Ovarian reserve diminished by oral cyclophosphamide therapy for granulomatosis with polyangiitis (Wegener's)

Arthritis Care Res (Hoboken). 2011 Dec;63(12):1777-81. doi: 10.1002/acr.20605.


Objective: Standard treatment for severe granulomatosis with polyangiitis (Wegener's) (GPA) is daily oral cyclophosphamide (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-Müllerian 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.

Trial registration: ClinicalTrials.gov NCT00005007.

Publication types

  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Anti-Mullerian Hormone / blood
  • Biomarkers / blood
  • Cyclophosphamide / administration & dosage
  • Cyclophosphamide / adverse effects*
  • Double-Blind Method
  • Etanercept
  • Female
  • Follicle Stimulating Hormone, Human / blood
  • Granulomatosis with Polyangiitis / drug therapy*
  • Humans
  • Immunoglobulin G / administration & dosage
  • Immunosuppressive Agents / administration & dosage
  • Immunosuppressive Agents / adverse effects*
  • Methotrexate / adverse effects*
  • Middle Aged
  • Ovary / drug effects*
  • Ovary / metabolism
  • Ovary / physiopathology
  • Primary Ovarian Insufficiency / blood
  • Primary Ovarian Insufficiency / chemically induced*
  • Primary Ovarian Insufficiency / physiopathology
  • Receptors, Tumor Necrosis Factor / administration & dosage
  • Time Factors
  • Treatment Outcome
  • United States
  • Young Adult


  • Biomarkers
  • Follicle Stimulating Hormone, Human
  • Immunoglobulin G
  • Immunosuppressive Agents
  • Receptors, Tumor Necrosis Factor
  • Anti-Mullerian Hormone
  • Cyclophosphamide
  • Etanercept
  • Methotrexate

Associated data

  • ClinicalTrials.gov/NCT00005007