When fetal preoptic area (POA) brain grafts that contain gonadotropin-releasing hormone cells are transplanted into the third ventricle of adult female hypogonadal mice, the animals respond with sexual maturation, persistent estrus, and the ability to ovulate reflexively after mating. However, the absence of normal spontaneous ovulatory cyclicity suggests an impairment in positive feedback. We, therefore, studied the effect of administration of progesterone alone or of sequential estradiol benzoate and progesterone on plasma levels of luteinizing hormone (LH) in groups of hypogonadal (HPG) mice in persistent estrus after receiving POA grafts (HPG/POA). Individual differences in responsivity to progesterone were related in part to the length of time in persistent estrus. Approximately 30% of HPG/POA grafts tested 2 months after graft showed increased levels of plasma LH. This was reduced to 10% when animals were tested 5 months after graft. Sequential administration of estradiol benzoate plus progesterone to intact HPG/POA mice was ineffective in elevating LH. The presence of corpora lutea in ovaries verified that only animals with a progesterone induced LH surge ovulated. Other HPG/POA mice were mated, and the occurrence of reflex ovulation was determined. Four of these mice delivered pups: 3 were previous responders to progesterone. One female mated again during the immediate postpartum period and delivered a second litter. Following weaning of all offspring, this animal displayed spontaneous ovarian cyclicity, confirmed by ovarian histology. This is the first proven example of spontaneous ovulation in a mutant mouse with a brain graft. The results show that some HPG/POA mice are capable of positive feedback responses, and rarely, of becoming spontaneous ovulators.