Hormonal Add-Back Therapy for Females Treated With Gonadotropin-Releasing Hormone Agonist for Endometriosis

Endometriosis often begins during adolescence. Appropriate management includes prompt initiation of therapy and long-term maintenance therapy. Gonadotropin-releasing hormone (GnRH) agonists are commonly used second-line therapy for patients who fail first-line therapies. These agents relieve symptoms and reduce endometrial lesions observed on laparoscopy and are the only therapeutic option for many young patients with debilitating pain. Long-term GnRH agonist therapy is associated with deleterious effects on bone mineral density (BMD). Previous studies have shown that 5% to 8% of spine BMD is lost in adults after only 3 to 6 months of GnRH agonist therapy and that BMD levels may not return to baseline after cessation of treatment. Add-back therapy with daily low doses of steroid hormone appears to mitigate these effects on bone. In a study that followed adults treated with GnRH agonists for 1 year, BMD was preserved in all 3 studied add-back groups, whereas patients receiving no add-back lost 6.3% of BMD. The benefits of add-back therapy were maintained for at least 8 months after completion of therapy. Current care for adolescents and young women is based on the effectiveness of add-back therapy in adults. A PubMed search for articles published up to April 2015 did not find any data on use of GnRH agonists with add-back for treatment of endometriosis in adolescents and young women. The aim of this single-site, randomized, double-blind, placebo-controlled 12-month trial was to assess whether norethindrone acetate (NETA) plus conjugated equine estrogens (CEEs) or NETA monotherapy is superior to maintain bone health in adolescents and young women with endometriosis treated with GnRH agonists. A total of 51 adolescents and young women with surgically confirmed endometriosis were randomized to receive add-back with NETA (5 mg/d) plus CEEs (0.625 mg/d) (group 1; n = 25) or NETA plus placebo (group 2; n = 26) for 12 months. After randomization, patients returned for assessments at 3, 6, 9, and 12 months. Dual-energy x-ray absorptiometry was used to measure body composition, bone mineral content, and BMD every 6 months. Quality-of-life measures were assessed every 3 months. Outcomes were compared using repeated-measures analysis of variance; analysis of data followed the intention-to-treat principle. Among the 51 randomized participants, 34 completed the trial; dropouts did not differ from those completing the trial. The 2 study groups had similar, normal measurements of BMD at baseline. Total body bone mineral content and BMD at 12 months increased in the NETA plus CEE group (bone mineral content +37 g, P < 0.001, and BMD +0.012 g/cm2, P = 0.05), but not in the NETA plus placebo group (bone mineral content, P = 0.31, and BMD, P = 0.65). Lean mass increased only in patients receiving NETA plus CEEs; the adjusted mean change was +1.4 kg at 12 months, P < 0.001. Increases in physical functioning domains of quality-of-life assessments occurred in both groups but were greater in the NETA plus CEE group (P = 0.005). Bone mineral content and BMD at the hip and spine remained stable in both groups throughout the study. No significant adverse events occurred with either add-back regimen. Bone health is preserved and quality of life improved in adolescents and young women with endometriosis treated for 12 months with a GnRH agonist. The data suggest that NETA plus CEEs add-back therapy is more effective for increasing total body bone mineral content, areal BMD, and lean mass than NETA monotherapy.