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Egyptian Rheumatology and Rehabilitation
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Premature ovarian failure in systemic lupus erythematosus patients: is it related to cyclophosphamide treatment?

Egyptian Rheumatology and Rehabilitation volume 46, pages 85–91 (2019)Cite this article

Abstract

Introduction

Systemic lupus erythematosus (SLE) is a chronic autoimmune systemic disease that mainly affects women during the childbearing period. Cyclophosphamide (CYC) is the drug of choice for severe SLE manifestations. However, many side effects had been reported. Premature ovarian failure (POF) is one of the serious complications that can occur in SLE patients.

Aim

The aim was to evaluate the prevalence of POF in female patients with SLE and whether it is related to CYC treatment or not.

Patients and methods

One hundred women with SLE satisfying the updated revised criteria for the classification of SLE were studied. The patients were allocated into two groups: CYC-treated group (n=55) and non-CYC-treated group (n=45). Patients were interviewed and demographic characteristics, clinical and serologic profiles, and menstrual histories were recorded. Disease activity was measured by the SLE disease activity index. Serum anti-Müllerian hormone was measured as a marker for ovarian reserve assessment in the two study groups.

Results

Ovarian failure occurred in 15 (27.3%) patients out of the 55 SLE patients treated with CYC. The cumulative CYC dose was significantly higher in patients with ovarian failure than in those without this condition (11.7 vs. 9.5 g; P=0.001). The cumulative dose of CYC and the older age at initiation were found to be associated more with POF.

Conclusion

In our population of female SLE patients, CYC-induced ovarian failure is a significant problem occurring in 27.3% of SLE patients receiving CYC. So, for SLE patients in whom the use of CYC is mandatory, a lower dosage and a shorter course of this agent should be considered. Co-treatment with gonadotropin-releasing hormone agonists might persevere the future fertility and ovarian function in young women. Ovarian banking before administration of CYC could be a possible solution in certain cases.

References

  1. Cervera R, Balasch J. Bidirectional effects on autoimmunity and reproduction. Hum Reprod Update 2008; 14:359–366.

    Article  CAS  Google Scholar 

  2. Akawatcharangura P, Taechakraichana N, Osiri M. Prevalence of premature ovarian failure in systemic lupus erythematosus patients treated with immunosuppressive agents in Thailand. Lupus 2016; 25:436–444.

    Article  CAS  Google Scholar 

  3. Chai HC, Phipps ME, Chua KH. Genetic risk factors of systemic lupus erythematosus in the Malaysian population: a minireview. Clin Dev Immunol 2012; 2012:963730.

    Article  Google Scholar 

  4. Wong M, La Cava A. Lupus, the current therapeutic approaches. Drugs Today (Barc) 2011; 47:289–302.

    Article  CAS  Google Scholar 

  5. Elizur SE, Chian RC, Pineau CA, Son WY, Holzer HE, Huang JY, et al. Fertility preservation treatment for young women with autoimmune diseases facing treatment with gonadotoxic agents. Rheumatology 2008; 47:1506–1509.

    Article  CAS  Google Scholar 

  6. Fox DA, McCune WJ. Immunosuppressive drug therapy of systemic lupus erythematosus. Rheum Dis Clin North Am 1994; 20:265–299.

    CAS  PubMed  Google Scholar 

  7. Petri M. Cyclophosphamide: new approaches for systemic lupus erythematosus. Lupus 2004; 13:366–371.

    Article  CAS  Google Scholar 

  8. Petri M, Brodsky RA, Jones RJ, Gladstone D, Fillius M, Magder LS. High-dose cyclophosphamide versus monthly intravenous cyclophosphamide for systemic lupus erythematosus: a prospective randomized trial. Arthritis Rheum 2010; 62:1487–1493.

    Article  CAS  Google Scholar 

  9. Persani L, Rossetti R, Cacciatore C. Genes involved in human premature ovarian failure. J Mol Endocrinol 2010; 45:257–279.

