The evidence is real, but the benefit is modest
STUDY: Li Y et al, Journal of Affective Disorders 2026; doi:10.1016/j.jad.2026.121892
STUDY TYPE: Systematic review and meta-analysis
FUNDING: Independent
Background
Depression rates nearly double during perimenopause. It’s not the low levels but the fluctuations in estrogen that are the culprit, disrupting serotonin and dopamine and worsening mood. This meta-analysis looked at the research on hormonal therapies.
The Study
- 12 randomized controlled trials (n = 835) comparing hormone replacement therapy to placebo
- In perimenopausal women with depressive symptoms (not necessarily full depression)
- Most trials used estrogen-based regimens, with treatment durations ranging from 8 weeks to 12 months
- Primary outcome = change in depressive symptom severity on validated rating scales.
Hormone therapy was associated with a small but statistically significant reduction in depressive symptoms compared to placebo (effect size 0.23, 95% CI −0.43 to −0.03). Tibolone, a synthetic steroid with estrogenic, progestogenic, and androgenic activity, showed a larger effect (0.56), though this is based on only two trials (intriguing, but not practice changing). Estrogen-only regimens showed a smaller, non-significant effect (0.13).
Route of administration didn’t matter; oral and transdermal routes performed similarly. Adding an antidepressant to hormone therapy didn’t clearly outperform hormone therapy alone.
Side effects were generally mild: breast tenderness, headache, nausea, and skin irritation, with few discontinuations.
Limitations: Most trials were small, methodologically variable, and conducted over a short period. The overall GRADE certainty is low, and the confidence interval for the primary outcome just barely cleared zero. Only two small trials tested estrogen in clinical depression (with positive results).
Practice Implications
- The effect size is small, but meaningful for some women and may bring relief for physical symptoms as well.
- Here’s another recent review of the timing, dosing, and how to coordinate with OBGYN or PCP.
- Learn more about where hormones fit in depression treatment, including HRT, testosterone, and thyroid in Difficult to Treat Depression.
— Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
