Cyclophosphamide-induced disturbance of gonadotropin secretion manifesting testicular damage

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Abstract
Gonadal function was evaluated in 23 men (aged 14.8–28.8 years) treated in childhood with cytotoxic drugs for a solid tumour. Group 1 (N = 14) had been treated with non-alkylating drugs only, while group 2 (N=9) received the alkylating drug cyclophosphamide in addition (range 3.8–19.5 g/m2). Median age at the start of treatment was 4.6 years (range 0.6–16.1) in group 1 and 13.9 years (range 3.7–16.9) in group 2. Data of the patients were compared with a reference group consisting of 14 normal men. Almost all patients of both groups showed normal development of puberty; 13 of the 14 men in group 1 showed normal hormonal values. In group 2, basal LH and FSH as well as the LH and FSH responses to GnRH showed higher levels compared to those of a reference group (p<0.001). Correlation analysis showed an evident correlation between the total dose of received cyclophosphamide and the basal FSH level (r=0.78; p=0.002), the FSH response to GnRH (r=0.73; p=0.002) and the LH response to GnRH (r=0.67; p=0.002). There was no correlation between the hormonal parameters and the doses of the other cytotoxic drugs. Semen analysis showed azoospermia in four boys of group 2 and in none of group 1. Two patients in group 2 had an elevated FSH response to GnRH while their semen analysis was normal. Conclusions: (1) There is a dose-response relationship between the basal FSH. the LH and FSH responses to GnRH and the dose of cyclophosphamide. In all cyclophosphamide-treated patients the FSH response to GnRH increased. (2) Increased gonadotropin secretion can be found while semen analysis is normal; an increased FSH response to GnRH can be the first manifestation of testicular damage. (3) Evaluation of gonadotropins, both basal and stimulated LH and FSH values, is an easy and useful method for following up gonadal function in cyclophosphamide-treated men, especially for detecting early and subtle testicular damage.

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