    Article  CAS  Google Scholar 

  10. Kokcu A. Premature ovarian failure from current perspective. Gynecol Endocrinol 2010; 26:555–562.

    Article  Google Scholar 

  11. Lin C, Chen Y, Chen D, Huang W, Lan J. Low dose intravenous cyclophosphamide–induced ovarian failure in Chinese patients with lupus nephritis. J Rheumatol ROC 2007; 21:53–58.

    Google Scholar 

  12. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997; 40:1725.

    Article  CAS  Google Scholar 

  13. Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH. Derivation of the SLEDAI. A disease activity index for lupus patients. The committee on prognosis studies in SLE. Arthritis Rheum 1992; 35:630–640.

    CAS  Google Scholar 

  14. Uribe AG, Vilá LM, McGwin GJr, Sanchez ML, Reveille JD, Alarcón GS. The systemic lupus activity measure-revised, the Mexican systemic lupus erythematosus disease activity index (SLEDAI), and a modified SLEDAI-2K are adequate instruments to measure disease activity in systemic lupus erythematosus. J Rheumatol 2004; 31:1934–1940.

    PubMed  Google Scholar 

  15. Gnoth C, Schuring AN, Friol K, Tigges J, Mallmann P, Godehardt E. Relevance of anti-Mullerian hormone measurement in a routine IVF program. Hum Reprod 2008; 23:1359–1365.

    Article  CAS  Google Scholar 

  16. Gourley MF, Austin HA, Scott D, Yarboro CH, Vaughan EM, Muir J, et al. Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. A randomized, controlled trial. Ann Intern Med 1996; 125:549–557.

    CAS  PubMed  Google Scholar 

  17. Barile-Fabris L, Ariza-Andraca R, Olguin-Ortega L, Jara LJ, Fraga-Mouret A, Miranda-Limón JM, et al. Controlled clinical trial of IV cyclophosphamide versus IV methylprednisolone in severe neurological manifestations in systemic lupus erythematosus. Ann Rheum Dis 2005; 64:620–625.

    Article  CAS  Google Scholar 

  18. Saoji VA. Premature ovarian failure due to cyclophosphamide: a report of four cases in dermatology practice. Indian J Dermatol Venereol Leprol 2008; 74:128–132.

    Article  Google Scholar 

  19. Wang CL, Wang F, Bosco JJ. Ovarian failure in oral cyclophosphamide treatment for systemic lupus erythematosus. Lupus 1995; 4:11–14.

    Article  CAS  Google Scholar 

  20. Warne GL, Fairley KF, Hobbs JB, Martin FI. Cyclophosphamide-induced ovarian failure. N Engl J Med 1973; 289:1159–1162.

    Article  CAS  Google Scholar 

  21. Belmont HM, Storch M, Buyon J, Abramson S. New York University/Hospital for joint disease experience with intravenous cyclophosphamide treatment: efficacy in steroid unresponsive lupus nephritis. Lupus 1995; 4:104–108.

    Article  CAS  Google Scholar 

  22. Langevitz P, Klein L, Pras M, Many A. The effect of cyclophosphamide pulses on fertility in patients with lupus nephritis. AmI J Reprod Immunol 1992; 28:157–158.

    Article  CAS  Google Scholar 

  23. Uldall PR, Kerr DN, Tacchi D. Sterlity and cyclophosphamide. Lancet 1972; 1:693–694.

    Article  CAS  Google Scholar 

  24. Simon B, Lee SJ, Partridge AH, Runowicz CD. Preserving fertility after cancer. CA Cancer J Clin 2005; 55:211–228.

    Article  Google Scholar 

  25. van Rooij IA, Tonkelaar I, Broekmans FJ, Looman CW, Scheffer GJ, de Jong FH, et al. Anti-müllerian hormone is a promising predictor for the occurrence of the menopausal transition. Menopause 2004; 11:601–606.

    Article  Google Scholar 

  26. Mok CC, Lau CS, Wong RW. Risk factors for ovarian failure in patients with systemic lupus erythematosus receiving cyclophosphamide therapy. Arthritis Rheum 1998; 41:831–837.

