Can hormone therapy worsen mood or anxiety symptoms?

Can Hormone Therapy Worsen Mood or Anxiety Symptoms?

The answer depends critically on the type of hormone therapy: gender-affirming hormone therapy (GAHT) consistently improves depression and anxiety in transgender individuals, while postmenopausal hormone replacement therapy (HRT) can worsen mood symptoms, particularly during progestin phases of sequential therapy. 1, 2

Gender-Affirming Hormone Therapy (GAHT)

GAHT does NOT worsen mood or anxiety—it improves these symptoms. The evidence is clear and consistent:

• Gender-affirming hormone therapy decreases depression and anxiety levels following treatment initiation, with moderate strength of evidence. 1
• Systematic reviews demonstrate a 20% decrease in depression after 1 year of GAHT treatment. 2
• 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. 2
• GAHT may improve gender dysphoria and quality of life while lessening depression, anxiety, and suicidality—it is considered life-saving for many transgender individuals. 3

Clinical Context for GAHT

• The mental health benefits of GAHT are so substantial that up to 35% of transgender individuals would continue hormone therapy even if diagnosed with a hormonally dependent cancer. 3
• Cessation of gender-affirming hormones (such as for fertility treatment) can result in partial reversal of physical changes that worsens dysphoria and compounds pre-existing mental health issues. 3

Postmenopausal Hormone Replacement Therapy (HRT)

HRT can worsen mood and anxiety symptoms, particularly when progestins are added to estrogen in sequential therapy. The evidence shows a complex picture:

When HRT May Worsen Mood

• The progestogenic component in combined HRT potentially counteracts the beneficial influence of estrogens on mood and can even induce negative mood symptoms. 4
• Higher doses of estrogen (3 mg vs 2 mg estradiol) significantly accentuate negative mood symptoms during the progestin phase, including tension, irritability, and depressed mood (P < 0.001). 5
• Current use of HRT in perimenopausal and postmenopausal women is associated with worse psychological well-being and mental health compared to women not using HRT. 6
• Women with a history of premenstrual syndrome (PMS) are at particularly high risk for progestin-induced adverse mood effects during sequential HRT. 7

Personality and Risk Factors

• Women with high anxiety-related personality traits, history of PMS, higher scores of indirect aggression, irritability, and lower life satisfaction are more likely to experience adverse mood effects with combined estrogen-progestin therapy. 7
• These women report more somatic anxiety, aim to avoid monotony, and show less impulse control. 7

When HRT May Help Mood

• Estrogen-only therapy (in women post-hysterectomy) is effective in improving mood in perimenopausal women. 4
• HRT use is associated with significantly improved depressive symptoms when used alone or in addition to antidepressant medication (P < 0.001) in specialized menopause clinic populations. 8
• Micronized progesterone is strongly preferred over synthetic progestins as it has lower rates of mood disturbance. 2

Clinical Algorithm for Decision-Making

For Transgender Patients:

1. Initiate or continue GAHT as planned—it improves mood and anxiety. 1, 2
2. Monitor for expected improvements in depression and anxiety over 6-12 months. 2
3. Do not discontinue GAHT due to mood concerns unless other medical contraindications arise. 3

For Postmenopausal Women:

1. Screen for history of PMS, anxiety disorders, and personality traits (high anxiety, irritability, low impulse control) before initiating combined HRT. 7
2. If no uterus present: Use estrogen-only therapy, which has more favorable mood effects. 2, 4
3. If uterus present and endometrial protection needed:
   • Use the lowest effective estrogen dose (2 mg estradiol valerate, not 3 mg). 5
   • Prescribe micronized progesterone instead of synthetic progestins (like medroxyprogesterone acetate). 2
4. Monitor mood symptoms closely during the first 2-3 treatment cycles, particularly during progestin phases. 7, 5
5. If negative mood symptoms emerge during progestin phase: Consider switching to continuous combined regimen, changing progestin type, or adding antidepressant therapy. 4

Critical Caveats

• The timing window matters for postmenopausal HRT: initiate within 10 years of menopause onset or before age 60 for favorable risk-benefit profile. 2
• Never initiate postmenopausal HRT in women with history of breast cancer, coronary heart disease, prior venous thromboembolism, stroke, active liver disease, or antiphospholipid syndrome. 2
• For severe depressive conditions in perimenopausal women, combination of antidepressant and HRT should be considered rather than HRT alone. 4
• Transgender individuals have increased baseline rates of anxiety, depression, bipolar disorder, obsessive compulsive disorder, and other psychiatric conditions compared to cisgender individuals, which should be considered in overall care planning. 3