Steroidal and nonsteroidal "add-back" therapy: extending safety and efficacy of gonadotropin-releasing hormone agonists in the gynecologic patient

OBJECTIVE: To assess the efficacy of various steroidal and nonsteroidal add-back regimes in ameliorating hypoestrogenic side effects of long-term GnRH agonist (GnRH-a) therapy in gynecologic patients. DESIGN: English language literature review. PATIENTS: Gynecologic patients administered GnRH-a as therapy for ovarian hyperandrogenism, premenstrual syndrome, dysfunctional uterine bleeding, uterine leiomyomata, and symptomatic endometriosis. INTERVENTIONS: Steroidal and nonsteroidal add-back regimes including estrogens with progestins, progestins alone, and progestins with organic bisphosphonates in combination with various GnRH-a for > or = 6 months of therapy. MAIN OUTCOME MEASURES: Vasomotor symptoms, bone density changes, lipid profiles, alterations in presenting symptoms, and disease state. RESULTS: Estrogens in combination with progestins were efficacious as add-back in the management of ovarian hyperandrogenic states, dysfunctional uterine bleeding, premenstrual syndrome, and leiomyomata. Medroxyprogesterone acetate alone is ineffective as add-back for treatment of endometriosis or leiomyomata. Norethindrone is effective as add-back in the management of endometriosis but not leiomyomata, although high doses alter lipid profiles in an undesirable fashion. Organic bisphosphonates show great promise in preserving bone density without other untoward effects. CONCLUSIONS: No single add-back regime is appropriate for all gynecologic indications for GnRH-a. Ideal protocols preserve the efficacy of agonists while suppressing associated vasomotor symptoms and bone density loss.