The role of hypothalamic (HTH) intracellular progestin receptors (PRs) in the activation and termination of sexual receptivity (heat) in female rats and guinea pigs was examined. In the first study, the progestin antagonist, RU 486, was found to inhibit progesterone-facilitated sexual behavior in ovariectomized (OVX) estrogen-treated guinea pigs. RU 486 bound in vitro to neural PRs, and decreased the availability of HTH PRs when administered to estradiol-treated animals. These findings support the hypothesis that intracellular PRs mediate the facilitation of sexual behavior by progesterone. In a second study, OVX rats were treated with daily injections of the pesticide, o,p'-DDT (which has estrogenic properties), for 3 days, followed by progesterone on day 4. A dose of 400 mg/kg o,p'-DDT resulted in the activation of sexual behavior in 50% of the animals, and increased HTH cytosol PR concentration by 43%. Following progesterone treatment, the concentration of nuclear-bound PRs increased 137%. These findings support the hypothesis that estrogen-induced PRs are required for the facilitation of sexual receptivity by progesterone, and contradict a recent study using DDT that suggested that estrogen induction of PRs is not necessary. The last three studies tested the hypothesis that loss of PRs from the HTH cell nuclei results in heat termination. A supplemental injection of progesterone given 8 h after an initial injection delayed heat termination by more than 2 h, and also delayed the loss of HTH nuclear PRs. In an attempt to further delay heat termination, OVX guinea pigs were treated with capsules containing estradiol and one of several doses of progesterone. Heat termination occurred at about the same time regardless of the dose of progesterone, and despite the continued presence of both hormones. Nuclear PRs were also found to decrease in the presence of continued administration of estradiol and progesterone. As nuclear PR levels decreased, sexual receptivity terminated. In the final study, RU 486 administered to estradiol-progesterone treated guinea pigs accelerated both the loss of nuclear PRs and the termination of sexual receptivity. These studies support the hypothesis that heat termination results from the loss of PRs from HTH cell nuclei, and provide further evidence that intracellular PRs are involved in mediating progesterone's effects on sexual behavior.