Alteration of sensitivity to progesterone facilitation of lordosis in guinea pigs by modulation of hypothalamic progestin receptors

Abstract

In order to delineate further the role of the progestin receptor system in the hypothalamus-preoptic area in the regulation of lordisis in female guinea pigs, we injected estradiol benzoate and progesterone in various regimens that result in sensitivity to, desensitization to, or restoration of sensitivity to progesterone-facilitation of lordosis. We attempted to correlate the effectiveness of progesterone to facilitate lordosis with the effectiveness of progesterone to cause accumulation of nuclear progestin receptors measured by an in vitro [ 3H]R 5020 binding assay. A progesterone injection 40 h after an estradiol benzoate injection in ovariectomized guinea pigs resulted in lordosis in 83% of the animals, caused a 30% depletion of cytoplasmic progestin receptors and a 200% increase in the concentration of nuclear progestin receptors 4 h after injection compared with control animals. By 24 h after the injection, after the period of sexual receptivity had terminated, the concentration of nuclear progestin receptors was no longer elevated, and the concentration of cytoplasmic progestin receptors was decreased to a level 55% lower than control animals. This depression was due to a decrease in the concentration of binding sites, not to in vitro competition of the injected progesterone with the [ 3H]R 5020 because similar results were obtained with cytosol in which progesterone had been removed by gel filtration prior to incubation. These progesterone-injected guinea pigs did not respond to a second progesterone injection 24 h after the first (64 h), and the injection resulted in 70% fewer nuclear progestin receptors than in oil-injected controls. This decreased accumulation appears to be due to the decreased level of cytoplasmic progestin receptors brought about by the first progesterone injection. Estradiol benzoate injected concurrently with the first progesterone injection restored behavioral sensitivity to the second progesterone injection and caused 160% greater accumulation of nuclear progestin receptors in response to the second progesterone injection than control animals that had received only progesterone. The increased concentration of nuclear progestin receptors in the estradiol-injected animals appear to be due to increased availability of cytoplasmic progestin receptors. It seems that estradiol increases and progesterone decreases the concentration of cytoplasmic progesterone receptors in hypothalamus-preoptic area such that a subsequent injection of progesterone results in a high or low concentration of nuclear progestin receptors. The accumulation of sufficient nuclear progestin receptors in response to the progesterone injection may be a requirement in the process by which progesterone facilitates lordosis in estradiol-primed rodents.