Table 3.

Human studies reporting cyclophosphamide-induced gonadotoxicity: subsequent assessment in the adult.

Cyclophosphamide dosage	Other drugs co-administered	Treatment length	Patients within the study		Effect		Reference
			n	Age, years	Short term (1–5 years)	Long term (6–10 years)
Grams per body weight
0.2–0.5 g/kg/day	Unknown	1.5–6 months	23 (prepubertal: 16; CYC treated: 23)	3.5–20	Abnormal histology 20–25% of tubules atrophic high cumulative doses	N/A	Pennisi et al. (1975)
0.104–0.2 g/kg	Prednisone	49–60 days	4 (CYC treated: 4)	9–13	N/A	Normal testis morphology
0.312–1.325 g/kg	N/A	89–489 days	4 (CYC treated: 4)	5–8.5	N/A	Damage to seminiferous epithelium with SCOs	Etteldorf et al. (1976)
0.475–0.846 g/kg	AsparaginaseCytarabineDoxorubicinMercaptopurineMethotrexatePrednisoloneVincristine	2–6 years	46	0.08–13	Tubular damage occasionally observed 4 years after treatment with unknown ‘low’ doses	N/A	Ise et al. (1986)
Grams/area
2.6–29 g/m2	AsparaginaseCytarabineDactinomycinDaunomycinDoxorubicinFluorouracilMechlorethamineMercaptopurineProcarbazineVincristine	Unknown	30 (prepubertal: 19; CYC treated: 10)	1.75–17	N/A	Abnormal morphology	Aubier et al. (1989)
2.75–7.5 g/m2	AsparaginaseCarmustineDoxorubicinMercaptoruineMethotrexatePrednisoneThioguanineVincristine	3–4 years	17 (prepubertal: 17; CYC treated: 5)	2.5–12.4	Reduced number of GC mm3	N/A	Müller et al. (1988)
Total dose
0.021–39 g	FluoxymesteroneMercaptopurineOxandrolonePrednisone	9 weeks to 19 months	7 (CYC treated: 7)	11–16	High doses; SCOs, peritubular fibrosis, normal morphology LCs. Low doses; active spermatogenesis 90% of tubules	N/A	Penso et al. (1974)

Studies suggest that the cumulative cyclophosphamide dose, age at treatment and patient’s sensitivity as well as the treatment regimen itself can influence the level of damage. As these patients often received a combination of chemotherapy drugs it is hard to determine the relative contributions of each drug. Studies were included only where the cyclophosphamide dosage and age of patient at time of treatment were known.

CYC, cyclophosphamide; GC, germ cell; LC, Leydig cell; SCO, Sertoli cell-only tubule.