Vaginal estradiol is used for symptoms that sit in the vagina and lower urinary tract after menopause. It acts mainly where it is applied, which is why its evidence base looks different from that of systemic estrogen. The trials below are the ones that measured symptoms directly.
The condition
The 2020 Menopause Society statement calls the combined condition genitourinary syndrome of menopause. Its symptoms include dryness, burning, irritation and pain with sex, and some urinary symptoms. The statement describes it as likely underdiagnosed and undertreated.
The softgel trial
REJOICE was a phase 3 randomized trial of 764 postmenopausal women with vulvar and vaginal atrophy, 747 of them in the modified intent-to-treat population. Women used a vaginal estradiol softgel at 4, 10 or 25 micrograms, or placebo, for 12 weeks. All three doses improved the co-primary outcomes (cell maturation, vaginal pH and dyspareunia) compared with placebo, except that dyspareunia at 4 micrograms reached a smaller margin (P=0.0149). The authors reported no systemic estrogen exposure of concern and no change in sex hormone-binding globulin.
Systemic exposure and labels
At low doses, blood estrogen levels remain within the range seen after menopause, according to the 2020 statement. Product labels nevertheless carry the same boxed warning as systemic hormone therapy, although the risks seen in systemic trials were not linked to vaginal use in those trials.
Long-term data and the lining of the uterus
The 2016 Cochrane update of local estrogen trials made the woman's own symptom rating the main outcome. Endometrial thickness was treated as a safety outcome, and the review rates the evidence on it as low quality because of poor reporting and imprecise estimates. The 2020 statement says long-term studies of endometrial safety for vaginal estrogen are lacking.
What this does not say
- The trials tested approved products at their studied doses. They do not test compounded vaginal creams or inserts.
- REJOICE ran for 12 weeks; the review of longer use relies on shorter studies.
- Trial averages are not predictions for one woman; a physician decides the dose and whether to continue.
How we use this
Our physicians start low, review symptoms at follow-up and keep the lowest effective dose. Where the trials are approved products, we say so, and we do not claim that compounded versions have the same evidence.
Vaginal estrogen is one option among others for these symptoms, including non-hormonal moisturizers and lubricants. We discuss which fits your history.
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- 1.Constantine GD et al. The REJOICE trial: a phase 3 randomized, controlled trial evaluating the safety and efficacy of a novel vaginal estradiol soft-gel capsule for symptomatic vulvar and vaginal atrophy. Menopause 2017;24(4):409-416. Menopause (NAMS)
- 2.The Menopause Society. The 2020 genitourinary syndrome of menopause position statement. Menopause 2020;27(9):976-992. Menopause (The Menopause Society)
- 3.Lethaby A et al. Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database Syst Rev 2016 (CD001500.pub3). Cochrane Library
- 4.Suckling J et al. Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database Syst Rev 2006 (CD001500.pub2). Cochrane Library