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

Abstract

Objective Standard treatment for severe granulomatosis with polyangiitis (GPA, previously Wegener’s granulomatosis) 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 under 50, 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 AMH<1.0ng/ml. Results Of 42 women in this analysis (mean age 35), 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, 6/8 who received CYC during the trial developed diminished ovarian reserve, compared to 0/4 who did not receive CYC (p<0.05). Changes in AMH correlated inversely with cumulative CYC dose (p=0.01), with a 0.74ng/ml decline in AMH for each 10g 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.

Outcomes of ovarian stimulation after treatment with chemotherapy

“…Alkylating agents, such as cyclophosphamide, are well known to cause follicular depletion, oocyte destruction, and stromal fibrosis [2][3][4], and the risk of ovarian dysfunction appears to occur in a dose-dependent fashion [5]. This effect has been demonstrated in both cancer patients [5][6][7][8] and in patients with autoimmune disease such as systemic lupus erythematosus and granulomatosis with polyangiitis [9,10]. Variable toxicity has been documented for multidrug regimens.…”

Therapeutisches Vorgehen bei ANCA-assoziierten Vaskulitiden

“…Auch eine auf weniger als 6 Monate befristete CYC-Therapie reduziert bei Patienten mit GPA die Ovarfunktion und kann somit die Fertilität einschränken [7]. Bei jungen Patientinnen sollten daher präventive Maßnahmen (z.…”

Fertilitätsprotektion bei rheumatologischen Erkrankungen

“…Nach einer CYC-Therapie kommt es bei knapp 60% der über 30-jährigen und bei 39% der unter 30-jäh-rigen Lupuspatientinnen zu einem POF und einer Amenorrhö [3]. Eine kürzlich erschienene Arbeit zeigte auch bei Patientinnen mit einer ANCA-assoziierten Vaskulitis negative Folgen der CYC-Therapie auf die ovarielle Reserve, gemessen anhand des Anti-Müller-Hormons (AMH; [4]). …”