The hypothesis that the termination of sexual receptivity (heat) in female guinea pigs results from loss of progestin receptors from hypothalamic cell nuclei was tested. First, we attempted to find an optimal dose of progesterone that would result in a prolonged period of sexual receptivity. Ovariectomized guinea pigs were implanted with 10% estradiol capsules. Forty hours later, each received one of several sized progesterone capsules before being tested hourly for lordosis. Surprisingly, none of the progesterone doses resulted in delayed heat termination. In order to determine whether elevated levels of estradiol and progesterone maintain elevated levels of nuclear progestin receptors despite the lack of effect on heat duration, animals were treated as described above except that only one size progesterone capsule (3.0 cm) or an empty capsule was implanted. Despite elevated serum progesterone concentrations, nuclear progestin receptor levels decreased gradually and approached control levels at about the same time as heat termination had occurred in similarly-treated animals. Cytosol progestin receptor levels decreased following progesterone treatment and remained lowered at all times measured. In order to further investigate the relationship between blood progesterone concentrations and retention of nuclear progestin receptors we decreased blood progesterone concentrations by removing progesterone capsules 2 h following insertion. Nuclear progestin receptor levels declined gradually concurrent with a decline in serum progesterone levels in animals exposed to progesterone capsules for only 2 h. In animals exposed to capsules continuously, nuclear progestin receptor levels again decreased but at a slightly slower rate. In order to test the effect of progesterone capsule removal on female sexual behavior, ovariectomized guinea pigs were treated as described and tested hourly for lordosis. Fewer animals in the group exposed to progesterone capsules for 2 h became sexually receptive as compared to animals continuously-exposed to progesterone capsules. Of those animals that did respond, heat termination had occurred by the same time that nuclear progestin receptor levels had returned to control levels in similarly-treated animals. These experiments support the hypothesis that heat termination results from the loss of progestin receptors from hypothalamic cell nuclei. In addition, they demonstrate that circulating progesterone levels play a role in regulating nuclear progestin receptor retention.