by Jennifer McDowall
Oestrogens are best known for their effects upon the female reproductive system, where they play a major role in ovulation, implantation, pregnancy maintenance, childbirth and lactation. However, these steroid hormones are also essential for sperm production in males, and have important physiological functions in the cardiovascular system, immune system, central nervous system, and in bone, where they support several diverse physiological processes such as cardiovascular protection, the humoral immune response, neuroprotection and bone remodelling. As such, oestrogens are important effectors of the endocrine system of all vertebrates. By contrast, plant phytoestrogens, which can mimic certain oestrogenic responses in animals, have no endocrine function during plant reproduction; instead they have a protective effect against oxidative stress.
The biological actions of oestrogens are only found in cells expressing oestrogen receptors. The nature and extent of the oestrogenic response depends upon the interactions of these receptors with several different proteins involved in various processes. Oestrogen hormone action, therefore, involves a high level of complexity.
Oestrogens and their action have long been a focus of the medical profession. Oestrogens have been used for birth control and hormone replacement therapy. The effects of oestrogen action have been the focus for several disease processes, including breast cancer, osteoporosis, cardiovascular disease, immune diseases and the loss of cognitive function.
Picture courtesy of M Danielsen, the Nuclear Receptor Resource Library
Oestrogen receptors (ERs) act as transcription factors, either activating or inhibiting the expression of a wide array of genes. Cells can respond to oestrogen in different, often opposing ways, because of the presence of two functionally distinct oestrogen receptors and their ability to interact with a number of different cofactors and signalling proteins. There are two receptors that can bind to oestrogen, the oestrogen receptor alpha (ERa) and the oestrogen receptor beta (ERb). These receptors are functionally distinct, having different tissue distributions and different ligand activation, and as such play different roles in gene activation. Both ERa and ERb interact with the same oestrogen ligand, oestradiol-17b, but they behave differently, sometimes even causing opposing effects. For example, ligand-bound ERa was found to activate transcription, while ligand-bound ERb inhibited transcription from the AP1 site. They can respond to synthetic ligands in different ways as well, for instance THC acts as an ERa agonist and as an ERb antagonist. ERb can act as a dominant inhibitor of ERa transcriptional activity in cells that express both receptors.
Both ERa and ERb can be subdivided into distinct functional domains that are responsible for different functions: the N-terminal transactivation domain AF-1, the DNA-binding domain, a flexible hinge region, the ligand-binding domain (also known as the hormone-binding domain), and a second transactivation domain, AF-2, located at the C-terminus within the ligand-binding domain. Many receptor-interacting proteins show a preference for either AF-1 or AF-2, and it is through these two sites that much of the variation in receptor action is mediated.