Ovarian Reserve Diminished by Oral Cyclophosphamide Therapy for Granulomatosis With Polyangiitis (Wegener’s) MEGAN E. B. CLOWSE, 1 SUSANNAH C. COPLAND, 1 TSUNG-CHENG HSIEH, 1 SHEIN-CHUNG CHOW, 1 GARY S. HOFFMAN, 2 PETER A. MERKEL, 3 ROBERT F. SPIERA, 4 JOHN C. DAVIS, JR., 5 W. JOSEPH MCCUNE, 6 STEVEN R. YTTERBERG, 7 E. WILLIAM ST.CLAIR, 1 NANCY B. ALLEN, 1 ULRICH SPECKS, 7 AND JOHN H. STONE, 8 FOR THE WGET RESEARCH GROUP Objective. Standard treatment for severe granulomatosis with polyangiitis (Wegener’s) (GPA) is daily oral cyclophos- phamide (CYC), a cytotoxic agent associated with ovarian failure. In this study, we assessed the rate of diminished ovarian reserve in women with GPA who received CYC versus methotrexate (MTX). Methods. Patients in the Wegener’s Granulomatosis Etanercept Trial received either daily CYC or weekly MTX and were randomized to etanercept or placebo. For all women ages <50 years, plasma samples taken at baseline or early in the study were evaluated against samples taken later in the study to compare levels of anti-Mu ¨ llerian hormone (AMH) and follicle-stimulating hormone (FSH), endocrine markers of remaining egg supply. Diminished ovarian reserve was defined as an AMH level of <1.0 ng/ml. Results. Of 42 women in this analysis (mean age 35 years), 24 had CYC exposure prior to enrollment and 28 received the drug during the study. At study entry, women with prior CYC exposure had significantly lower AMH, higher FSH, and a higher rate of early menstruation cessation. For women with normal baseline ovarian function, 6 of 8 who received CYC during the trial developed diminished ovarian reserve, compared to 0 of 4 who did not receive CYC (P < 0.05). Changes in AMH correlated inversely with cumulative CYC dose (P < 0.01), with a 0.74 ng/ml decline in AMH level for each 10 gm of CYC. Conclusion. Daily oral CYC, even when administered for less than 6 months, causes diminished ovarian reserve, as indicated by low AMH levels. These data highlight the need for alternative treatments for GPA in women of childbearing age. Introduction Among women treated with cyclophosphamide (CYC), ovarian failure has long been viewed as an unfortunate but inevitable consequence of therapy. However, with recent successes in ovarian preservation and new alternative therapies for vasculitis, patients with this condition may now be able to avoid this treatment complication. Al- though the frequency of ovarian failure following CYC therapy in patients with vasculitis has not been previously ClinicalTrials.gov identifier: NCT00005007. Supported by Amgen; a contract with the NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases (N01-AR-9-2240); a grant from the FDA Office of Orphan Products (FD-R-001652-01); General Clinical Research Cen- ter grants from the NIH National Center for Research Re- sources to Johns Hopkins University School of Medicine (M01-RR0-2719), Boston University (M01-RR0-00533), Uni- versity of Michigan (M01-RR-0042), and Duke University (M01-RR-30); and the Charles Hammond Research Fund of Duke University Medical Center’s Department of Obstetrics and Gynecology. 1 Megan E. B. Clowse, MD, MPH, Susannah C. Copland, MD, Tsung-Cheng Hsieh, MS, Shein-Chung Chow, PhD, E. William St.Clair, MD, Nancy B. Allen, MD: Duke University Medical Center, Durham, North Carolina; 2 Gary S. Hoff- man, MD: Cleveland Clinic Foundation, Cleveland, Ohio; 3 Peter A. Merkel, MD, MPH: Boston University, Boston, Massachusetts; 4 Robert F. Spiera, MD: Hospital for Special Surgery, New York, New York; 5 John C. Davis, Jr., MD, MPH: University of California, San Francisco; 6 W. Joseph McCune, MD: University of Michigan, Ann Arbor; 7 Steven R. Ytterberg, MD, Ulrich Specks, MD: Mayo Clinic, Roches- ter, Minnesota; 8 John H. Stone, MD, MPH; Massachusetts General Hospital, Boston. Dr. Allen has received consultant fees, speaking fees, and/or honoraria (less than $10,000) from Genentech. Address correspondence to Megan E. B. Clowse, MD, MPH, Box 3535, Trent Drive, Durham, NC 27710. E-mail: megan.clowse@duke.edu. Submitted for publication April 20, 2011; accepted in revised form August 16, 2011. Arthritis Care & Research Vol. 63, No. 12, December 2011, pp 1777–1781 DOI 10.1002/acr.20605 © 2011, American College of Rheumatology BRIEF REPORTS 1777