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Three Part Question

In [young female patients with SLE undergoing CYC therapy], does [the use of GnRH-a when compared to no intervention], prevent [premature ovarian failure]?

Clinical Scenario

A 15-year-old girl with acute renal failure was found to have class IV systemic lupus erythematosus (SLE) nephritis on renal biopsy. A decision was taken to start her on the routine National Institute of Health protocol of pulsed methyl-prednisolone and monthly intravenous cyclophosphamide (CYC) (0.5–1.0 g/m2 of body surface area). With her post-pubertal status and the possibility of CYC induced gonadal toxicity, the question was raised as to whether she should be put on gonadotropin releasing hormone analogue (GnRH-a) therapy for ovarian protection.

Search Strategy

Medline: 1950–to date; EMBASE: 1974–to date; CINAHL: 1982–to date via Dialog DataStar
Cochrane Library
The search was conducted independently by both authors between December 2006 and January 2007
[Lupus or Systemic lupus erythematosus] AND [cyclophosphamide] AND [gonadal toxicity or premature ovarian failure or fertility] AND [gonadotropin releasing hormone analogue or GnRH or GnRH-a] Limits: English, Human

Search Outcome

Total number of hits: five, of which two studies were eligible

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Blumenfeld et al, 2000, Israel	Study population: 8 females (7 SLE), age: 20–30 years Control: 9 females (8 SLE), age: 20–43 years Follow-up: 2–15 years	Case control study Level of evidence: 4	Premature ovarian failure (POF)	Study population: none had POF Control: 5 had POF	This study did suggest benefits of adjuvant GnRH-a in reducing POF among young women with SLE. Drawbacks: Non-randomised Controls not matched Small population Not paediatric Lack of details of 2 study individuals despite their inclusion in analysis Side effects not elaborated
Somers et al, 2005, USA	Study population: 20 females with SLE, age: 17–32 years Matched control: 20 females with SLE Follow-up: study population 0.6–9.3 years, control 0.8–16.7 years	Case control study Level of evidence: 3b	POF	Study population: 1 had POF Control: 6 had POF (p<0.05)	Hazard of developing ovarian failure within 10 years of CYC treatment was ten times greater in control group compared to study population Drawbacks: Non-randomised Historical matched control Minimum age 17 years, but adequate details missing Residual ovarian function measured only in presence of suggestive symptoms

Comment(s)

Cyclophosphamide (CYC) is an alkylating agent widely used to treat renal and extra-renal involvement in SLE. This cytotoxic agent reacts with DNA bases and damages DNA repair mechanisms, inhibiting replication and leading to cell death. In animal studies, CYC has been shown to reduce the number of ovarian granulosa cells, resulting in decreased circulating levels of progesterone and oestrogen and ovarian fibrosis (Ataya). As the numbers of germ cells are limited and cannot be regenerated, the damage is usually cumulative and irreversible (Blumenfeld, 2000). Gonadal toxicity due to CYC therapy in SLE has also been reported in many human studies (Langevitz). Although CYC does not seem to cause ovarian toxicity before menarche (Wallace). post-pubertal girls are at increased risk of developing ovarian failure. A recent study by Brunner et al on ovarian function in childhood onset SLE (onset at age <=18 years) reported decreased ovarian reserve in 31% of patients exposed to CYC compared to none in the non-CYC group. While CYC prolongs survival and reduces end organ damage in SLE (Houssiau) it may also cause an unacceptably high incidence of gonadal toxicities. Various options for ovarian preservation have been mentioned, such as cryopreservation of oocyte, cryopreservation of embryo, oral contraceptive pills (OCPs) and GnRH-a.8 Unfortunately, all have some drawbacks. Oocyte preservation is still an experimental technique and has significant legal implications in the UK, while the cryopreservation of embryos is expensive and only suitable for women in a stable partnership. Moreover, both techniques may induce an SLE flare during hormonal manipulation.2 OCPs have little data to demonstrate efficacy (Blumenfeld, 1999). Another option is GnRH-a which provides ovarian protection against chemotherapy by ovarian suppression and by decreasing ovarian blood flow as it induces a stage of reversible medical castration (Blumenfield, 2003). As shown in the table, we found only two studies in our search on the use of GnRH-a in young women with SLE. The study by Blumenfeld et al (2000) reported five cases of premature ovarian failure (POF) out of a total of eight in the control group, while none of the eight patients treated with GnRH-a developed POF. In the other study by Somers et al,2 one patient amongst the 20 in the GnRH-a group developed POF compared to six out of 20 in the non-intervention group. Both of these were case series with historical control comparisons. Although the age ranges were 20–30 years for the study by Blumenfeld et al and 17–32 years for the study by Somers et al, little information was available relating to the youngest patients in the group. GnRH-a administration does not come without potential side effects. It may result in symptoms of hypo-oestrogenism including menopausal symptoms and osteoporosis which it might not be possible to treat with oestrogen due to fear of SLE flare up. Young females exposed to CYC are at sizable risk of being left with a reduced ovarian reserve and may develop POF and infertility in later life (Silva) GnRH-a may potentially be a good option for preserving their ovarian function. Better designed studies primarily on post-pubertal girls with longer follow-ups are needed to arrive at a definite conclusion. With SLE survival rates increasing, the need for preservation of gonadal function should now be a priority. This is especially important as approximately 20% of cases are being diagnosed during childhood (Carreno). Premature ovarian failure secondary to cytotoxic therapy has been shown to result in emotional disturbances and depression and hence its prevention should contribute to a better quality of life (Chapman).

