Vaginal Testosterone Cream vs Estradiol Vaginal Ring for Vaginal Dryness or Decreased Libido in Women Receiving Aromatase Inhibitors for Early-Stage Breast Cancer: A Randomized Clinical Trial.
OBJECTIVE
Aromatase inhibitors (AI) are associated with significant urogenital atrophy, affecting quality of life and drug compliance.


OBJECTIVE
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 (E2), defined as E2 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.


METHODS
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 E2 assay variability over time and between the 2 interventions.


METHODS
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 E2 levels.


RESULTS
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 E2 was 20 (<2 to 127) pg/mL. At baseline, E2 was above the postmenopausal range (>10 pg/mL) in 28 of 76 women (37%). Persistent E2 elevation was observed in none with a vaginal ring and in 4 of 34 women (12%) with IVT. Transient E2 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.


CONCLUSIONS
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 E2 was common and complicates this assessment. Vaginal atrophy, sexual interest, and sexual dysfunction were improved. Further study is required to understand E2 variability in this setting.


BACKGROUND
clinicaltrials.gov Identifier: NCT00698035.
Helen Diller Family Comprehensive Cancer Center, University of California-San Francisco, San Francisco.
Michelle E
ME
Melisko
Helen Diller Family Comprehensive Cancer Center, University of California-San Francisco, San Francisco.
Mindy E
ME
Goldman
Helen Diller Family Comprehensive Cancer Center, University of California-San Francisco, San Francisco.
Jimmy
J
Hwang
Helen Diller Family Comprehensive Cancer Center, University of California-San Francisco, San Francisco.
Amy
A
De Luca
Samuel Merritt University, Oakland, California.
Sally
S
Fang
Helen Diller Family Comprehensive Cancer Center, University of California-San Francisco, San Francisco.
Laura J
LJ
Esserman
Helen Diller Family Comprehensive Cancer Center, University of California-San Francisco, San Francisco.
Amy J
AJ
Chien
Helen Diller Family Comprehensive Cancer Center, University of California-San Francisco, San Francisco.
John W
JW
Park
Helen Diller Family Comprehensive Cancer Center, University of California-San Francisco, San Francisco.
Hope S
HS
Rugo
D000282:Administration, Intravaginal; D000328:Adult; D000368:Aged; D000728:Androgens / Q000008:administration & dosage / Q000009:adverse effects*; D047072:Aromatase Inhibitors / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000188:drug therapy*; D003274:Contraceptive Devices, Female / Q000009:adverse effects; D004334:Drug Administration Schedule; D004958:Estradiol / Q000008:administration & dosage / Q000009:adverse effects*; D004967:Estrogens / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D006801:Humans; D007989:Libido / Q000187:drug effects; D008875:Middle Aged; D009367:Neoplasm Staging; D017698:Postmenopause; D011446:Prospective Studies; D011788:Quality of Life; D013739:Testosterone / Q000008:administration & dosage / Q000009:adverse effects*; D016896:Treatment Outcome; D014621:Vagina / Q000473:pathology*; D014622:Vaginal Creams, Foams, and Jellies / Q000008:administration & dosage / Q000494:pharmacology; D014623:Vaginal Diseases / Q000139:chemically induced / Q000188:drug therapy
D000728:Androgens; D047072:Aromatase Inhibitors; D004967:Estrogens; D014622:Vaginal Creams, Foams, and Jellies; D013739:Testosterone; D004958:Estradiol