    Article  CAS  Google Scholar 

  27. McDermott EM, Powell RJ. Incidence of ovarian failure in systemic lupus erythematosus after treatment with pulse cyclophosphamide. Ann Rheum Dis 1996; 55:224–229.

    Article  CAS  Google Scholar 

  28. D’Cruz D, Cuadrado MJ, Mujic F, Tungekar MF, Taub N, Lloyd M, et al. Immunosuppressive therapy in lupus nephritis. Clin Exp Rheumatol 1997; 15:275–282.

    PubMed  Google Scholar 

  29. Richardson SJ. The biological basis of the menopause. Ballieres Clin Endocrinol Metab 1993; 7:1–16.

    Article  CAS  Google Scholar 

  30. Silva CA, Bonfa E, Stensen M. Maintenance of fertility in patients with rheumatic diseases needing anti-inflammatory and immunosuppressive drugs. Arthritis Care Res 2010; 62:1682–1690.

    Article  Google Scholar 

  31. Ioannidis JP, Katsifis GE, Tzioufas AG, Moutsopoulos HM. Predictors of sustained amenorrhea from pulsed intravenous cyclophosphamide in premenopausal women with systemic lupus erythematosus. J Rheumatol 2002; 29:2129–2135.

    CAS  PubMed  Google Scholar 

  32. Yang XY, Zhu X, Liang LQ, Zhan ZP, Ye YJ. Risk factors of ovarian failure in the patients with systemic lupus erythematosus receiving cyclophosphamide therapy. Zhonghua Yi Xue Za Zhi 2005; 85:960–962.

    PubMed  Google Scholar 

  33. Medeiros MM, Silveira VA, Menezes AP, Carvalho RC. Risk factors for ovarian failure in patients with systemic lupus erythematosus. Braz J Med Biol Res 2001; 34:1561–1568.

    Article  CAS  Google Scholar 

  34. Anderson RA, Wallace WH. Fertility preservationin girls and young women. Clin Endocrinol 2011; 75:409–419.

    Article  Google Scholar 

  35. Weenen C, Laven JS, Von Bergh AR, Cranfield M, Groome NP, Visser JA, et al. Anti-Müllerian hormone expression pattern in the human ovary: potential implications for initial and cyclic follicle recruitment. Mol Hum Reprod 2004; 10:77–83.

    Article  CAS  Google Scholar 

  36. Andersen CY, Schmidt KT, Kristensen SG, Rosendahl M, Byskov AG, Ernst E. Concentrations of AMH and inhibin-B in relation to follicular diameter in normal human small antral follicles. Hum Reprod 2010; 25:1282–1287.

    Article  CAS  Google Scholar 

  37. La Marca A, Malmusi S, Giulini S, Tamaro LF, Orvieto R, Levratti P, Volpe A. Anti-Müllerian hormone plasma levels in spontaneous menstrual cycle and during treatment with FSH to induce ovulation. Hum Reprod 2004; 19:2738–2741.

    Article  Google Scholar 

  38. van Disseldorp J, Lambalk CB, Kwee J, Looman CW, Eijkemans MJ, Fauser BC, Broekmans FJ. Comparison of inter- and intra-cycle variability of anti-Müllerian hormone and antral follicle counts. Hum Reprod 2010; 25:221–227.

    Article  Google Scholar 

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Authors and Affiliations

  1. Rheumatology and Rehabitation Department, Minia University, 27 Nefriti Street, Minia, Egypt

    Rasha M. Ghaleb MD

  2. Obstetric and Gynecology Department, Minia University, Minia, Egypt

    Khaled A. Fahmy

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  1. Rasha M. Ghaleb MD
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Correspondence to Rasha M. Ghaleb MD.

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Ghaleb, R.M., Fahmy, K.A. Premature ovarian failure in systemic lupus erythematosus patients: is it related to cyclophosphamide treatment?. Egypt Rheumatol Rehabil 46, 85–91 (2019). https://doi.org/10.4103/err.err_53_18

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