Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Apr;210(2):295-305.
doi: 10.1007/s10549-024-07564-8. Epub 2024 Dec 27.

Effects of vaginal estrogen on serum estradiol during aromatase inhibitor therapy in breast cancer patients with vulvovaginal atrophy: a prospective trial

Mária Faltinová  1 , Leena Vehmanen  1 , Heli Lyytinen  1 , Hanna Savolainen-Peltonen  2 , Anni Virtanen  3 , Mikko Haanpää  1 , Esa Hämäläinen  3   4 , Aila Tiitinen  2 , Johanna Mattson  5
Affiliations

Effects of vaginal estrogen on serum estradiol during aromatase inhibitor therapy in breast cancer patients with vulvovaginal atrophy: a prospective trial

Mária Faltinová et al. Breast Cancer Res Treat. 2025 Apr.

Abstract

Purpose: This study aimed to analyze changes in serum estradiol (E2) levels during concurrent vaginal estradiol therapy and adjuvant letrozole in postmenopausal breast cancer (BC) patients with vulvovaginal atrophy (VVA). Secondary objectives included assessing the effects of therapy on vaginal atrophy, quality of life (QoL) and menopause-related symptoms.

Methods: 20 postmenopausal patients undergoing adjuvant letrozole therapy and experiencing VVA symptoms were treated with vaginal estradiol for 12 weeks. Gynecologic examination and symptom screening were conducted at baseline and after 12 weeks. Serum E2 levels were analyzed at baseline, and at two, four, eight, and 12 weeks. E2 levels were measured using both a routine liquid chromatography-tandem mass spectrometry (LC-MS/MS) method and a highly sensitive (hsE2-MS) LC-MS/MS method.

Results: At baseline, serum E2 levels, measured with hsE2-MS, were below the lower limit of quantification (LLOQ) in all patients. E2 remained below LLOQ throughout the treatment period in three patients (15%). Persistent E2 elevation above LLOQ was observed in six patients (30%), while isolated E2 elevations occurred in 10 patients (50%). One patient experienced transient E2 elevation in two sporadic measurements. Serum E2 variations were shown by using both LC-MS/MS methods. Vaginal pH, vaginal maturation index (VMI), and VVA symptoms significantly improved during treatment.

Conclusion: Intravaginal estradiol therapy (10ug) during adjuvant letrozole resulted in transient increases in systemic E2 levels among early BC patients with VVA. Highly sensitive LC-MS/MS is a promising method for monitoring E2 levels during aromatase inhibitor (AI) therapy.

Keywords: Aromatase inhibitor; Breast cancer; Estradiol; Intravaginal estrogen therapy; Liquid chromatography tandem mass spectrometry; Vulvovaginal atrophy.

PubMed Disclaimer

Conflict of interest statement

Declarations. Conflict of interests: The authors declare no relevant financial or non-financial conflicts of interest. Ethical approval: This study was performed in accordance with the principles of the Declaration of Helsinki. Approval was obtained from the Ethics committee of Helsinki University Hospital on April 20, 2020. The trial is registered in the Helsinki and Uusimaa Hospital District Clinical Trials Register (EudraCT Number 2019–001234-34). Consent to participate: Informed consent was obtained from all participants included in this study. Consent to publication: The authors confirm that this manuscript does not contain any individual person’s data in any form.

