Gonadotropin-releasing hormone agonists during cyclophosphamide for ovarian protection in systemic lupus erythematosus

This study aimed to assess whether co-treatment with gonadotropin-releasing hormone agonists during cyclophosphamide therapy protects ovarian function and preserves fertility in women with systemic lupus erythematosus. We performed a systematic review and meta-analysis of comparative cohort studies including premenopausal women with systemic lupus erythematosus treated with intravenous cyclophosphamide with or without gonadotropin-releasing hormone agonists. The primary outcome was primary ovarian insufficiency, with pregnancy and serious adverse events as secondary outcomes. Two reviewers independently selected studies, extracted data, and assessed risk of bias. Pooled risk ratios with 95% confidence intervals were calculated using fixed-effect models. Five cohort studies including 162 women (93 with gonadotropin-releasing hormone agonists and 69 controls) met the inclusion criteria; no randomized controlled trials were available. Premature ovarian insufficiency occurred in 5 of 93 women receiving gonadotropin-releasing hormone agonists and in 28 of 69 controls, corresponding to a risk ratio of 0.16 (95% confidence interval (CI): 0.07–0.37). Pregnancy was more frequent after gonadotropin-releasing hormone agonist co-treatment (19 of 87 versus 6 of 60 women; risk ratio: 1.82, 95% CI: 0.86–3.86), although this difference did not reach statistical significance. The incidence of serious adverse events was similar between groups (10 of 36 versus 10 of 34 women; risk ratio: 0.99; 95% CI: 0.50–1.93). In premenopausal women with systemic lupus erythematosus receiving cyclophosphamide, co-treatment with gonadotropin-releasing hormone agonists markedly reduces the risk of primary ovarian insufficiency without evidence of added serious toxicity and may increase subsequent pregnancy. However, the absence of randomized controlled trials represents a major limitation, and larger prospective randomized or well-controlled studies with a standardized long-term reproductive follow-up are needed to confirm these findings.