Treatment with the GnRH agonist (GnRHa) deslorelin (D) and low-dose add-back estradiol (E2) is effective in reducing pain, bleeding and uterine volume (UV) while maintaining bone mineral density (BMD) in women with symptomatic uterine fibroids (UF)

Abstract

Objective: GnRHa are effective for treatment of UF related symptoms but use is limited by toxicities including loss of BMD. The purpose of this study was to assess the impact of adding E2 on the efficacy of daily D in reducing UF symptoms and loss of BMD. Design: Two hundred sixty-five women with menorrhagia secondary to UF were randomized to 12 months (m) of treatment in a multi-institutional, 5-arm, double-blind, placebo-controlled, dose range finding study. Materials/Methods: Baseline evaluations included 2 m of daily diary entries to record pelvic pain using a validated 10-cm linear analog scale and bleeding severity by the method of Janssen et al based on the number of pads and/or tampons used weighted by degree of saturation. UV was calculated from ultrasound measurements in 3 dimensions. BMD of the lumbar spine (L1-L4)was measured in duplicate by DEXA. Treatment was placebo nasal spray (NS) and placebo transdermal (TD) patch, 1 mg D NS and placebo TD, 1 mg D NS and 25 g E2 TD, 1 mg D NS and 50 g E2 TD, or 1 mg D NS and 75 g E2 TD. Daily diary entries to capture pelvic pain and bleeding were made for the duration of treatment. Pelvic pain was quantified by adding the diary entries for each 28-day interval. Response was scored if baseline score was reduced by greater than or equal to 50%. Bleeding score was calculated from diary entries during each 28-day interval. Response was scored if score was 75 or less (equivalent to about 40 ml; normal menstrual volume). The average of the 2 pre-treatment months was used as the baseline for pain and bleeding. UV and BMD were measured again after 6 m of treatment. Results: This interim report is of 185 women completing 6 m of treatment. The study is ongoing and data following 12 m of treatment will be reported separately. Pelvic pain decreased in 82% of women receiving active treatment compared to 56% receiving placebo. Bleeding scores were reduced significantly in 76% of women receiving active treatment compared to 11.7% receiving placebo. When the cut-off bleeding score of 25 was used (less than 1/3 normal menstrual flow), that score or better was achieved by 65% of women receiving active treatment compared to only 3.3% receiving placebo. UV decreased an average of 21% in the active treatment arms and increased an average of 26% with placebo. Although not significant, there was a trend toward greater decrease in UV with the lower E2 doses. BMD loss decreased with increasing E2 dose with only 0.4% loss in the 50 g/day E2 arm compared to 3% in the D alone arm. Based on these findings, the 50 g/day add-back dose of E2 was selected as optimal in preserving the efficacy of the GnRHa alone while minimizing loss of BMD. Conclusions: Women with symptomatic UF have significant pelvic pain and bleeding, often with increased uterine volume. Treatment with D and low-dose add-back E2 for 6 m significantly reduced pain, bleeding, and uterine volume, with minimal loss of BMD. Supported by: This study was supported by Balance Pharmaceuticals, Inc., Santa Monica, CA.