Vaginal Testosterone Cream vs Estradiol Vaginal Ring for Vaginal Dryness or Decreased Libido in Women Receiving Aromatase Inhibitors for Early-Stage Breast Cancer
Authors: Michelle E. Melisko, Mindy E. Goldman, Jimmy Hwang, Amy De Luca, Sally Fang, Laura J. Esserman, Amy J. Chien, John W. Park, Hope S. Rugo
Journal: JAMA Oncology (2016)

<h3>Importance</h3> Aromatase inhibitors (AI) are associated with significant urogenital atrophy, affecting quality of life and drug compliance. <h3>Objective</h3> To evaluate safety of intravaginal testosterone cream (IVT) or an estradiol-releasing vaginal ring (7.5 μg/d) in patients with early-stage breast cancer (BC) receiving an AI. Intervention was considered unsafe if more than 25% of patients had persistent elevation in estradiol (E<sub>2</sub>), defined as E<sub>2</sub>greater than 10 pg/mL (to convert to pmol/L, multiply by 3.671) and at least 10 pg/mL above baseline after treatment initiation on 2 consecutive tests at least 2 weeks apart. <h3>Design, Setting, and Participants</h3> Postmenopausal (PM) women with hormone receptor (HR)–positive stage I to III BC taking AIs with self-reported vaginal dryness, dyspareunia, or decreased libido were randomized to 12 weeks of IVT or an estradiol vaginal ring. Estradiol was measured at baseline and weeks 4 and 12 using a commercially available liquid chromatography and tandem mass spectrometry assay; follicle-stimulating hormone levels were measured at baseline and week 4. Gynecologic examinations and sexual quality-of-life questionnaires were completed at baseline and week 12. This randomized noncomparative design allowed safety evaluation of 2 interventions concurrently in the same population of patients, reducing the possibility of E<sub>2</sub>assay variability over time and between the 2 interventions. <h3>Main Outcomes and Measures</h3> The primary objective of this trial was to evaluate safety of IVT or an estradiol vaginal ring in patients with early-stage BC receiving an AI; secondary objectives included evaluation of adverse events, changes in sexual quality of life using the Cancer Rehabilitation Evaluation System sexuality subscales, changes in vaginal atrophy using a validated 4-point scale, and comparison of E<sub>2</sub>levels. <h3>Results</h3> Overall, 76 women signed consent (mean [range] age, 56 [37-78] years), 75 started treatment, and 69 completed 12 weeks of treatment. Mean (range) baseline E<sub>2</sub>was 20 (&lt;2 to 127) pg/mL. At baseline, E<sub>2</sub>was above the postmenopausal range (&gt;10 pg/mL) in 28 of 76 women (37%). Persistent E<sub>2</sub>elevation was observed in none with a vaginal ring and in 4 of 34 women (12%) with IVT. Transient E<sub>2</sub>elevation was seen in 4 of 35 (11%) with a vaginal ring and in 4 of 34 (12%) with IVT. Vaginal atrophy and sexual interest and dysfunction improved for all patients. <h3>Conclusions and Relevance</h3> In PM women with early-stage BC receiving AIs, treatment with a vaginal ring or IVT over 12 weeks met the primary safety end point. Baseline elevation in E<sub>2</sub>was common and complicates this assessment. Vaginal atrophy, sexual interest, and sexual dysfunction were improved. Further study is required to understand E<sub>2</sub>variability in this setting. <h3>Trial Registration</h3> clinicaltrials.gov Identifier: NCT00698035