Clinical Bottom Line

Young women suffering from systemic lupus erythematosus (SLE) treated with cyclophosphamide (CYC) have a high risk of ovarian failure. (Grade C) GnRH is a promising option for ovarian preservation in SLE but should currently be regarded as an experimental therapy.

References

1. Blumenfeld Z, Shapiro D, Shteinberg M, et al. Preservation of fertility and ovarian function and minimizing gonadotoxicity in young women with systemic lupus erythematosus treated by chemotherapy. Lupus 2000; 9: (6): 401–5.
2. Somers EC, Marder W, Christman GM, et al. Use of a gonadotropin-releasing hormone analog for protection against premature ovarian failure during cyclophosphamide therapy in women with severe lupus. Arthritis Rheum 2005; 52: (9): 2761–7.
3. Ataya KM, Valeriote FA, Ramahi-Ataya AJ. Effect of cyclophosphamide on the immature rat ovary. Cancer Res 1989; 49: (7): 1660–4.
4. Langevitz P, Klein L, Pras M, et al. The effect of cyclophosphamide pulses on fertility in patients with lupus nephritis. Am J Reprod Immunol 1992; 28: (3–4): 157–8.
5. Wallace WH, Shalet SM, Tetlow LJ, et al. Ovarian function following the treatment of childhood acute lymphoblastic leukaemia. Med Pediatr Oncol 1993; 21: (5): 333–9.
6. Brunner HI, Bishnoi A, Barron AC, et al. Disease outcomes and ovarian function of childhood-onset systemic lupus erythematosus. Lupus 2006; 15: (4): 198–206.
7. Houssiau F. 30 years of cyclophosphamide: assessing the evidence. Lupus 2007; 16: (3): 212–16.
8. Blumenfeld Z, Avivi I, Ritter M, et al. Preservation of fertility and ovarian function and minimizing chemotherapy-induced gonadotoxicity in young women. J Soc Gynecol Investig 1999; 6: (5): 229–39.
9. Blumenfeld Z. Gynaecologic concerns for young women exposed to gonadotoxic chemotherapy. Curr Opin Obstet Gynecol 2003; 15: (5): 359–70.
10. Silva CA, Leal MM, Leone C, et al. Gonadal function in adolescents and young women with juvenile systemic lupus erythematosus. Lupus 2002; 11: (7): 419–25.
11. Carreno L, Lopez-Longo FJ, Monteagudo I, et al. Immunological and clinical differences between juvenile and adult onset of systemic lupus erythematosus. Lupus 1999; 8: (4): 287–92.
12. Chapman RM. Effects of cytotoxic therapy on sexuality and gonadal function. Semin Oncol 1982; 9: (1): 84–94.