Ovarian dysfunction with moderate-dose intravenous cyclophosphamide (modified NIH regimen) and mycophenolate mofetil in young adults with severe lupus: a prospective cohort study

Abstract

Background Ovarian toxicity is a dreaded complication of cyclophosphamide (CYC). With the use of lower cumulative doses of intravenous CYC (modified NIH regimens) and availability of better markers of ovarian toxicity, the incidence of ovarian dysfunction needs reassessment. Lupus disease activity, by itself, is also believed to affect ovarian function negatively. Methods This single-centre prospective cohort study recruited 50 female patients of severe lupus aged 18–40 years. Twenty-five patients each received induction with either monthly intravenous CYC (0.5–0.75 g/m 2 ) for 6–9 months or daily oral mycophenolate mofetil (MMF). Details of menstrual irregularities; serum levels of FSH, LH, estradiol, AMH, and inhibin B; and sonographic assessment of ovarian volume and antral follicular count were done at baseline and 6 months after treatment. Amenorrhoeic patients were re-evaluated at 1 year. Results Mean (SD) age of subjects in the CYC and MMF groups was 31.4 (6.3) and 28.4 (4.4) years, respectively. Mean (SD) SLEDAI at the initiation of therapy was 7.2 (2.5) in the CYC group and 5.8 (3.4) in the MMF group. The mean cumulative dose of CYC used was 4.6 (1.8) g. Three patients in the CYC group (versus none in MMF) had amenorrhoea at 6 months—two of these regained menses within 6 months, while only one (4%) developed sustained amenorrhoea (lasting more than 12 months) at 41 years of age, likely menopause. Serum FSH levels increased ( p = 0.03), while AMH ( p = 0.002) and inhibin B ( p < 0.001) levels decreased significantly with 6 months of CYC therapy. Ovarian volume also reduced significantly ( p = 0.005) with 6 months of CYC therapy, while antral follicular count reduced numerically ( p = 0.32). Levels of AMH, inhibin-B, estradiol, ovarian volume, and antral follicular count after 6 months therapy were significantly lesser in the CYC group compared to the MMF group, despite being similar before the start of therapy. Conclusions Ovarian dysfunction with monthly intravenous CYC (modified NIH regimen) was predominantly subclinical, with a negative effect on ovarian reserve. No premature ovarian failure was noted at 1 year. No ovarian dysfunction occurred in the MMF group, despite having patients with severe background lupus. Use of intravenous CYC for induction may thus not be restricted in young lupus females with incomplete families for fear of gonadotoxicity, especially in life- or organ-threatening situations, where the benefits outweigh this subclinical risk.

The Effect of Wet Cupping Therapy on Anxiety and Thiol/Disulfide Homeostasis in Premature Ovarian Failure: An Experimental Study

“…31,32 The mechanisms of CYC to induce anxiety are explained by E2 withdrawal due to ovarian injury and increased oxidative stress. 12,33 In our study, the dose of CYC determined to create a POF model caused damage to the ovaries, created anxiety-like behaviors, and decreased serum E2 levels, but this decrease was not significant. 12,17 This shows that E2 withdrawal time is not sufficient.…”

Premature Ovarian Insufficiency in Systemic Sclerosis

“…Indeed, cyclophosphamide, which is used as a first-line immunosuppressive medicine in the treatment of life-threatening organ involvement of SLE, SSc and vasculitides, is an alkylating agent that causes gonodotoxicity. Consistent with this general knowledge, recent studies showed an increased risk of ovarian failure in SLE patients treated with cyclophosphamide compared to SLE patients treated with mycophenolate, azathioprine, calcineurin inhibitors, and steroids [18][19][20]. For RA patients, there are inconsistent studies.…”

Glycyrrhiza glabra alcoholic root extract ameliorates hyperglycemia, hyperlipidemia, and glycation‐induced free iron‐mediated oxidative reactions

“…In another study, it has been reported about the ameliorative effects of CoQ10 on Follicle Stimulating Hormone Receptor and Proliferating Cell Nuclear Antigen genes, IVF rate, and embryo development in cyclophosphamide‐induced mice model of ovarian injury (Delkhosh et al, 2019). On the other hand, a moderate intravenous dose of cyclophosphamide along with mycophenolate mofetil treatment has been found to be effective in severe systemic lupus erythematosus young adults accompanied with mild or negligible gonadotoxicity (Sharma et al., 2020). Similarly, isoliquiritigenin and formononetin derived from G. glabra have been reported to improve the IVF rate in mice (Tung et al., 2015).…”