A systematic review and meta-analysis of the gonadotoxic effects of cyclophosphamide and benefits of gonadotropin releasing hormone agonists (GnRHa) in women of child-bearing age with autoimmune rheumatic disease

Abstract

Objectives: To systematically review risk of sustained amenorrhea with intravenous (IV) cyclophosphamide in autoimmune rheumatic disease (ARD), and evaluate efficacy of gonadotropin-releasing hormone agonists (GnRHa) to reduce this risk. Methods: Systematic search for papers reporting incidence of sustained amenorrhea >= 12 months in ARD following: IV cyclophosphamide; or GnRHa and IV cyclophosphamide compared to IV cyclophosphamide alone. Results: From 31 articles and 1388 patients (mean age 27.7 years) sustained amenorrhea occurred in 273 patients (19.7%). Of 56 patients (mean age range 23.9-25.6 years) receiving GnRHa and IV cyclophosphamide, and 37 controls (mean age range 25-30.1 years) given IV cyclophosphamide only, sustained amenorrhea occurred in 2/56 (3.6%) patients treated with GnRHa, compared to 15/37 (40.5%) controls. Pooled odds ratio of sustained amenorrhea with GnRHa and cyclophosphamide versus cyclophosphamide alone was 0.054 (95% CI 0.0115-0.2576 p < 0.001), corresponding to a number needed to treat of 2.7 (95% CI 1.955-4.388) and absolute risk reduction of 36.95% (95% CI 35.6-38.4%). Conclusion: Sustained amenorrhea with IV cyclophosphamide was observed in patients with ARD, especially with increasing age and cumulative doses >5 g. GnRHa reduced this risk and should be considered with IV cyclophosphamide in women of childbearing age with ARD.