The Effect of Hormone Replacement Therapy Upon Depressed Mood

A systematic review 1 including 26 studies was abstracted in DARE. The average number of patients in the studies was 47 (range 10 to 110). 14 studies assigned pariticipants to treatment or control groups through random assignment. Estrogen significantly reduced depressed mood (effect size = 0.69). Studies that compared estrogen treatment with estrogen plus progesterone treatment yielded a mean effect size of 0.62, indicating that the addition of progesterone to the estrogen reduced the effect of HRT on depressed mood.

Another systematic review 2 evaluating the effectiveness of treatments included 108 trials assessing psychological symptoms and 125 trials assessing quality of life. Compared with placebo, estrogen was effective for depressive symtoms: standardized effect size was -0.36 (95% CI -0.53 to -0.20; 18 trials, n=2 104) and for anxiety symptoms: standardized effect size was -0.34 (95% CI -0.50 to -0.18; 13 trials, n=1 718). The pairwise psychological outcome standardized mean differences for depression symptoms were -0.43 (-0.60 to -0.26) for SSRI/SNRI; -0.41 (-0.57 to -0.25) for high estrogen; -0.31 (-0.48 to -0.15) for standard estrogen, and -0.12 (-0.42 to 0.18) for low estrogen. Compared with placebo, for quality of life the stardardized effect size for standard dose estrogen was 0.55 (95% CI 0.41 to 0.69; 26 trials, n=31 263) and for high dose estrogen 0.76 (95% CI 0.48 to 1.03; 5 trials, n=789).

An RCT 3 examined the efficacy of transdermal estradiol plus intermittent micronized progesterone (HRT) in preventing depressive symptom onset among initially euthymic perimenopausal and early postmenopausal women (n=172). Women assigned to placebo were more likely to score at least 16 on the CES-D (Center for Epidemiologic Studies Depression Scale, 0-60 points) at least once during the intervention phase (32.3% vs 17.3%; OR 2.5, 95% CI 1.1 to 5.7) and had a higher mean CES-D score compared to HRT. Mood benefits of HRT vs placebo were evident among women in the early menopause transition but not the late menopause transition or postmenopause. Mood benefits of HRT increased with a greater number of stressful life events in the 6 months preceding enrollment.

EMAS position statement 4 of management of depressive symptoms in peri- and postmenopause: Menopausal hormone therapy may improve depressive symptoms in peri- but not in postmenopausal women, especially in those with vasomotor symptoms.

References

• Zweifel JE, O'Brien WH. A meta-analyfsis of the effect of hormone replacement therapy upon depressed mood. Psychoneuroendocrinology 1997 Apr;22(3):189-212. [PubMed][DARE]
• Grant MD, Marbella A, Wang AT et al. Menopausal Symptoms: Comparative Effectiveness of Therapies [Internet].Rockville (MD): Agency for Healthcare Research and Quality (US); 2015 Mar.
• Gordon JL, Rubinow DR, Eisenlohr-Moul TA et al. Efficacy of Transdermal Estradiol and Micronized Progesterone in the Prevention of Depressive Symptoms in the Menopause Transition: A Randomized Clinical Trial. JAMA Psychiatry 2018;75(2):149-157. [PubMed]
• Stute P, Spyropoulou A, Karageorgiou V et al. Management of depressive symptoms in peri- and postmenopausal women: EMAS position statement. Maturitas 2020;131():91-101. [PubMed]