Pediatrik Romatolojik Hastalıklarda Kullanılan Siklofosfamid Tedavisi Gonad Yetmezliğine Neden Olur Mu?

Abstract

Introduction: Cyclophosphamide (CYC) with its immunosuppressive properties continues to be the drug of choice in patients with severe rheumatic disease, such as vasculitis and systemic lupus erythematosus (SLE). However, ovarian failure due to cytotoxicity of CYC remains to be a major concern in adolescent female patients with high probability of survival. Objectives: To analyze the risk of ovarian failure in women, diagnosed with rheumatic diseases and treated with CYC during adolescence. Methods: This is a single-center cross-sectional cohort study involving 41 female patients diagnosed with SLE and vasculitis between 2000 and 2023. Of these 41 female patients, 26 (17 SLE, 9 vasculitis) received CYC therapy and 15 (12 SLE, 3 vasculitis) with similar age distribution and tanner stages didn’t receive CYC therapy (control group). Patient characteristics, history of illness and treatment were recorded while presence of amenorrhea and pregnancy were questioned in detail. Serum follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol, anti mullerian hormone (AMH) and progesterone measurments and transabdominal pelvic ultrasonographic assessments were carried out in the early follicular phase. Analyses were done comparing the patients who received CYC and who didn’t and further evaluation was done by dividing patients who received CYC into two groups as high and low cumulative CYC doses (>3g or ≤ 3g, respectively) since cumulative CYC dose is an important risk factor for gonadal failure. Results: Median age of the subjects in the CYC and control groups at the time of current evaluation was 19 (12-34) and 18 (13-37) years respectively and in the meantime both groups had tanner stages of 4 and 5. The median age at CYC initiation was 13 (8-18) years while the median of cumulative CYC dosage was 2.3 (0,4-24) grams and treatment duration were 6 (1-17) months. With a median follow up of 6 (1-17) years, there were no statistically significant differences between serum FSH, LH, estradiol and progesterone levels between the groups. Notably, the AMH was comparably lower in the group with high cumulative CYC doses compared to low cumulative CYC doses and control group (1.86, 2.64 and 4.05 ng/mL respectively; p=0.230). The median ovarian volume was reduced significantly in the CYC group compared to the control group (4.85 and 8.30 cm3 respectively; p=0.039), although being similar for low and high cumative CYC doses. Mean follicular count was similar for all groups. 5 women (19,2%) developed transient amenorrhea however none had sustained amenorrhea. The incidence of amenorrhea was independent of CYC treatment and age at CYC initiation. Five pregnancies occurred during follow-up. Conclusion: None of the patients evaluated with a history of amenorrhea and FSH values met the diagnostic criteria for premature ovarian failure (POF). In line with these results low AMH levels with high cumulative CYC doses may indicate a need for watchful monitoring in terms of POF. Yet, it is thought that younger age at treatment initiation and low cumulative CYC doses reduces the risk of POF and thus using CYC in the management of pediatric rheumatic diseases may not be restricted in this particular group.