The evidence is thin but promising — and the timing matters
STUDY: Xiang X et al, Medicina 2024;60:1076
STUDY TYPE: Literature review
FUNDING: Independent
Background
About a third of perimenopausal women develop depression — and antidepressants, the current first-line treatment, don’t address the hot flashes, insomnia, genitourinary symptoms, or bone loss that often accompany it. Hormone replacement therapy (HRT) treats those physical symptoms, and this review looks at whether it also treats depression.
The Review
The authors examined the mechanistic, efficacy, safety, and timing literature on HRT for perimenopausal depression.
Mechanism: Falling estrogen reduces serotonin and dopamine, triggers inflammation, lowers BDNF, and dysregulates the hypothalamic-pituitary-adrenal (HPA) axis — all established pathways in depression.
Efficacy: HRT improved depressive symptoms as monotherapy in three out of four small trials, and augmented antidepressants in two trials. It also improved sleep quality. All trials were small; only two involved a placebo control; most did not involve clinical depression.
Timing matters: HRT initiated during perimenopause — not years after — is where benefits are seen.
Dosing: Menopausal depression studies used 17β-estradiol (Estraderm) transdermal 0.05 mg/day with additional medroxyprogesterone acetate 10 mg/day for 1 week of every month
Safety: The data are mostly reassuring. No clear signal for endometrial cancer, cardiovascular disease, or breast cancer across multiple large trials. The exception is thrombosis and stroke — the picture is murkier, with risk appearing to vary by treatment duration, ethnicity, and baseline cardiovascular history.
Contraindications to HRT |
| History of estrogen-sensitive cancer (eg, breast, ovarian, or uterine) |
| Unexplained vaginal bleeding |
| History of deep venous thrombosis (DVT), pulmonary embolism, blood clotting disorder, or stroke |
| Conditions that increase the risk of stroke (uncontrolled hypertension or elevated triglycerides) |
Practice Implications
- Consider HRT for perimenopausal women who have depression and are also struggling with physical symptoms llke vasomotor symptoms, sleep, or genitourinary complaints.
- HRT is best managed by a specialist, who can better weigh its medical risks as monitor for excessive bleeding, fibroid growth, and blood pressure changes.
- If you think HRT is indicated, contact the OBGYN or other specialist to explain that other psychiatric treatments have not worked and ask if HRT is a possibility.
- To minimize the risks, they will often use HRT for a limited time, usually five years, although longer periods are becoming more common as more reassuring data has appeared.
- Learn more in our interview with Ruta Nonacs, MD, PhD in print or podcast.
—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
What’s Your Take? Share in Comments
- When do you recommend HRT in psychiatry?
