Safety and Serum Estradiol Levels in Hormonal Treatments for Vulvovaginal Atrophy in Breast Cancer Survivors: A Systematic Review and Meta-Analysis.

Vulvo-vaginal atrophy (VVA) or genitourinary syndrome of menopause (GSM) is a common condition among breast cancer (BC) patients, especially those undergoing antiestrogen therapy. Despite being an option in refractory cases, the safety of hormonal treatment remains uncertain in this population. The aim of this study was to review the safety and serum estrogen levels of hormonal therapy in patients with BC history presenting with VVA symptoms. Pubmed, Embase, and Cochrane were searched for studies comparing different hormonal treatment options for VVA in breast cancer survivors. Statistical analysis was performed using a random effects model and heterogeneity using Cochran's Q-statistic and the I2 index. We included 17 studies, of which 5 were randomized controlled trials (RCTs). Treatment modalities included in this study were topical vaginal estradiol and estriol preparations, vaginally applied testosterone, DHEA, and ospemifene. We found that, among patients treated with the estriol and estradiol preparations, there was an average increase of 7.67 pg/mL (SMD 7.67 pg/mL; 95% CI -1.00, 16.35; p < .001). Analysis of the testosterone group found temporary peaks of serum estradiol levels, but 1 study showed persistent elevation above normal postmenopausal levels. One study with prasterone revealed no elevation of serum estradiol concentration. One study with ospemifene demonstrated no increase in the risk of BC recurrence. In conclusion, among treatments available for BC survivors, low-dose vaginal estrogen showed the smallest changes in serum estradiol levels and had the most evidence, but safety remains unclear, especially for patients on aromatase inhibitors. Alternative treatments such as ospemifene need more data supporting safety and efficacy. These results suggest that concerns related to cancer recurrence should keep aiming for the lowest possible concentration.