Oestrogen Receptors

The physiological roles of the oestrogen receptors

The ERs control a variety of different physiological processes, and they have been implicated in numerous diseases. Below are some of the major areas of oestrogen involvement.

Female and male reproduction

In females, the distribution and roles of ERa and ERb in mammary glands differ from one another. The presence of ERa in the mammary stroma cells is required for the oestrogen proliferative response in the epithelium, which involves the stroma-derived hepatocyte growth factor (HGF). Oestrogen-bound ERa can induce the progesterone receptor and mediate the differentiation of the epithelium. ERb cannot mediate oestrogen-dependent growth and development of the mammary glands in the absence of ERa. Integrin signalling is thought to interact with HGF and oestrogen to modulate their proliferative effects. Oestrogen has been recognised as playing a dominant role in the induction and progression of mammary carcinomas. The expression of the laminin-specific integrin a-6 is associated with breast cancer progression, laminin itself being able to modulate the action of oestrogen in breast cancer cells. The over-expression of certain cofactors is also associated with breast cancer. The drug tamoxifen, used in the treatment of breast cancer, acts as an ER antagonist, and may act to inhibit growth factor production in stromal cells.

Oestrogens are essential for fertility, but are not required for the development of the female reproductive tract. ERs are involved in ovulation, implantation, pregnancy maintenance and childbirth. It is thought that ERa may mediate the proliferative effects, while ERb mediates the differentiative effects of oestrogen within the follicles. Progesterone can act through the progesterone receptor (isoform A) to negatively regulate the action of oestrogen by preventing ERa from activating transcription. Oestrogen and certain ER cofactors have been implicated in the progression of ovarian cancers.

In males, oestrogen is required for normal testicular function, however exposure to it during development can cause disorders in the structure and function of the testis. Oestrogens are produced by the aromatisation of testosterone by the cytochrome P450 aromatase enzyme complex in both males and females. ERs function to regulate the expression of proteins involved in fluid reabsorption. ERb is widely expressed in the urogenital tract and the testis, whereas the level of ERa expression is low, and absent in testis. However, ERa is required for male fertility; disruption of ERa affects sperm morphology, inhibits water reabsorption and decreases fertility.

Cardiovascular system

Oestrogens affect the cardiovascular system, and have an influence on lipid profiles, fat distribution, the tone of vascular and smooth muscle cells, endocrine factors produced by the vascular wall (endothelins, nitric oxide), fibrinogen levels, blood platelets, inflammatory factors and coagulation. Some of the effects of the ERs in the cardiovascular system are known to be by non-transcriptional ER signal transduction. For instance, ERa can physically couple to PI3K (phosphatidylinositol 3_OH kinase), leading to the activation of the PIK3 signalling cascade, and the subsequent phosphorylation and activation of nitric oxide synthetases. The release of nitric oxide then triggers a vasodilatation effect on the vascular wall.

The lack of oestrogen has been linked to an increase in cardiovascular disease. Oestrogens may help modulate the cardiovascular effects of stroke and epilepsy.

Immune system

ERs are expressed in primary lymphoid organs and in peripheral immune cells. ERa is required for the development of the thymus in both sexes, while ERb may be responsible for the regulation of B cell formation in bone marrow, supporting the action of oestrogen in immune development and modulation. Oestrogens enhance the humoral immune response; oestrogen treatment was found to increase the number of antibody-producing cells and the levels of autoantibodies without increasing B cell count. ERs regulate the level of gonadotrophin-releasing hormone (GRH) and GRH receptor, which are produced by immune cells and have an enhancing effect on the immune response.

Oestrogens are thought to play a role in autoimmune disorders. The oestrogen/androgen balance is important in regulating the immune and inflammatory responses in both males and females. Oestrogens enhance and testosterone suppresses the autoantibody response, and a low androgen:oestrogen ratio has been found in patients of both sexes with rheumatoid arthritis. ERs may have a role in systemic lupus erythematosus as well. Autoimmune disorders are more common in women, possibly because of the higher levels of autoantibodies. Oestrogen appears to accelerate the progression of autoimmune diseases by enhancing the T helper-2 pathway.

Central nervous system

Oestrogens can exert effects on the brain, including cognitive function, co-ordination of movement, pain and neuroprotection. Oestrogens act as potent neurotrophic factors during development and in adulthood; they influence sex-specific differentiation of the hypothalamus; they act as potent growth factors that influence brain development, cell survival, and neural plasticity; they function as neuroprotectants of the nigrostriatal dopaminergic system. Oestrogens can alter the expression of genes involved in apoptosis and axonal regeneration. The relative levels of ERa and ERb vary between different areas of the brain, with the levels of ERa being higher than those of ERb in the cortex, hippocampus and hypothalamus. ERa itself is expressed at a higher level in the hypothalamus than in the hippocampus. Oestrogen action in the brain is thought to occur through ER-dependent and ER-independent mechanisms, which involve both the modulation of gene transcription and non-genomic cytoplasmic signalling pathways. There are several examples of non-genomic oestrogen action in the brain: oestradiol-17b can activate the calcium and cAMP/PKA signalling pathways during the differentiation of midbrain dopaminergic neurons; oestradiol-17b can protect hippocampal and cortical neurons from excitotoxic cell death through the activation of the MAPK pathway.

Recent evidence shows oestrogens to be protective against Alzheimer’s disease, Parkinson’s disease and schizophrenia, through their ability to protect against neuronal cell death and by enhancing neurogenesis and cognitive function. Oestrogens may enhance recovery from neurological injuries such as stroke; females usually suffer less stroke injury than males. The brain accelerates both oestrogen synthesis and ER expression at sites of injury. Oestrogens are thought to exert their neuroprotective effects through several different routes.

Skeletal system

Oestrogens have an important role in bone metabolism and homeostasis, producing significantly beneficial effects on skeletal growth and bone maturation. Oestrogens are involved in the modelling of bone in adolescence, initiating pubertal bone growth and later limiting longitudinal bone growth in women. In adults, oestrogens are crucial for the maintenance of bone mass in both males and females, acting to suppress bone resorption by osteoclasts and to promote bone formation by osteoblasts. ERa mediates the growth-promoting effects of oestrogen, while ERb acts during puberty to limit longitudinal and radial bone growth in females. Oestrogens regulate several factors important for bone metabolism; these include the stimulation of the anabolic growth factor IGF-1; the inhibition of the cytokines IL-1 (interleukin), tumour necrosis factor and IL-6, which are involved in bone resorption; and the stimulation of osteoprotegrin, which is involved in the inhibition of osteoclasts function.

The development of osteoporosis in women is associated with the decrease in oestrogen levels following menopause. Males with non-functional ERs, or who are unable to synthesize oestrogen, are susceptible to osteoporosis. The drug raloxifene used in the treatment of osteoporosis acts as an ER agonist on bone and serum lipids, and as an antagonist on uterus and breast tissue.