Extended GnRH Agonist and NETA Add-Back: An Effective and Safe Option for Refractory Endometriosis/Adenomyosis Pain

This prospective, open-label, two-arm clinical study evaluated the efficacy and safety of prolonged gonadotropin-releasing hormone agonist (GnRH-a) therapy exceeding 24 months, combined with norethisterone acetate (NETA) add-back, in women experiencing endometriosis-associated pain refractory to standard treatments. Eighty-one premenopausal women with confirmed endometriosis and/or adenomyosis received either Triptorelin SR 11.25 mg or Goserelin acetate 10.8 mg every three months, together with daily NETA 5 mg for 24 months. Significant reductions in dysmenorrhea and deep dyspareunia were observed, with mean visual analogue scale scores decreasing from 7.9 to 2.3 and 6.1 to 0.6, respectively (P < 0.0001), along with improvements in dyschezia, dysuria, bloating, alternating bowel habits, and cold intolerance. Mild osteopenia occurred in only 2.4% of participants, and no major adverse events were reported, confirming safety through laboratory and imaging follow-up. These findings suggest that long-term GnRH-a therapy with NETA add-back is highly effective and well-tolerated in women with severe, treatment-resistant endometriosis-related pain, and may serve as a viable second-line medical treatment when surgery is not feasible.