Why vaginal atrophy treatments should have low estradiol


In a recent study, vulvovaginal atrophy treatments with lower estradiol concentrations were the most effective at preventing breast cancer recurrence.

Why vaginal atrophy treatments should have low estradiol | Image Credit: © Zerbor - © Zerbor - stock.adobe.com.

Why vaginal atrophy treatments should have low estradiol | Image Credit: © Zerbor - © Zerbor - stock.adobe.com.

Treatments for breast cancer (BC) should aim for the lowest possible estradiol concentration, according to a recent study published in Clinical Breast Cancer.


  • The study emphasizes the importance of aiming for the lowest possible estradiol concentration in the treatment of breast cancer, particularly in hormone receptor (HR) positive cases.
  • Various treatment modalities such as chemotherapy, radiotherapy, surgery, and adjuvant hormone treatment are used to reduce the risk of breast cancer recurrence, but they can lead to genitourinary symptoms.
  • Aromatase inhibitors (AIs) are commonly associated with genitourinary symptoms but have shown greater potential in reducing breast cancer recurrence compared to selective estrogen receptor modulators.
  • Genitourinary syndrome of menopause (GSM) and vulvovaginal atrophy (VVA) rates increase with the more frequent use of AIs in breast cancer treatment, impacting patients' quality of life and adherence to treatment.
  • Studies reviewed in the article suggest that low-dose estrogen treatments like estriol cream, estriol gel, and estradiol tablets do not increase breast cancer recurrence or mortality over 5.5 years and can effectively improve VVA symptoms.

BC is the most common form of cancer in women, and hormone receptor (HR) positive BC makes up 75% of BC cases. The risk of recurrence is often reduced through chemotherapy, radiotherapy, surgery, and adjuvant hormone treatment.

Treatment modalities that reduce estrogen production may cause or exacerbate genitourinary symptoms. Aromatase inhibitors (AIs) are the method most frequently associated with genitourinary symptoms and have been associated with a greater reduction in BC recurrence than certain selective estrogen receptor modulators.

As AIs are used more frequently during breast cancer, genitourinary syndrome of menopause (GSM) and vulvovaginal atrophy (VVA) rates also increase. These symptoms reduce quality of life and may decrease adherence to BC treatment. Local hormone treatments may be used to treat GSM and VVA, but there is little long-term outcome data on these treatment methods.

To determine the safety and efficacy of hormonal therapy against VVA in patients with BC history, investigators conducted a systematic review and meta-analysis. Literature was found through searches of the PubMed/MEDLINE, EMBASE, and Cochrane databases.

Eligibility criteria included being an observational or investigational study and describing the impact of hormonal treatments on VVA in patients with a BC history. Participants included BC survivors with VVA caused by antiestrogen treatment.

Hormonal-based treatments were the intervention evaluated, with non-hormonal treatments or placebo used as controls. Outcomes included estrogen plasma levels, breast cancer recurrence, disease-free survival, patient-centered outcomes, and mortality. The main variation in serum estradiol concentration was the primary outcome of the analysis.

Eligibility was determined by 2 reviewers, with studies that both reviewers agreed on included. The risk of bias was independently assessed by 2 authors, with randomized trials assessed using the Cochrane tool.

There were 17 studies included in the final analysis. Common estrogen therapies evaluated in these studies included estriol cream, estriol cream 1 mg/g, estriol gel, estradiol vaginal gel 1 mg, low-dose estradiol vaginal gel, gynoflor tablets, ultra-low dose estriol vaginal gel, estriol or estradiol tablets, estrogen ring, estradiol 10 mg, and estradiol vaginal ring 2 mg.

Studies evaluating estriol low-dose gel, estriol cream, and estradiol mg tablets did not find an increase in breast cancer recurrence or mortality over 5.5 years. Additionally, improvements in vaginal atrophy scores were found after low-dose estradiol application.

Ultra-low dose estriol vaginal gel was associated with significant improvements in dyspareunia, pruritus, and vaginal dryness compared to placebo. Increased estriol levels were observed in the first week of treatment, but these normalized over time.

Studies evaluating estradiol vaginal rings found significantly increased circulating estradiol levels following treatment. These levels did not significantly change from baseline to week 16 of treatment.

These results indicated minimal changes in estradiol concentration from low-dose gel, cream, and tablets, as well as efficacy in improving VVA symptoms. Investigators recommended efforts on preventing cancer recurrence aim for the lowest possible concentration.


Comini AM, Carvalho BM, José Barbosa Moreira M, et al. Safety and serum estradiol levels in hormonal treatments for vulvovaginal atrophy in breast cancer survivors: asystematic review and meta-analysis. Clinical Breast Cancer. 2023. doi:10.1016/j.clbc.2023.08.003

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