Table 2.

Human studies reporting cyclophosphamide-induced gonadotoxicity: assessment of immediate testicular damage.

Cyclophosphamide dosage	Other drugs co-administered	Treatment length	Male patients		Effect of cyclophosphamide				Reference
			n	Age (years)	Testicular histology	Number of germ or somatic cells/TFI	Interstitial fibrosis/basement membrane thickening	Testicular size
Grams/kg body weight
0.002 g/kg/day	Unknown	3 months	1 (prepubertal: 1; CYC treated: 1)	6	Abnormal, atrophic tubules	SCOs	Present	Small	Hyman and Gilbert (1972)
0.003–0.024 g/kg/day	Unknown	<50–400 days	7 (prepubertal: 7; CYC treated: 7)	3–11	Normal	N/A	N/A	N/A	Arneil (1972)
0.475–0.846 g/kg	AsparaginaseCytarabineDoxorubicinMercaptopurineMethotrexatePrednisoloneVincristine	2–6 years	46	0.08–13	Abnormal	Reduced TFI >0.130 g/kg CYC. Normal TFI intermittently treated higher cumulative CYC. Poorly developed somatic cells younger patients	N/A	N/A	Ise et al. (1986)
Grams/area
0.12–8.5 g/m2	AsparaginaseBleomycinCarmustineCytarabineDacarbazineDactinomycinDaunorubicinDoxorubicinFluorouracilLomustineMercaptopurineMethotrexateMitomycin CNitrogen mustardPrednisoneProcarbazineTeniposideVinblastineVincristineVindesine	0.08–1 year	32 (prepubertal: 21; CYC treated: 13)	<11	Abnormal when treated with multiagent regimen including CYC	N/A	N/A	N/A	Matus‐Ridley et al. (1985)
0.5–1.2 g/m2	AsparaginaseCytarabineDaunorubicinDoxorubicinMercaptopurineMethotrexatePrednisoneVincristine	1.2–88.8 months	10 (prepubertal: 8; CYC treated: 2)	9.4–16.6	N/A	Complete loss of GCs CYC treated	N/A	N/A	Müller et al. (1985)
>1 g/m2	AsparaginaseCytarabineDoxorubicinMercaptopurineMethotrexatePrednisoloneVincristine	12–77 months	44 (prepubertal: 27)	3.5–15	N/A	Reduced TFI (<40%) >1 g/m2 CYC	Present	N/A	Lendon et al. (1979)
3–16 g/m2	AsparaginaseCytarabineDexamethasoneDoxorubicinMercaptopurineMethotrexatePrednisoloneThioguanineVincristine	~1.8 years	37 (prepubertal: 37; CYC treated: 16)	1.1–16.1	N/A	Depletion of spermatogonial pool with reduced TFI (19%)	N/A	N/A	Poganitsch-Korhonen et al. (2017)
<4.8 g/m2	AsparaginaseCytarabineDaunorubicinHydroxyureaLomustineMethotrexatePrednisoloneThioguanineVincristine	3–4 years	25 (prepubertal: 24)	1.23–12.35	Abnormal	Complete loss or depletion of GC pool. Normal SC	N/A	Small	Quigley et al. (1989)
6.2–11.4 g/m2	AsparaginaseCytarabineDoxorubicinMercaptopurineMethotrexatePrednisoloneTeniposideVincristine	6.6–7.6 years	23 (prepubertal: 23; CYC treated: 6)	2.8–8.6	N/A	Depletion in SSCs (↓ CD9 and OCT4) and more differentiated spermatogonia (↓ MAGE4). Recovery noted	N/A	N/A	Nurmio et al. (2009a)
8–16.8 g/m2	AsparaginaseCytarabineDaunorubicinDexamethasoneEnocitabineHydrocortisoneMercaptopurineMethotrexatePrednisoloneVincristine	Unknown	12 (CYC treated: 7)	1–12	N/A	Reduced TFI (<50%) with morphological changes to GCs and SCs but not linked to CYC	Present	N/A	Kobayashi et al. (1996)
Total dose
1.4–20.8 g	AsparaginaseCytarabineDoxorubicinMercaptopurineMethotrexatePrednisoloneVincristine	~4.4 years	37 (CYC treated: 14)	1.6–14.3	Abnormal	GC damage and reduced TFI (<50%)	N/A	N/A	Wallace et al. (1991)
7.79 g	Prednisolone	180 days	1 (prepubertal: 1; CYC treated: 1)	3–4	Normal	N/A	N/A	Normal	Berry et al. (1972)

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.

^#Information not included in study.

CYC, cyclophosphamide; GC, germ cell; SC, Sertoli cell; SCO, Sertoli cell-only tubule; SSC, spermatogonial stem cell; TFI, tubular fertility index.