Unconventional Estrogen Signaling in Health and Disease

Abstract

Estrogen is a key hormone involved in the development and homeostasis of several tissue types in both males and females. By binding estrogen receptors, estrogen regulates essential functions of gene expression, metabolism, cell growth, and proliferation by acting through cytoplasmic signaling pathways or activating transcription in the nucleus. However, disruption or dysregulation of estrogen activity has been shown to play a key role in the pathogenesis and progression of many diseases. This review will expatiate on some of the unconventional roles of estrogen in homeostasis and disease.

Keywords: cardiovascular disease; diabetes; disease; estrogen; lymphangioleiomyomatosis.

Figure 1.

ERα signaling pathways. Estrogen receptor (ER) α can be activated by estrogen and growth factors to control transcription of target genes. Growth factors regulate kinase signaling via receptor tyrosine kinases (RTKs) to activate phosphoinositide 3-kinase (PI3K)/Akt, mitogen-activated protein kinase (MAPK)/p90 Ribosomal S6 Kinase (RSK), and mechanistic target of rapamycin complex 1 (mTORC1)/40S Ribosomal S6 Kinase 1 (S6K1) pathways. Estrogen-stimulated ERα can activate these pathways via Src. Plasma membrane-associated estrogen receptors (mER), GPR30 and ERα splice variants ER-36/ER-46 also activate intracellular signaling cascades.