Treatment of Hematological Malignancy

The effect of chemotherapy used in the treatment of lymphomas, especially Hodgkin's disease, on testicular function has been widely reported. Several studies have reported azoospermia with raised FSH levels in more than 90% of men after cyclical chemotherapy with MVPP (mustine, vinblastine, procarbazine, and prednisolone) (16,17).

In an attempt to reduce the gonadotoxic effect of MVPP by halving the alkylating drug and reducing the procarbazine dose, a hybrid combination of chlorambucil, vinblastine, prednisolone, procarbazine, doxorubicin, vincristine, and etoposide (ChlVPP/EVA) has been used. However, in a direct comparison with MVPP, hybrid chemotherapy had the same effect on gonadal function (18). However, an alternative regimen, consisting of ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) is less gonadotoxic. Viviani et al. (19) studied a total of 53 men treated with combination chemotherapy for Hodgkin's disease. Of the 29 men treated with MOPP (similar to MVPP but with vinblastine replaced by vincristine), 28 were azoospermic, at a median time of 6 mo after the completion of therapy. Of these men, 21 were retested 18 to 58 mo after the initial analysis and only in 3 was there any recovery of spermatogenesis. However, the impact of ABVD was considerably less, with a normal sperm count in 11 of 24 patients and oligospermia in a further 5. Furthermore, full recovery of spermatogenesis occurred within 18 mo of the first evaluation in all 13 men in whom the sperm count was repeated.

Other chemotherapy regimens used for the treatment of lymphomas have also been investigated. The effect on adult testicular function has been assessed in patients treated for Hodgkin's disease with ChlVPP (chlorambucil, vinblastine, procarbazine, and prednisolone) during childhood. Testicular dysfunction, as indicated by raised gonadotropin levels, was found in a significant proportion of a cohort of 46 male patients treated with ChlVPP reported by Mackie et al. (20), with 89% and 24% having raised FSH and LH levels, respectively. The use of COPP (cyclophosphamide, vincristine, procarbazine, and prednisolone), which includes the gonadotoxic agent cyclophosphamide in addition to procarbazine, is associated with even more marked gonadal dysfunction. Charak et al. (21) found azoospermia in all 92 patients after treatment with six or more COPP cycles, along with significant rises in gonadotropin levels compared with pretreatment values. Median follow-up in this study was 6 yr, with 17% of patients treated more than 10 yr previously, suggesting that germinal epithelial failure is likely to be permanent.

In addition to effects on the germinal epithelium, there is also some evidence for Ley-dig cell dysfunction after chemotherapy for lymphomas. Howell et al. (22) measured testosterone and LH levels in 135 men treated with either MVPP or ChlVPP/EVA hybrid. They demonstrated significantly higher LH levels in patients compared with a cohort of age-matched controls (mean LH 7.8 vs 4.1 IU/L). They suggested that this raised LH level indicated a reduction in hypothalamic-pituitary negative feedback consequent to a small reduction in testosterone production. This may still result in testosterone levels that fall in the cross-sectional normal range, and they thus defined mild Leydig cell dysfunction as a raised LH level in the presence of a testosterone level that is in the lower half of the normal range or is frankly subnormal. This combination was found in 44 men (31%) after chemotherapy with a further 10 (7%) having a raised LH level alone. This suggests that a significant proportion of men treated with cytotoxic chemotherapy have biochemical abnormalities, suggesting mild testosterone deficiency.

Chemotherapy regimens used for the treatment of non-Hodgkin's lymphoma (NHL) are generally less gonadotoxic than are those used for Hodgkin's disease. Pryzant et al. (1) reported on 71 patients treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone)-based chemotherapy. All men were rendered azoospermic during treatment, but by 5 yr after treatment, 67% had recovered to normospermic levels, with a further 5% to oligospermia. The reduced prevalence of permanent azoospermia in men treated for NHL compared with patients with Hodgkin's disease is probably related to the absence of procarbazine in the standard regimens used for NHL

(23), although the reduction in the dose of alkylating agents may also be important. The absence of procarbazine and alkylating drugs is also the likely explanation for the reduced toxicity of ABVD reported by Viviani et al. (19). Other regimens not containing procarbazine, which have been used for NHL, are also less gonadotoxic. VAPEC-B (vincristine, doxorubicin, prednisolone, etoposide, cyclophosphamide, and bleomycin)

(24), VACOP-B (vinblastine, doxorubicin, prednisolone, vincristine, cyclophosphamide, and bleomycin) (25), MACOP-B (mustine in place of vinblastine) (25), and VEEP (vincristine, etoposide, epirubicin, and prednisolone) (26) have all been associated with normal posttreatment fertility in the majority of men.

Testicular function after high-dose chemotherapy used as preparation for bone marrow transplantation has also been studied. Sanders et al. (27) reported on 155 men treated with cyclophosphamide (200 mg/kg) or busulphan and cyclophosphamide (busulphan 16 mg/kg, cyclophosphamide 200 mg/kg). After an average of 2 to 3 yr after the transplant, 67 of the 109 patients who received cyclophosphamide (61%) but only 8 of the 46 (17%) patients treated with busulphan and cyclophosphamide had recovery of testicular function defined by normal LH, FSH, and testosterone levels with evidence of sperm production. The only prospective study to examine testicular function after high-dose treatment reported data in 13 men who received either BEAM (BCNU, etoposide, Ara-C, and mel-phalan) (n = 11) or melphalan and single fraction TBI (n = 2) (28). All had previously received multiagent chemotherapy, and four had abnormal semen parameters before transplantation. All patients were azoospermic 2-3 mo posttransplantation, associated with raised FSH levels. LH levels increased and testosterone levels decreased after transplantation, indicating Leydig cell, apparent as well as germ cell failure.

These findings were also confirmed by Howell et al. (22) who studied 68 patients treated with high-dose chemotherapy (either cyclophosphamide, BCNU and etoposide, busulphan and cyclophosphamide or BCNU, etoposide, doxorubicin, and melphalan) as conditioning for bone marrow transplantation. They demonstrated a raised FSH in 60 patients (88%) and a raised LH level in 47 men (69%), 22 of whom (32%) also had a testosterone level in the lower half of the normal range, or frankly, subnormal.

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