Previous studies addressing the ovarian protective effects of luteinizing hormone releasing hormone agonists (LHRHa) against adverse effects of chemotherapy have examined histologic and/or hormonal parameters without evaluating reproductive performance. In this report, we initially established a model for chronic treatment of female rats with cyclophosphamide (CTX) that allowed long term survival. In a second experiment, thirty seven female cycling rats (age: 70 days) were divided into 4 treatment groups. They were given either CTX (4 mg/kg/day, 5 days/week) for a total of 76 days (217 mg/kg) and/or the LHRHa leuprolide (Lupron) 5 micrograms/day by subcutaneous minipump (Alza) for 98 days. LHRHa was started 10 days before CTX and ended 12 days after the last CTX injection. All LHRHa-treated rats entered persistent diestrus. At the end of treatment, most rats treated with CTX only were in persistent estrus. Breeding was started at 218 days of age. A laparotomy to count implantation sites was performed 15 to 16 days after vaginal plug/sperm was demonstrated. All nonpregnant rats were remated. Chi square and ANOVA were used for statistical analysis. The data presented demonstrate that: 1. LHRHa given before and after CTX increased the pregnancy rate/mating (from 4/11 to 9/10; P < 0.05), the number of implantations/mated rat (from 2.5 +/- 1.4 to 13.7 +/- 1.7; P < 0.01), and reduced the need for remating (from 7/11 to 1/10; P < 0.05); 2. LHRHa-treated rats performed better than controls. We conclude that LHRHa protects against chemotherapy-induced fertility reduction in female rats.