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Vaginal Estradiol: Mental Health and Mood Impact

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At a glance

  • Approved use / moderate to severe vulvar and vaginal atrophy due to menopause [1]
  • Serum estradiol, 10-microgram vaginal tablet insert / mean 6.6 to 14.8 pg/mL [2]
  • Untreated postmenopausal range / proposed undetectable to 10.7 pg/mL [2]
  • Mood terms in the vaginal cream label / mental depression, nervousness, mood disturbances, irritability, no rates given [1]
  • Systemic estrogen and mood (KEEPS-Cog) / oral conjugated equine estrogens improved depression and anxiety scores; transdermal estradiol was similar to placebo [4]

Does vaginal estradiol treat depression or anxiety?

No. The estradiol vaginal cream label covers one indication, moderate to severe symptoms of vulvar and vaginal atrophy due to menopause [1]. Depression and anxiety are not on it.

A 2018 practice guideline on perimenopausal depression names antidepressants and psychotherapy as front-line treatments and notes that estrogen therapy is not approved to treat perimenopausal depression. It describes evidence that estrogen has antidepressant effects in perimenopausal women, particularly those with vasomotor symptoms, and calls the data on estrogen plus progestin sparse and inconclusive [3]. The mood and cognition trials cited on this page, KEEPS-Cog and ELITE, used oral or transdermal products, not vaginal ones [4][6].

What the labels list for mood

The estradiol vaginal cream label lists mental depression, nervousness, mood disturbances and irritability among reactions reported with estrogen and/or progestin therapy, without frequencies [1]. For comparison, the label for a systemic transdermal product, the Climara patch, recorded depression in 1 percent of women at 0.025 mg per day, 5 percent at 0.05 mg per day and 8 percent at 0.1 mg per day, versus 0 percent on placebo [5]. That is a patch, not a vaginal product.

In KEEPS-Cog, a 4-year randomized trial in 693 recently postmenopausal women, oral conjugated equine estrogens 0.45 mg per day (n=220) improved depression and anxiety scores relative to placebo, while transdermal estradiol 50 mcg per day (n=211) was similar to placebo; both were given with micronized progesterone, and neither showed a cognitive benefit [4].

How much estradiol reaches the bloodstream

The estradiol vaginal cream label says that systemic absorption may occur with its use, and that the warnings, precautions and adverse reactions associated with oral estrogen treatment should be taken into account [1]. Measured serum levels are published for vaginal inserts, which are different products from the cream. Reported mean levels during treatment were 3.6 to 3.9 pg/mL with a 4-microgram softgel insert, 4.6 to 7.4 pg/mL with a 10-microgram softgel insert, 6.6 to 14.8 pg/mL with a 10-microgram tablet insert, 7.1 to 9.1 pg/mL with a 25-microgram softgel insert and 16.7 to 22.7 pg/mL with a 25-microgram tablet insert [2].

Frequently asked questions

Does vaginal estradiol help with depression?
No. The estradiol vaginal cream label lists only moderate to severe vulvar and vaginal atrophy as an indication [1]. A 2018 guideline on perimenopausal depression names antidepressants and psychotherapy as front-line treatments [3].
Can vaginal estradiol cause mood changes?
The estradiol vaginal cream label lists mental depression, nervousness, mood disturbances and irritability among reported reactions, without rates, and states that systemic absorption may occur and that oral estrogen warnings and adverse reactions should be taken into account [1].
Does vaginal estradiol affect memory?
The cognition trials used systemic products. In ELITE, 567 postmenopausal women took oral 17-beta estradiol 1 mg per day or placebo (women with a uterus also received cyclic micronized progesterone) for a mean of 57 months, with no significant difference in verbal memory (difference -0.06, 95% CI -0.22 to 0.09) [6]. The boxed warning in the vaginal cream label includes probable dementia [1].
Could treating genitourinary syndrome of menopause affect how someone feels?
Vaginal estradiol treats vulvovaginal symptoms, not depression. Genitourinary syndrome of menopause involves dryness, pain with sex and urinary symptoms that can impair sexual function and quality of life [7][8]. In a survey of 31,581 US women, distressing sexual problems were associated with depression, anxiety and urinary incontinence [11]. That is an association; the evidence here does not show that vaginal estradiol improves mood.

References

  1. U.S. National Library of Medicine, DailyMed. Estradiol Vaginal (vaginal) prescribing information. Estradiol Vaginal (vaginal) label
  2. Santen RJ, Mirkin S, Bernick B, Constantine GD. Systemic estradiol levels with low-dose vaginal estrogens. Menopause. 2020;27(3):361-370. Systemic estradiol levels with low-dose vaginal estrogens
  3. Maki PM, Kornstein SG, Joffe H, Bromberger JT, Freeman EW, Athappilly G, et al. Guidelines for the evaluation and treatment of perimenopausal depression: summary and recommendations. Menopause. 2018;25(10):1069-1085. Guidelines for the evaluation and treatment of perimenopausal depression: summary and recommendations
  4. Gleason CE, Dowling NM, Wharton W, Manson JE, Miller VM, Atwood CS, et al. Effects of Hormone Therapy on Cognition and Mood in Recently Postmenopausal Women: Findings from the Randomized, Controlled KEEPS-Cognitive and Affective Study. PLoS Med. 2015;12(6):e1001833; discussion e1001833. Effects of Hormone Therapy on Cognition and Mood in Recently Postmenopausal Women: Findings from the Randomized, Controlled KEEPS-Cognitive and Affective Study
  5. U.S. National Library of Medicine, DailyMed. Climara estradiol transdermal system (Bayer) prescribing information. Climara estradiol transdermal system (Bayer) label
  6. Henderson VW, St John JA, Hodis HN, McCleary CA, Stanczyk FZ, Shoupe D, et al. Cognitive effects of estradiol after menopause: A randomized trial of the timing hypothesis. Neurology. 2016;87(7):699-708. Cognitive effects of estradiol after menopause: A randomized trial of the timing hypothesis
  7. Portman DJ, Gass ML, Vulvovaginal Atrophy Terminology Consensus Conference Panel. Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women's Sexual Health and the North American Menopause Society. Menopause. 2014;21(10):1063-8. Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women's Sexual Health and the North American Menopause Society
  8. The NAMS 2020 GSM Position Statement Editorial Panel. The 2020 genitourinary syndrome of menopause position statement of The North American Menopause Society. Menopause. 2020;27(9):976-992. The 2020 genitourinary syndrome of menopause position statement of The North American Menopause Society
  9. Kingsberg SA, Krychman ML. Resistance and barriers to local estrogen therapy in women with atrophic vaginitis. J Sex Med. 2013;10(6):1567-74. Resistance and barriers to local estrogen therapy in women with atrophic vaginitis
  10. Stuenkel CA, Davis SR, Gompel A, Lumsden MA, Murad MH, Pinkerton JV, et al. Treatment of Symptoms of the Menopause: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015;100(11):3975-4011. Treatment of Symptoms of the Menopause: An Endocrine Society Clinical Practice Guideline
  11. Shifren JL, Monz BU, Russo PA, Segreti A, Johannes CB. Sexual problems and distress in United States women: prevalence and correlates. Obstet Gynecol. 2008;112(5):970-8. Sexual problems and distress in United States women: prevalence and correlates
Evidence overview for Vaginal Estradiol: Mental Health and Mood Impact