Figures

Fig. 1
Fig. 1
Individual variations in E2 levels for each BC patient treated with concomitant letrozole and vaginal estradiol (Vagifem®) at baseline and at 2, 4, 8 and 12 weeks, measured by two different LC–MS/MS methods. The blue line represents the routine E2-MS method (LLOQ of 10 pmol/L) and the red line the highly sensitive hsE2-MS method (LLOQ of 5 pmol/L). In order to clarify the method comparison all the results below the LLOQs were artificially set at 0 pmol/L of E2 for the both E2-MS and hsE2-MS methods in the Figs. 1a–1d. a Patients with E2 levels below the LLOQ (n = 3; 15%). Throughout the study, three patients consistently maintained serum E2 levels below the LLOQ. These patients demonstrated a reliable suppression of E2 during treatment with letrozole and vaginal estrogen therapy. A significant discrepancy was noted in Patient 11, whose E2 levels remained below the LLOQ of 5 pmol/L according to all measurements taken with the hsE2-MS method. In contrast, the E2-MS method unexpectedly indicated high E2 levels in this patient. b Patient with transient E2 elevations (n = 1; 5%). c Patients with isolated E2 elevations (n = 10; 50%) Half of the study participants experienced isolated E2 elevations at various time points during the study. These spikes in E2 levels did not persist and were no consistent over multiple time points. d Patients with persistent E2 elevations (n = 6; 30%) Six patients demonstrated persistent E2 elevations across multiple consecutive measurements, indicating a more sustained rise in E2 levels during letrozole and vaginal estrogen therapy
Fig. 1
Fig. 1
Individual variations in E2 levels for each BC patient treated with concomitant letrozole and vaginal estradiol (Vagifem®) at baseline and at 2, 4, 8 and 12 weeks, measured by two different LC–MS/MS methods. The blue line represents the routine E2-MS method (LLOQ of 10 pmol/L) and the red line the highly sensitive hsE2-MS method (LLOQ of 5 pmol/L). In order to clarify the method comparison all the results below the LLOQs were artificially set at 0 pmol/L of E2 for the both E2-MS and hsE2-MS methods in the Figs. 1a–1d. a Patients with E2 levels below the LLOQ (n = 3; 15%). Throughout the study, three patients consistently maintained serum E2 levels below the LLOQ. These patients demonstrated a reliable suppression of E2 during treatment with letrozole and vaginal estrogen therapy. A significant discrepancy was noted in Patient 11, whose E2 levels remained below the LLOQ of 5 pmol/L according to all measurements taken with the hsE2-MS method. In contrast, the E2-MS method unexpectedly indicated high E2 levels in this patient. b Patient with transient E2 elevations (n = 1; 5%). c Patients with isolated E2 elevations (n = 10; 50%) Half of the study participants experienced isolated E2 elevations at various time points during the study. These spikes in E2 levels did not persist and were no consistent over multiple time points. d Patients with persistent E2 elevations (n = 6; 30%) Six patients demonstrated persistent E2 elevations across multiple consecutive measurements, indicating a more sustained rise in E2 levels during letrozole and vaginal estrogen therapy
Fig. 1
Fig. 1
Individual variations in E2 levels for each BC patient treated with concomitant letrozole and vaginal estradiol (Vagifem®) at baseline and at 2, 4, 8 and 12 weeks, measured by two different LC–MS/MS methods. The blue line represents the routine E2-MS method (LLOQ of 10 pmol/L) and the red line the highly sensitive hsE2-MS method (LLOQ of 5 pmol/L). In order to clarify the method comparison all the results below the LLOQs were artificially set at 0 pmol/L of E2 for the both E2-MS and hsE2-MS methods in the Figs. 1a–1d. a Patients with E2 levels below the LLOQ (n = 3; 15%). Throughout the study, three patients consistently maintained serum E2 levels below the LLOQ. These patients demonstrated a reliable suppression of E2 during treatment with letrozole and vaginal estrogen therapy. A significant discrepancy was noted in Patient 11, whose E2 levels remained below the LLOQ of 5 pmol/L according to all measurements taken with the hsE2-MS method. In contrast, the E2-MS method unexpectedly indicated high E2 levels in this patient. b Patient with transient E2 elevations (n = 1; 5%). c Patients with isolated E2 elevations (n = 10; 50%) Half of the study participants experienced isolated E2 elevations at various time points during the study. These spikes in E2 levels did not persist and were no consistent over multiple time points. d Patients with persistent E2 elevations (n = 6; 30%) Six patients demonstrated persistent E2 elevations across multiple consecutive measurements, indicating a more sustained rise in E2 levels during letrozole and vaginal estrogen therapy
Fig. 2
Fig. 2
Vaginal pH: changes in mean values at baseline and after 12 weeks of vaginal estradiol treatment
Fig. 3
Fig. 3
VMI: changes in cell types at baseline and after 12 weeks of vaginal estradiol treatment
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Burstein HJ, Lacchetti C, Anderson H, Buchholz TA, Davidson NE, Gelmon KA, Giordano SH, Hudis CA, Solky AJ, Stearns V et al (2019) Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: ASCO clinical practice guideline focused update. J Clin Oncol 37(5):423–438. 10.1200/JCO.18.01160 - PubMed
    1. Bekes I, Huober J (2023) Extended adjuvant endocrine therapy in early breast cancer patients—review and perspectives. Cancers 15(16):4190. 10.3390/cancers15164190 - PMC - PubMed
    1. Ganz PA, Rowland JH, Desmond K, Meyerowitz BE, Wyatt GE (1998) Life after breast cancer: understanding women’s health-related quality of life and sexual functioning. J Clin Oncol 16(2):501–514. 10.1200/jco.1998.16.2.501 - PubMed
    1. Cella D, Fallowfield LJ (2008) Recognition and management of treatment-related side effects for breast cancer patients receiving adjuvant endocrine therapy. Breast Cancer Res Treat 107(2):167–180. 10.1007/s10549-007-9548-1 - PubMed
    1. Chirgwin JH, Giobbie-Hurder A, Coates AS, Price KN, Ejlertsen B, Debled M, Gelber RD, Goldhirsch A, Smith I, Rabaglio M et al (2016) treatment adherence and its impact on disease-free survival in the breast international group 1–98 trial of tamoxifen and letrozole, alone and in sequence. J Clin Oncol 34(21):2452–2459. 10.1200/jco.2015.63.8619 - PMC - PubMed

MeSH terms

LinkOut - more resources