Improved long-term survival in young women with lymphoma and leukemia has increased attention to the preservation of their future fertility. We have attempted to minimize the gonadotoxic effect of chemotherapy by cotreatment with a GnRH agonist analog, inducing a temporary prepubertal milieu. Our prospective clinical case series includes 92 women with lymphoma, aged 15-40 years, 10 with leukemia and 18 undergoing chemotherapeutic treatments for nonmalignant autoimmune diseases. Depot D-TRP6-GnRH-a was injected monthly from before the initiation of chemotherapy until its conclusion, for up to 6 months. We used 82 similarly treated patients with lymphoma not given GnRH-a as a comparison group. All but five of the surviving evaluable patients with GnRH-a/chemotherapy cotreatment resumed spontaneous ovulation and menses or conceived, whereas 53% of the patients in the comparison group experienced premature ovarian failure (P<.01). Mechanisms to explain this apparent chemoprotective effect are discussed, and the work of other investigators in this area is reviewed.