Cyclophosphamide is one of the more commonly used drugs in nephrology, especially in the treatment of lupus nephritis and systemic vasculitis, which is a milestone.
Cyclophosphamide is an alkylating agent that acts as both a broad-spectrum antitumor agent and an immunosuppressant. Its role as an immunosuppressant is to kill antigen-sensitive small lymphocytes non-specifically by inhibiting cell proliferation and limiting their conversion into immunoblasts. It has an inhibitory effect on both humoral and cellular immunity. It can improve hormone efficacy, reduce the dosage of glucocorticoids and decrease the side effects of glucocorticoids. It is mainly used in nephrology for frequent relapses and refractory nephrotic syndrome, autoimmune diseases such as systemic lupus erythematosus, ANCA-associated small vasculitis, chronic nephritis, etc.
The main side effects of cyclophosphamide are.
1, carcinogenic, teratogenic
2, bone marrow suppression
3.Hemorrhagic cystitis
4.Reproductive toxicity
5.Gastrointestinal symptoms
6.Severe hair loss
7.Infection increase.
Therefore, the maximum dose of cyclophosphamide is generally 150 mg/Kg body weight.
However, it seems that the reproductive toxicity of cyclophosphamide has not received sufficient attention from clinical workers. The use of cyclophosphamide is still more common in children with refractory nephrotic syndrome and young infertile SLE patients. Young patients with infertility as a result of cyclophosphamide use also exist.
The toxic effects of cyclophosphamide on the gonads are mainly reflected in.
1, the impact on male reproductive function: cyclophosphamide mainly affects the number and function of male sperm and sex hormone levels. Long-term use of cyclophosphamide is likely to cause sperm deficiency, which usually occurs 2-3 months after the start of treatment and persists during the treatment period, but its gonadotoxic effects will gradually disappear after stopping the drug. Cyclophosphamide damages the seminiferous tubules of the testis and subsequently the spermatogenic cells. With the destruction of germ cells, the follicle-stimulating hormone (FSH) in the body also changes, and its concentration tends to increase both at basal state and after stimulation by luteinizing hormone (LH). Some studies have found that LH responsiveness to luteinizing hormone-releasing hormone (LHRH) is significantly higher in cyclophosphamide treated patients.
The risk of persistent amenorrhea in women with lupus has been shown to correlate with the age of initial cyclophosphamide treatment and the cumulative dose received. a meta-analysis of six studies suggests that cumulative doses of cyclophosphamide between 12 and 25 g can lead to persistent amenorrhea in patients with SLE.
However, not every patient using cyclophosphamide causes reproductive toxicity. The risk factors for the development of gonadal damage are generally.
1. Initial age.
One study showed that patients under 30 years of age had a <10% risk of developing amenorrhea at their cumulative cyclophosphamide doses of 12 g and 18 g, respectively, and up to 60% over 40 years of age. Despite the low rate of amenorrhea in younger women, a higher number of women still experience infertility, infertility or inability to have a second pregnancy after the end of treatment. This suggests that cyclophosphamide may still have a toxic effect on ovarian function in young women, so careful consideration is needed when applying it.
2. Cumulative dose.
Persistent amenorrhea occurs in 50% of women receiving a dose of 8 g/m2, and when the dose reaches 12 g/m2, 90% of women are unable to avoid persistent amenorrhea even with protective measures. However, if the dose of cyclophosphamide is <10g, the risk of amenorrhea in young women is greatly reduced.
3. Duration of cyclophosphamide treatment.
The duration of cyclophosphamide treatment, like the cumulative dose, is closely related to the degree of gonadal damage in both sexes. As the duration of cyclophosphamide treatment increases, the sperm count decreases significantly. For premenopausal women who wish to preserve their fertility, the cumulative dose of intravenous cyclophosphamide should be limited to less than 8 g/m2, preferably less than 5 g/m2, and the duration of treatment should be limited to 6 months. However, even if the cumulative dose is controlled to less than 5g/m2, the gonadotoxic effect of cyclophosphamide cannot be completely avoided, and about 1/3 of patients will eventually develop ovarian failure in clinical practice.
Currently, with the introduction of many new immunosuppressive drugs, the selectivity of the drugs is becoming more and more extensive, but cyclophosphamide, with its unique efficacy and low price, is still widely used in clinical practice. However, for patients who wish to preserve reproductive function, clinicians can choose less reproductive toxic drugs such as cyclosporine, tacrolimus, and mycophenolate to avoid reproductive toxicity caused by cyclophosphamide, or consult a physician to take necessary measures to protect reproductive capacity when cyclophosphamide must be used.