Gonadotropin-Releasing Hormone Agonists during Cyclophosphamide for Ovarian Protection in Systemic Lupus Erythematosus: A Systematic Review and Meta-Analysis

ABSTRACT: 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 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% confidence interval 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% confidence interval, 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 standardized long-term reproductive follow-up are needed to confirm these findings. LAY SUMMARY: Systemic lupus erythematosus is an autoimmune disease that often affects young women. When the disease is severe, the drug cyclophosphamide, which can damage the ovaries and cause early menopause and infertility, may be used. With our study, we wanted to assess whether adding injections of gonadotropin-releasing hormone agonists, drugs that temporarily switch off the ovaries, can protect fertility. We combined results from five studies, including 162 women with systemic lupus erythematosus who received cyclophosphamide with or without these hormone injections. Early permanent loss of ovarian function occurred in 5 of 93 women who received the injections, compared with 28 of 69 women who did not. More women in the injection group later became pregnant (19 of 87 versus 6 of 60). Serious side effects were similar in both groups. These findings suggest that temporary ovarian suppression during cyclophosphamide treatment can reduce the risk of losing fertility in young women with systemic lupus erythematosus.