep, and certain brain regions. It does not show that HRT causes or worsens those changes. The women who ended up on HRT in this dataset already looked different before treatment started, in terms of mental health.
The study also does not control for the type of HRT evaluated, which we now know makes a difference to long-term health. The bottom line is that a large snapshot comparison can’t separate cause from selection. It’s a reason to read studies like this one carefully.
We do know that mood and brain health can decline during the menopause transition. Modern HRT — using transdermal estradiol, micronized progesterone (for women with a uterus), and testosterone — can provide relief of physical and psychological symptoms for many women.
Dr. Christelle Langley, one of the study’s authors, offered another practical note. Staying active and eating well can help during menopause, regardless of HRT use. She also encouraged more openness about the mental health side of menopause.
See our project on hormones for menopause, and our other news articles about menopause.
