Oestrogen Receptors, Receptor Variants and Oestrogen Actions in the Hypothalamic‐Pituitary Axis

Abstract

Information on oestrogen action has grown exponentially in the past decade, and recent studies have begun to de®ne the mechanism of ligand-dependent activation and cell-speci®c effects. Oestrogenmediated gene transcription in a speci®c tissue depends on several factors, the most important of which is the presence of at least one of the two nuclear oestrogen receptor (ER) isoforms, ERa and ERb. The presence and levels of speci®c ER isoform variants, along with receptor coactivator, corepressor and integrator proteins, directly modulate overall nuclear ER activity. The structure of the ligand, including both physiological oestrogens and synthetic oestrogen receptor modulators, in¯uences ER interactions with these other proteins and thus determines the biological response. Furthermore, peptide and neurotransmitter-stimulated intracellular signalling pathways activate speci®c enzyme cascades and may modify the receptors and their interacting proteins, resulting in either independent or ligand-enhanced ER-mediated responses. Finally, several rapid effects of oestrogen probably occur at the membrane through nongenomic pathways that may or may not require the same ER proteins that are found in the nucleus. This review concentrates on the pituitary-hypothalamic axis and the genomic effects of oestrogen, and discusses the current knowledge of each of these factors in determining oestrogen actions in the neuroendocrine system.Oestrogen has numerous biological effects including those on reproductive tissues, bone, liver, pituitary and brain, and its importance in complicated processes such as bone and mineral metabolism, cardiac and vascular function and neuroprotection are just beginning to be understood (1±4). As each physiological system is studied, it is clear that there are general mechanisms of the action of oestrogen, particularly those relating to gene transcription. However the expression of oestrogen receptor (ER) forms and other proteins interacting with the receptor, as well as the activation of other intracellular signalling pathways that cross-talk with the ER, can profoundly in¯uence the overall response to oestrogen in a given cell or tissue. Physiological effects of oestrogen on the neuroendocrine system include direct actions on hypothalamic neurones and pituitary cells and indirect effects through glia and endothelial cells (4). These ultimately result in altered rates of synthesis and secretion of nearly all pituitary hormones, particularly prolactin and the gonadotropins luteinizing hormone (LH) and follicle stimulating hormone (5±7). There are both positive and negative effects of oestrogen on pituitary hormones, occurring either though the hypothalamus or directly at the level of the pituitary gland. Stimulatory effects of oestrogen are noted on prolactin, which acts in females to promote mammary gland development and lactation or milk production. Positive oestrogen feedback on the reproductive axis occurs at the time of the proestrus surge of oestrogen and LH prior to ovulation. Negative fee...

Differential Expression of Estrogen Receptors in Two Hippocampal Regions During the Estrous Cycle of the Rat

“…However, these variants are not hormonally regulated, and represent only between 10% and 15% of the total receptor levels. Different variants for ERb have also been described (Shupnik, 2002); however, the contribution of both ERb and ERa variants to explain the differences observed between isoforms in the hippocampus requires more investigation.…”

Environmental Estrogens Stimulate Gene Transcription in the Prolactin Promoter

“…The prolactin gene, however, is not the only E 2 sensitive gene expressed in the pituitary. Indeed, E 2 regulation gene expression and hormone release in the anterior pituitary is evidenced by the ubiquitous expression of ERs in the APG (Shupnik, 2002). Thus, the ability of xenoestrogens and phytoestrogens to stimulate complex promoter activity in pituitary cells may present some particular implications for overall health, but reproductive health in particular (Adeyoa-Osiguwa et al, 2003).…”

Rapid signaling mechanisms of estrogens in the developing cerebellum

“…Studies comparing properties and activities of different alternative splice variants of ERs indicate that the different isoforms play a major role in determining the specific cellular response evoked by endogenous or environmental estrogens (Belcher, 1999;Bollig and Miksicek, 2000;Fasco et al, 2000;Fuqua et al, 1999;Omoto et al, 2003;Petersen et al, 1998;Shupnik, 2002). For example, the two major splice variants of ERβ, ERβ1 and ERβ2, differ from one another by the insertion of a 54 base pair alternatively spliced exon (Kuiper et al, 1998).…”