Association of Vaginal Estradiol Tablet With Serum Estrogen Levels in Women Who Are Postmenopausal

Abstract

ImportanceHalf of women who are postmenopausal have genitourinary discomfort after menopause. Recommended therapies include low-dose vaginal estrogen. Individuals with a history of breast cancer or venous thromboembolism may have concerns about the safety of this intervention.ObjectiveTo compare serum estrogen concentrations with the use of vaginal estrogen, 10 μg, tablet vs placebo in women who are postmenopausal.Design, Setting, and ParticipantsThis is a secondary, post hoc analysis of data from a randomized clinical trial of treatment for moderate to severe genitourinary syndrome in women who are postmenopausal. The study was conducted at Kaiser Permanente Washington Health Research Institute and the University of Minnesota from April 11, 2016, to April 23, 2017. Measurements and data analysis were performed from November 3, 2020, to September 23, 2022.InterventionsParticipants were randomly assigned to vaginal estradiol tablet (10 μg/d for 2 weeks and then twice weekly) plus placebo gel (3 times weekly) or dual placebo for 12 weeks.Main Outcomes and MeasuresIn this post hoc analysis, baseline and week 12 serum estradiol, estrone, and sex hormone–binding globulin (SHBG) concentrations were measured by a chemiluminescent assay. Week 12 values of the 3 analytes were compared by baseline participant characteristics. Linear models compared week 12 estradiol concentrations between treatment groups, adjusted for baseline characteristics.ResultsA total of 174 women, mean (SD) age 61 (4) years, were included. Those in the estrogen group (n = 88) were more likely to have higher geometric mean (SD) week 12 serum estradiol concentrations (4.3 [2.2 pg/mL]) than those in the placebo group (n = 86) (3.5 [2.1] pg/mL) (P = .01). Adjusted for pretreatment hormone concentrations, age, clinical site, and body mass index, assignment to the estrogen vs placebo treatment group was significantly associated with higher week 12 estradiol concentrations (23.8% difference; 95% CI, 6.9%-43.3%). Most (121 of 174 [69.5%]) participants had enrollment serum estradiol concentrations higher than 2.7 pg/mL. Of women starting treatment at estradiol levels lower than or equal to 2.7 pg/mL, 38.1% (8 of 21) in the estrogen group and 34.4% (11 of 32) in the placebo group had estradiol concentrations higher than 2.7 pg/mL after 12 weeks of study participation (P = .78). Treatment assignment was not associated with week 12 estrone or SHBG concentrations.Conclusions and RelevanceIn this secondary analysis of a randomized clinical trial, a significant, although small, increase in serum estradiol levels was noted after 12 weeks of vaginal estrogen administration. The clinical relevance of this small increase is uncertain.Trial RegistrationClinicalTrials.gov Identifier: NCT02516202

Vaginal Estrogen Therapy Use and Survival in Females With Breast Cancer

“…The 2 cohorts comprised 49 237 females with breast cancer (between 40 and 79 years of age) and 5795 breast cancerspecific deaths, with a median (IQR) duration of follow-up of 8 (5)(6)(7)(8)(9)(10)(11)(12) years in the Wales cohort and 5 (3-7) years in the Scotland cohort. Overall, 5% of females (2551) used vaginal estrogen therapy after diagnosis and 1% (556) received systemic HRT.…”

“…Trials have shown increased recurrence in patients with breast cancer who received systemic hormone replacement therapy (HRT) . A recent trial observed a small increase in serum estradiol with use of a vaginal estradiol tablet (10 μg) …”

“…4 A recent trial observed a small increase in serum estradiol with use of a vaginal estradiol tablet (10 μg). 5 There have been no large randomized clinical trials of vaginal estrogen therapy in patients with breast cancer that are powered to investigate recurrence or mortality, 6 and observational studies have been limited by small sample size 7,8 and unavailable confounders. 9 A recent observational Danish study showed no increase in recurrence in patients with breast cancer who received vaginal estrogen therapy aside from a subgroup who received both vaginal estrogen therapy and aromatase inhibitors.…”

Hormonal Medications for Genitourinary Syndrome of Menopause

“…A post hoc secondary analysis of circulating estradiol (n = 88) associated with the use of 10 mcg vaginal estradiol tablets compared with non-users (n = 86) indicated less than 1 pg/ml difference in circulating estradiol attributable to the treatment. 24 Systemic absorption is considered low with the 6.5 ug estradiol ring, 10 ug or less vaginal tablets or softgel inserts, or if vaginal creams are dosed at low levels (such as CEE at 0.5 mg and estradiol at 0.5 mg). 1 To facilitate compliance, the choice of therapy should be guided by the degree and concern of systemic absorption and patient preference; cost often plays a role.…”

Genitourinary Syndrome of Menopause in Cancer Survivors

“…Limited trial data suggests that the ring and suppository formulations are not associated with appreciable rises in systemic levels of estrogen and are likely safe. [11][12][13][14] Local estrogen creams applied to the introitus and vulva can also be used to alleviate discomfort, taking caution to avoid the usual doses of vaginal estrogen creams because of the greater likelihood of systemic absorption. Vaginal estrogen is not shown to impact disease, with the exception of a single study that suggested a higher risk of recurrence for breast cancer survivors on AI's using vaginal estrogen.…”