Effect of a gonadotropin-releasing hormone analog for
ovarian function preservation after intravenous
cyclophosphamide therapy in systemic lupus erythematosus
patients: a retrospective inception cohort study
and Atsushi KAWAKAMI
Division of Advanced Preventive Medical Sciences, Department of Immunology and Rheumatology,
Center for Bioinformatics and
Molecular Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan,
Development Center, Nagasaki University Hospital, Nagasaki, Japan,
Unit of Advanced Preventive Medical Sciences, Department of
Center for Comprehensive Community Care Education, and
Department of Obstetrics and Gynecology,
Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
Objective: To determine the effect of leuprolide acetate, a synthetic gonadotropin-releasing hormone analog
(GnRH-a) on ovarian function preservation in systemic lupus erythematosus (SLE) patients treated with
cyclophosphamide (CYC) in clinical practice.
Methods: We enrolled 30 premenopausal female SLE patients who fulﬁlled the 1997 American College of
Rheumatology revised criteria and were treated with intravenous CYC (IVCY) in 2008–2017. We used Kaplan–
Meier survival estimates to compare the GnRH-a-treated patients and those not treated with GnRH-a as controls.
We performed Cox regression analyses to identify factors associated with premature ovarian failure (POF), inci-
dences of cardiovascular events, strokes and osteoporosis after IVCY therapy.
Results: After a mean follow-up of 41 months, POF developed in one of the 16 GnRH-a-treated patients (6%)
versus seven of the 14 controls (50%). Signiﬁcantly improved cumulative ovarian protection over time was
observed in the GnRH-a-treated group (P = 0.030). The hazard model analysis showed that treatment with
GnRH-a during IVCY therapy is an independent factor associated with POF after IVCY therapy (adjusted hazards
ratio = 0.12, 95% CI 0.01–0.67, P = 0.013) but not incidences of cardiovascular events, strokes or osteoporosis.
Conclusion: The combined use of GnRH-a with IVCY therapy was associated with a signiﬁcant reduction of
POF among premenopausal women with SLE, suggesting that the addition of GnRH-a can be a strategy to pre-
vent POF among premenopausal women with SLE after IVCY therapy.
Key words: cyclophosphamide, gonadotropin-releasing hormone analog, premature ovarian failure, systemic
Correspondence: Dr Tomohiro Koga, Center for Bioinformatics and Molecular Medicine, Nagasaki University Graduate School of
Biomedical Sciences, 1–12–4 Sakamoto, Nagasaki 852-8523, Japan. Email: email@example.com
© 2018 Asia Paciﬁc League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd
International Journal of Rheumatic Diseases 2018; 21: 1287–1292