Assessing Risk for Ovarian Dysfunction With Intravenous Cyclophosphamide in Women With Severe Lupus

Although monthly intravenous cyclophosphamide (CYC) was associated with subclinical ovarian dysfunction, with a negative effect on ovarian reserve in women with lupus, it did not increase risk for premature ovarian failure after 1 year of follow-up, according to study results published in Arthritis Research & Therapy.

A meta-analysis published in 2004 estimated that the risk for ovarian failure with CYC treatment was between 11% and 59%; however, the majority of the studies included in the analysis were published in before 2000, when amenorrhea alone was used as a marker of ovarian failure and CYC was administered in much higher doses. Investigators of this study sought to update the safety information of CYC in young women with severe lupus.

The current single-center, prospective, cohort study included women with severe lupus aged between 18 and 40 years. Patients received induction with either monthly intravenous CYC (0.5-0.75 g/m²) for 6 to 9 months or daily oral mycophenolate mofetil (MMF). Luteinizing hormone, follicle-stimulating hormone (FSH), estradiol, anti-Mullerian hormone (AMH), and inhibin B were measured at baseline and 6 months after treatment initiation. Menstrual irregularities were captured by patient reports at 6 months; women who reported amenorrhea or oligomenorrhea were re-evaluated at 1 year. Sonographic assessment of ovarian volume and antral follicular count were performed at baseline and 6 months.

A total of 50 women with systemic lupus erythematosus (SLE) were enrolled, among whom 25 received CYC and 25 received MMF. Demographic characteristics and family histories were comparable between groups. Mean age was 31.4±6.4 years in the CYC group and 28.4±4.4 years in the MMF group. Mean SLE Disease Activity Index at baseline was 7.2±2.5 and 5.8±3.4 in the CYC and MMF groups, respectively. Mean cumulative CYC dose was 4.6±1.8 g. Three patients in the CYC group had amenorrhea at 6 months, among whom 2 regained menses in 6 months. One patient developed sustained amenorrhea, which researchers suggested may be a result of menopause. No patients in the MMF group developed amenorrhea.

Over 6 months, mean FSH levels increased significantly in the CYC group (P =.03), while AMH (P =.002) and inhibin B (P <.001) levels decreased significantly. Levels of AMH, inhibin B, and estradiol were significantly lower in the CYC vs MMF group at 6 months, despite being similar at baseline. Ovarian volume also decreased significantly over 6 months (P =.005) in the CYC group, but not in the MMF group. Antral follicular count was numerically reduced in patients who received CYC, though the reduction was not statistically significant (P =.32).

While monthly intravenous CYC was associated with decreased ovarian volume and changes in hormone levels, ovarian dysfunction was largely subclinical. According to the researchers, a small percentage of women experienced amenorrhea, among whom most were able to regain their menstrual cycle with time. In the context of severe lupus, in which symptoms may be organ- or life-threatening, intravenous CYC for induction should remain an option.

Study limitations included its observational design, lack of randomization of treatment choice that may have led to potential selection bias, and small sample size.

“Use of intravenous CYC for induction [should] not be restricted in young [women with] lupus…where the benefits outweigh this subclinical risk,” the investigators concluded.

Reference

Sharma SK, Jain S, Bahl P, et al. Ovarian dysfunction with moderate-dose intravenous cyclophosphamide (modified NIH regimen) and mycophenolate mofetil in young adults with severe lupus: a prospective cohort study. Published online August 14, 2020. Arthritis Res Ther. 2020;22(1):189.