Sequential inhibition by progesterone: Effects on sexual receptivity and associated changes in brain cytosol progestin binding in the female rat

Abstract

The purpose of this study was to examine the role of cytosol progestin receptors (CPRs) in the activation of mating behavior in the estrogen (E 2) stimulated, ovariectomized rat, following the administration of a dose of progesterone (P; 2.5 mg) which is sufficiently large to inhibit the re-induction of sexual receptivity by subsequent P (‘sequential inhibition’). In order to control for competition by unlabeled P in our binding studies, aliquots of cytosol supernatants were passed through LH-20 columns prior to in vitro incubation with the radioactive ligand, [ staggered 3 H] R5020 (double column assay). Three days following E 2 priming, all animals used in biochemical studies received either P (2.5 mg) or vehicle injections (propylene glycol; PG) 24, 28 or 72 h prior to the administration of P (0.5 mg). When P (0.5 mg) was given 24 h after P or PG treatment, animals which had received P previously showed significantly decreased lordosis quotients (LQ), lordosis quality (LS) and proceptivity scores relative to PG controls (‘sequential inhibition’). The inhibitory effects of previous P (2.5 mg) were transient, and were not observed if P (0.5 mg) was delayed until 72 h after P or PG treatment. Three days following E 2 priming, all animals used in biochemical studies received either P (2.5 mg) or PG. When we did not control for competition by unlabeled P, [ staggered 3 H] R5020 binding in the cortex, mediobasal hypothalamus-preoptic area (MBH-POA) and pituitary was decreased by 60%, 3 h after 2.5 mg P. When we used the double column assay to remove P in the tissue, [ staggered 3 H] R5020 binding in all tissues was decreased by 20% at 3 h after 2.5 mg P. By 24 h, after 2.5 mg P, the competitive effect of tissue P on [ staggered 3 H] R5020 binding was not measurable; and cytosol progestin receptor (CPR) levels were less than or equal to those seen at 3 h. By 72 h after 2.5 mg P, CPRs had returned to control levels in all tissues. Our data suggest: (1) the double column assay is necessary to estimate CPR levels when P is present in the tissue; (2) when one controls for competition by P, CPR depletion 3 h after P is measurable but not extensive; depletion occurs in tissues in which CPRs are induced by E 2 (pituitary, MBH-POA), as well in cerebral cortex, where CPR levels are not included by E 2; (3) at 24 h, CPR levels are less than or equal to those seen at 3 h in all tissues; this may be the result of the initial depletion associated with nuclear translocation, or it may indicate that P regulates its own receptor concentration in the central nervous system (down-regulation); and (4) after a large dose of P (2.5 mg), reduced CPR levels correlated with P's reduced ability to facilitate sexual receptivity.