One way to treat various autoimmune diseases is chemotherapy with the alkylating agent cyclophosphamide, which may cause irreversible damage to the gonads. Some diseases where this therapy is an option are systemic lupus erythematosus (SLE), Behcet’s disease, chronic inflammatory demyelinising polyradiculoneuropathy (CIPD), the Goodpasture’s syndrome, Wegener’s granulomatosis and various forms of systemic vasculitis.
It is difficult to give a general prognosis for therapy-induced gonadal damage due to limited and heterogeneous data.
Risk of therapy-induced damage to the gonads
In a study published in 2002, 84 female patients (29 ± 10 years) with autoimmune diseases (56 with SLE) received a mean intravenous cyclophosphamide dose of 0,9 ± 0,14 g every 4 weeks over and average of 13 ± 6,5 cycles. In a follow-up of 5,1 ± 3,7 years, 27% developed an amenorrhea. On average, premature ovarian failure occurred at the age of 40 ± 7,6 years. The risk correlated highly significantly with age at therapy onset (Huong et al. J Rheumatol 2002, 29:2571-2576).
In a study published in 2004, 67 female patients with SLE (28,9 ± 8,3 years) were treated intravenously with 0,5-0,75 mg/m2 cyclophosphamide every 4 weeks over 6 cycles followed by the same dose every 3 months over a further 18 months. In a follow-up of 74,4 ± 20,6 months, 37.3% developed an amenorrhea over a variable period. However, in 14.9% of the patients, this amenorrhea also persisted afterwards (Park et al. Lupus 2004, 13:569-574).
In a 2004 review, the influence of cyclophosphamide on the ovarian function in SLE patients was analysed. The studies were designed extremely heterogeneously (n between 8-92, different dosages and cycle numbers) and showed an incidence of premature ovarian insufficiency of between 11-55%. The route of administration (oral vs. i.v.) seems to have been of no influence. However, the higher cumulative doses applied orally seem to increase ovarian toxicity. The likelihood of persisting amenorhhea rose with patient age, and the authors specified a cut-off of > 32 years (Katsifis & Tzioufas Lupus 2004, 13:673-678).
These figures have been confirmed by another group reporting
- premature ovarian failure after therapy with cyclophosphamide for 50% of SLE patients < 30 years and 60% of patients between 30 and 40 years (Manger et al. Autoimmun Rev 2006, 5:269-272).
Apart from cyclophosphamide, the alkylating agent colchicine may be used e.g. to treat Behcet’s disease. A review showed that it is unlikely to have a negative influence on spermiogenesis (Haimov-Kochman & Ben-Chetrit Hum Reprod 1998, 13:360-362).
Possibilities of fertility protection
As a rule, the full range of fertility protection measures can be offered since the cytotoxic therapy is often only initiated two weeks after the diagnosis or can be postponed so that there is a sufficient time window available.
The following fertility protection measures are possible:
- Ovarian stimulation and cryopreservation of fertilised and unfertilised oocytes.
- As an alternative especially for patient below 35, ovarian tissue may be laparoscopically retrieved and cryopreserved. The risk of metastasis when the tissue is retransplanted must however be discussed although no such metastasis has been reported in humans after the transplantations performed so far.
- In addition to the measures mentioned, GnRH analogues may be administered during chemotherapy. However, there is no clear evidence of the effectiveness of GnRH agonists yet. The general conclusion from the nine controlled studies published so far points to a protective effect, however (Blumenfeld & von Wolff Hum Reprod Update 2008 in press).
Cryopreservation of sperm is an established procedure. Before the cytotoxic therapy, one or several sperm samples are obtained by ejaculation. Cryopreservation is also useful when the sperm quality is poor. If the cryopreserved sperm is to be used at a later stage, there is a choice between the relatively simple intrauterine insemination or ICSI treatment. In principle, the prophylactic preservation of sperm can be recommended before the cytotoxic therapy is started.