The extent and reversibility of cytotoxic damage generally depends on the agent and cumulative dose received, although significant individual variation has been observed. The effects of alkylating agents on testicular function have been studied extensively.
Cyclophosphamide, either alone or in combination with other agents, is known to damage the germinal epithelium. In a meta-analysis of 30 studies that examined gonadal function following various chemotherapy regimens, gonadal dysfunction correlated with the total cumulative dose of cyclophosphamide; more than 300 mg/kg was associated with >80% risk of gonadal dysfunction . A study of men treated for pediatric solid tumors reported permanent azoospermia in 90% of men treated with cyclophosphamide doses >7.5 g/m2 . Other studies have also found that 7.5-9 g/m2 of cyclophosphamide is associated with a significant risk of testicular injury [5,39].
Although tumor cytotoxicity data indicates that 1.1 g/m2 cyclophosphamide is approximately equivalent to 3.8 g/m2 ifosfamide , the relative gonado-toxic effect is not well known. In a recent series of male childhood survivors of osteosarcoma 4-17 years after therapy (median: 9 years),the incidence of azoospermia related to ifosfamide therapy (median 42 g/m2), versus no ifosfamide, was statistically significant (P=0.005). Six patients were normospermic: five had received no ifosfamide and one had received low-dose ifosfamide (24 g/m2). Azoospermia occurred in 15 of the 19 patients who received ifos-
famide. Infertility in the others may have been related to cisplatin (560-630 mg/m2). One patient had oligospermia .
Hodgkin's disease (HD) patients treated with six or more courses of mechlorethamine, vincristine, procarbazine and prednisone (MOPP) have also demonstrated permanent azoospermia attributable to both of the alkylating agents, mechlorethamine and procarbazine. Procarbazine appears to play a major role in this process. Hassel et al. studied testic-ular function after OPA/COMP (vincristine, pred-nisone, adriamycin/cyclophosphamide, vincristine, methotrexate, prednisone) chemotherapy without procarbazine in boys with HD. These patients showed no major testicular damage, compared with boys who had received OPPA/COPP (including procar-bazine). This again, points out that procarbazine is a potent gonadotoxic agent . The treatment of Hodgkin's disease with combination chemotherapy regimens, such as ChlVPP (chlorambucil, vinblastine, procarbazine and prednisolone) or COPP (cy-clophosphamide, vincristine, procarbazine and pred-nisolone),has also been reported (in several studies) to result in permanent azoospermia in 99-100% of patients treated with 6-8 courses of these regimens [15,49]. After ChlVPP,both FSH and LH were elevated (by 89 % and 24 %, respectively), and azoospermia occurred in all seven patients tested. Charak and co-workers found azoospermia in all 92 patients following treatment with six or more cycles of COPP; 17% of patients had been treated more than 10 years previously, suggesting that germinal epithelial failure is likely to be permanent . CHOP (cyclophos-phamide, doxorubicin, vincristine, prednisolone) or CHOP-like regimens, such as those used for non-Hodgkin's lymphoma (NHL), are generally less gonadotoxic than those used for HD,presumably due to the absence of procarbazine in the treatment for NHL (e.g. VAPEC-B, VACOP-B, MACOP) [54, 64]. Azoo-spermia occurring on therapy for NHL is likely to recover within the following year . Efforts to reduce the risk of sterility after Hodgkin's disease include, among other related regimens, the use of ABVD (adriamycin, bleomycin, vinblastine and dacarbazine). This is an effective combination that does not contain the alkylating agents, chlorambucil or procarbazine [43, 86]. Viviani and co-workers showed that, while recovery of spermatogenesis after MOPP was rare, all who experienced oligospermia after ABVD recovered completely by 18 months . Hybrid regimens (i. e. alternating cycles of ABVD with ChlVPP or MOPP) are also less gonadotoxic than MOPP, ChlVPP or COPP given alone.
Nitrosoureas, used in the treatment of brain tumors in childhood, may also cause gonadal damage in boys [1,47,71]. In nine children treated for medul-loblastoma with craniospinal radiation and a nitro-sourea (carmustine or lomustine, plus vincristine in four boys and procarbazine in three), there was clinical and biochemical evidence of gonadal damage. Specifically, these children presented with elevated serum FSH and small testes for the stage of pubertal development, compared with eight children similarly treated but without chemotherapy. The authors concluded that nitrosoureas were responsible for the gonadal damage, with procarbazine also contributing in the three children who received this drug.
PVB (cisplatin, vinblastine and bleomycin), which is used in patients with germ cell tumors, is a standard chemotherapy and results in minimal effects on long-term testicular function. Patients, however, can be affected by ejaculatory failure, caused by damage to the thoracolumbar sympathetic plexus during retroperitoneal lymph node dissection, and by preexisting germ cell defects. Hansen et al. found that whether patients were treated with orchiectomy, or with orchiectomy plus PVB, sperm production 1.5 years after treatment was similar. Approximately half in each group had sperm counts below the normal control reference level . Lampe et al. analyzed the data on 170 patients with testicular germ cell cancers who had undergone treatment with either cisplatin or carboplatin-based chemotherapy .After median of 30 months from the completion of chemotherapy, they discovered that azoospermia occurred in 54 (32%) of the patients and oligospermia occurred in 43 (25%). The probability of recovery to a normal sperm count was higher in men who: a) had a normal pretreatment sperm count, b) had received carbo-platin rather than cisplatin-based therapy and c) had undergone a treatment with fewer than 5 cycles of chemotherapy. Recovery continued for more than two years, with the calculated chance of spermatogenesis at two years being 48%, and the calculated chance of spermatogenesis at five years being 80% [34,44].
Heyn and colleagues described the late effects of therapy on testicular function in patients between the ages of 10 months and 19 years afflicted with paratesticular rhabdomyosarcoma as a result of cyclophosphamide, radiation and retroperitoneal lymph node dissection. Tanner staging was normal in 45 patients for whom it was recorded. However, eight had loss of normal ejaculatory function. The available data showed that elevated FSH values and/or azoospermia occurred in greater than half the patients. Testicular size was decreased in those who received either cyclophosphamide or testicular irradiation .
The importance of alkylating agents in the induction of gonadal toxicity is noted by contrasting the above outcomes to those of children with acute lym-phoblastic leukemia (ALL). In general, testicular function is normal in boys after chemotherapy for ALL. All 37 survivors of childhood ALL evaluated at two time points after the completion of treatment (median age 9.7 years and again 18.6 years later) completed pubertal development normally and had a testosterone concentration within the normal adult range . Six men showed evidence of severe damage to the germ epithelium, with azoospermia or elevated FSH; all of these patients had received cyclophosphamide as part of their chemotherapy regimen . Thus, it may be inferred that, in contrast to alkylating agents, the classic anti-metabolites used in the treatment of childhood ALL are not associated with long-term gonadal toxicity. Although both vin-cristine and corticosteroids can cause immediate inhibition of spermatogenesis, following the cessation of these agents,spermatogenesis recovery occurs .
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