Hormone Therapy for Depression: Evidence-Based Recommendations
Primary Recommendation
Hormone replacement therapy (HRT) is effective for treating depression specifically in perimenopausal and early postmenopausal women (under age 60 or within 10 years of menopause) who have concurrent vasomotor symptoms, but it is NOT recommended as a primary antidepressant treatment for general depression or for women beyond this therapeutic window. 1, 2
Clinical Context: When Hormones Help Depression
Menopausal Depression with Vasomotor Symptoms
Estrogen therapy demonstrates significant antidepressant effects in perimenopausal and early postmenopausal women, with meta-analytic data showing an effect size of 0.69, meaning the average treated patient had lower depressed mood than 76% of control patients 3
The antidepressant benefit is strongest when depression co-occurs with hot flashes, night sweats, or other menopausal symptoms, as HRT addresses both the hormonal withdrawal and mood disturbance simultaneously 1, 3
Transdermal estradiol 50 μg daily (changed twice weekly) combined with micronized progesterone 200 mg at bedtime is the preferred regimen for women with an intact uterus experiencing both menopausal symptoms and depressed mood 1
Timing Is Critical: The Therapeutic Window
HRT for mood benefits must be initiated within 10 years of menopause onset or before age 60 to maintain a favorable risk-benefit profile 1, 4
Starting HRT more than 10 years after menopause or after age 60 increases cardiovascular risks (7 additional CHD events, 8 more strokes, 8 more pulmonary emboli per 10,000 women-years) that outweigh any mood benefits 4
Women who discontinue HRT after prolonged use face a 2.63-fold increased risk of developing new depressive symptoms, suggesting that stopping treatment requires careful monitoring and potentially transitioning to conventional antidepressants 5
Hormone-Specific Antidepressant Effects
Estrogen Alone
Estrogen monotherapy shows the most robust antidepressant effects (effect size 0.69) and is appropriate for women without a uterus 3, 2
Estrogen's mood benefits derive from both peripheral endocrine effects and direct CNS actions on non-endocrine brain circuitry, including modulation of serotonergic systems 2
Progesterone Considerations
Adding synthetic progestins (particularly medroxyprogesterone acetate) reduces the antidepressant effect of estrogen (effect size drops from 0.69 to 0.45) and may actually worsen mood in some women 3
Micronized progesterone is strongly preferred over synthetic progestins as it has lower rates of mood disturbance while still providing endometrial protection 1
Transdermal estradiol combined with synthetic progestin specifically increases risk of incident depressive symptoms (OR 1.59) in elderly women, making this combination particularly problematic 5
Testosterone Augmentation
- Testosterone alone or combined with estrogen shows the strongest antidepressant effects (effect sizes 1.37 and 0.90 respectively) in research settings, though this is not part of standard clinical guidelines 3, 2
Gender-Affirming Hormone Therapy and Depression
Transgender Populations
Gender-affirming hormone therapy (GAHT) consistently improves depression in transgender individuals, with systematic reviews showing a 20% decrease in depression after 1 year of treatment in both trans men and trans women 6
Trans men on testosterone therapy show quality of life improvements of 5.5 points on a 10-point scale after 1 year, with no evidence of adverse mental health outcomes from hormonal therapy 6
The mental health benefits of GAHT in transgender people stem from alignment of physical characteristics with gender identity, not from direct neurochemical antidepressant effects, making this a distinct clinical scenario 6
When NOT to Use Hormones for Depression
Absolute Contraindications
Never initiate HRT for depression in women with: history of breast cancer, coronary heart disease, prior venous thromboembolism or stroke, active liver disease, or antiphospholipid syndrome 1, 4
Do not use HRT as primary treatment for major depressive disorder in women without menopausal symptoms, as conventional antidepressants have superior efficacy and safety profiles in this context 2
Avoid initiating HRT in women over 60 or more than 10 years past menopause, even with depression, due to unfavorable cardiovascular risk profile 4
Clinical Scenarios Requiring Conventional Antidepressants
For postmenopausal women with depression but no vasomotor symptoms, use SSRIs, SNRIs, or other standard antidepressants as first-line treatment rather than HRT 7, 2
When depression is severe (Hamilton Depression Rating Scale >15), combination therapy with HRT plus fluoxetine is more effective than HRT alone (5-point greater reduction in HAMD scores), but conventional antidepressants should still be the primary treatment 8
Practical Treatment Algorithm
Step 1: Assess Menopausal Status and Symptoms
If perimenopausal or <10 years postmenopausal with vasomotor symptoms AND depression: Consider HRT as it addresses both conditions 1, 3
If >10 years postmenopausal or age >60: Do not use HRT for depression; use conventional antidepressants 4, 7
If depression without menopausal symptoms: Use conventional antidepressants as first-line 2
Step 2: Screen for Contraindications
Verify absence of: breast cancer history, cardiovascular disease, thromboembolism history, liver disease, antiphospholipid antibodies 1, 4
If contraindications present: Use SSRIs/SNRIs, gabapentin, or cognitive behavioral therapy for both mood and vasomotor symptoms 7
Step 3: Select Appropriate Regimen
With intact uterus: Transdermal estradiol 50 μg twice weekly + micronized progesterone 200 mg nightly 1
After hysterectomy: Transdermal estradiol 50 μg twice weekly alone 1
If depression severe: Add fluoxetine or other SSRI to HRT regimen 8
Step 4: Monitor and Reassess
Evaluate mood response at 6-12 weeks using validated scales (Hamilton Depression Rating Scale or similar) 9, 8
Plan for shortest duration necessary, typically until age 51 (average menopause age) for surgical menopause, then reassess 1
If discontinuing HRT after prolonged use, monitor closely for depression recurrence (2.63-fold increased risk) and consider transitioning to conventional antidepressants 5
Critical Pitfalls to Avoid
Do not prescribe HRT as a primary antidepressant in women without menopausal symptoms – conventional antidepressants are more appropriate 2
Do not use synthetic progestins (medroxyprogesterone acetate) when mood is a concern – they attenuate estrogen's antidepressant effects and may worsen depression 3, 5
Do not initiate HRT for depression in women beyond the 10-year/age-60 window – cardiovascular risks exceed any mood benefits 4
Do not abruptly discontinue HRT in women using it long-term without depression monitoring – risk of new-onset depression increases significantly 5
Do not assume all hormone formulations have equal mood effects – estrogen alone is superior to estrogen-progestin combinations for depression 3