Mechanisms of Action and Cross-Talk Between Estrogen Receptor and Progesterone Receptor Pathways

Abstract

The intriguing biology of estrogens and progestins in their diverse target cells is determined by the structure of the hormonal ligand, the receptor subtype or isoform involved, the nature of the hormone-responsive gene promoter, and the character and balance of coactivators and corepressors that modulate the cellular response to the receptor-ligand complex. Estrogens regulate the growth, differentiation, and functioning of diverse target tissues, both within and outside of the reproductive system. Most of the actions of estrogens appear to be exerted through the estrogen receptor (ER) of target cells, an intracellular receptor that is a member of a large superfamily ofproteins, whichfunction as ligand-activated transcriptionfactors, regulating the synthesis of specific RNAs and proteins. To understand how the ER discriminates between estrogen ligands, which activate the ER, and antiestrogen ligands, which fail to effectively activate the ER, we have generated and analyzed human ERs with mutations or other alterations in portions of the receptor. These studies provide evidence for the promoter-specific and cell-specific actions of the estrogen-occupied and antiestrogen-occupied ER, highlight a regional dissociation ofthe hormone-binding and transcription activationfunctions in domain E ofthe receptor, and indicate that some ofthe contact sites ofestrogens and antiestrogens in the ER are likely different. In addition, multiple interactions among different cellular signaling pathways are involved in the regulation ofgene expression and cell proliferation by the ER. In several cell types, protein kinase activators and some growth factors enhance the transcriptional activity of the ER. Cyclic AMP also alters the agonist/antagonist balance of some antiestrogens. Estrogens, and antiestrogens to a lesser extent, as well as protein kinase activators and growth factors, increase phosphorylation of the ER and possibly other proteins involved in the ER-specific response pathway, suggesting that changes in cellular phosphorylation state will be important in determining the biologic activity of the ER and the effectiveness of antiestrogens as estrogen antagonists. The ER also has important interrelationships with the progesterone receptor (PR) system in modulation of biologic responses. Liganded PR-A and PR-B can each suppress estradiol-stimulated ER activity, with the magnitude of repression dependent on the PR isoform, progestin ligand, promoter, and cell type. Thesefindings underscore the mounting evidencefor the importance of interactions between members of the steroid hormone receptorfamily. (J Soc Gynecol Investig 2000;7:S33-7) Copyriglht © 2000 by the Society for Gynecologic Investigation.

Protection against Genital Herpes Infection in Mice Immunized under Different Hormonal Conditions Correlates with Induction of Vagina-Associated Lymphoid Tissue

“…One possibility is that the ratios of the two hormones in this group may be at a threshold level, allowing progesterone to antagonize the estradiol effect on susceptibility in some mice and not in others. This phenomenon of situation-dependent antagonism of estradiol effects by progesterone is well recognized (11). Other examples where progesterone by itself does not appear to regulate an immune function but does clearly interfere with estradiol effects have been documented (13,33).…”

Neisseria gonorrhoeae Survival during Primary Human Cervical Epithelial Cell Infection Requires Nitric Oxide and Is Augmented by Progesterone

“…Steroid hormones often have antagonist effects that are not equal in all (mammalian) cell types (4,5,25,49). In this regard, there are at present very limited data describing the response(s) of (primary) cervical epithelial cells to combined, variable physiological concentrations of estrogens and progestagens-such as would occur in vivo throughout the female menstrual cycle-or how these responses potentially might be altered during bacterial infection.…”

Hypothalamic progesterone receptor-A mediates gonadotropin surges, self priming and receptivity in estrogen-primed female mice

“…It will be interesting to determine the molecular fingerprints of these adjacent neurons. Within individual neurons, PR-B also may be regulating the downregulation of ERa in the VMN, an effect that, in vitro, is mediated by both PR-A and PR-B in a ligand and cell-specific manner (DonCarlos et al 1995, Katzenellenbogen 2000. Previous protein and mRNA studies have shown such a role for PR in other reproductive tissue (Ismail et al 2002).…”