Hormonal Add-Back Therapy for Females Treated With Gonadotropin-Releasing Hormone Agonist for Endometriosis: A Randomized Controlled Trial

Abstract

Objective: To assess whether add-back therapy with norethindrone acetate or norethindrone acetate plus conjugated equine estrogens is superior to maintain bone health in adolescents and young women using gonadotropin-releasing hormone agonists for endometriosis. Gonadotropin-releasing hormone agonists are associated with deleterious effects on bone. Hormonal add-back may mitigate these effects.

Methods: Adolescents and young women (n=51) received a random, double-blind assignment to add-back with norethindrone acetate (5 mg/day) plus conjugated equine estrogens (0.625 mg/day) or norethindrone acetate plus placebo for 12 months. Body composition, bone mineral content, and bone mineral density (BMD) were obtained by dual-energy X-ray absorptiometry every 6 months. Quality-of-life measures were collected every 3 months. Intention-to-treat comparison of outcomes was conducted by repeated-measures analysis of variance.

Results: Thirty-four adolescents and young women completed the trial; dropouts did not differ from those who completed the trial. Bone mineral density was normal at baseline. At 12 months, total body bone mineral content and BMD had increased in the norethindrone acetate plus conjugated equine estrogens group (bone mineral content +37 g, P<.001 and BMD +0.012 g/cm, P=.05), but not in those receiving norethindrone acetate plus placebo (bone mineral content P=.19 and BMD P=.95). Lean mass increased only in those receiving conjugated equine estrogens (+1.4 kg, P=.001). Improvements in physical functioning domains of quality-of-life assessments were greater with norethindrone acetate plus conjugated equine estrogens (P=.005). No differences were seen at the hip or lumbar spine by dual-energy X-ray absorptiometry. No significant adverse events occurred.

Conclusion: Hormonal add-back successfully preserved bone health and improved quality of life for adolescents and young women with endometriosis during 12 months of gonadotropin-releasing hormone agonist therapy. Combination norethindrone acetate plus conjugated equine estrogens add-back appears to be more effective for increasing total body bone mineral content, areal BMD, and lean mass than norethindrone acetate monotherapy.

Clinical trial registration: ClinicalTrials.gov; www.clinicaltrials.gov, NCT00474851.

Level of evidence: I.

Figures

Figure 1

Patient recruitment, enrollment, and disposition.

Figure 2

Longitudinal measurement of total body bone mineral density and bone mineral content and body composition in adolescent females with endometriosis randomized to 12 months of treatment with norethindrone acetate and conjugated equine estrogens or norethindrone acetate and placebo. The bars represent the 25th to 75th percentiles for the measure at each time point. Total body bone mineral density (g/cm2) (A); total body bone mineral content (grams) (B); lean mass (grams) (C); fat mass (grams) (D).

Figure 3

Changes in quality of life over time in adolescent females with endometriosis randomized to 12 months of treatment with norethindrone acetate and conjugated equine estrogens or norethindrone acetate and placebo. The dashed line at 50 represents the United States mean score for each measure. The bars represent the 25th to 75th percentiles for the measure at each time point. Physical Summary Score (A); Mental Summary Score (B).

Figure 4

Safety measures (aspartate aminotransferase, alanine aminotransferase, total cholesterol, and triglycerides) in adolescent females with endometriosis randomized to 12 months of treatment with norethindrone acetate and conjugated equine estrogens or norethindrone acetate and placebo. The bars represent the 25th to 75th percentiles for the measure at each time point. Aspartate aminotransferase (international units per liter) (A); alanine aminotransferase (international units per liter) (B); total cholesterol (mg/dL) (C); triglycerides (mg/dL) (D).