Estrogen Receptors

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What Are Estrogens?
"Estrogens" are a family of related molecules that stimulate the development and maintenance of female characteristics and sexual reproduction.

The natural estrogens produced by women are steroid molecules, which means that they are derived from a particular type of molecular skeleton containing four rings of carbon atoms. The most prevalent forms of human estrogen are estradiol and estrone. Both are produced and secreted by the ovaries, although estrone is also made in the adrenal glands and other organs.

Estrogen Target Tissues
Estrogens are hormones, which means that they function as signaling molecules. A signaling molecule exerts its effects by traveling through the bloodstream and interacting with cells in a variety of target tissues.

The breast and the uterus, which play central roles in sexual reproduction, are two of the main targets of estrogen. In addition, estrogen molecules act on the brain, bone, liver, and heart

Estrogen Receptors
Estrogens act on target tissues by binding to parts of cells called estrogen receptors.
An estrogen receptor is a protein molecule found inside those cells that are targets for estrogen action. Estrogen receptors contain a specific site to which only estrogens (or closely related molecules) can bind.

The target tissues affected by estrogen molecules all contain estrogen receptors; other organs and tissues in the body do not. Therefore, when estrogen molecules circulate in the bloodstream and move throughout the body, they exert effects only on cells that contain estrogen receptors.

Estrogen Receptors Trigger Gene Activation
Estrogen receptors normally reside in the cell's nucleus, along with DNA molecules.
In the absence of estrogen molecules, these estrogen receptors are inactive and have no influence on DNA (which contains the cell's genes). But when an estrogen molecule enters a cell and passes into the nucleus, the estrogen binds to its receptor, thereby causing the shape of the receptor to change. This estrogen-receptor complex then binds to specific DNA sites, called estrogen response elements, which are located near genes that are controlled by estrogen.

After it has become attached to estrogen response elements in DNA, this estrogen-receptor complex binds to coactivator proteins and more nearby genes become active. The active genes produce molecules of messenger RNA, which guide the synthesis of specific proteins. These proteins can then influence cell behavior in different ways, depending on the cell type involved.

Estrogen-Induced Changes in Cell Behavior
In liver cells, for example, estrogen alters the production of proteins that influence cholesterol levels in the blood.
Cholesterol does not readily dissolve in blood, so before it can be transported through the body, it first becomes bound to special cholesterol-carrying proteins called lipoproteins. The liver produces two such lipoproteins, called low-density lipoprotein (LDL) and high-density lipoprotein (HDL). LDL-cholesterol is considered to be the "bad" form of cholesterol because it tends to release cholesterol directly onto the inner wall of arteries, creating the "plaque" that can lead to heart disease. In contrast, HDL is considered to be the "good" form of cholesterol because it inhibits the formation of plaque and carries cholesterol away from the arteries and back to the liver.

The net effect of estrogen's action on liver cells is to increase the amount of HDL cholesterol and to decrease the amount of LDL cholesterol. By increasing HDL and decreasing LDL, estrogen helps to lower the risk of heart disease.

Estrogen-Induced Stimulation of Cell Proliferation
In some target tissues, the main effect of estrogen is to cause cells to grow and divide, a process called cell proliferation.
In breast tissue, for example, estrogen triggers the proliferation of cells lining the milk glands, thereby preparing the breast to produce milk if the woman should become pregnant.

Estrogen-Induced Proliferation of Existing Mutant Cells
Although estrogen does not appear to directly cause the DNA mutations that trigger the development of human cancer, estrogen does stimulate cell proliferation.
Therefore, if one or more breast cells already possesses a DNA mutation that increases the risk of developing cancer, these cells will proliferate (along with normal breast cells) in response to estrogen stimulation. The result will be an increase in the total number of mutant cells, any of which might thereafter acquire the additional mutations that lead to uncontrolled proliferation and the onset of cancer.

In other words, estrogen-induced cell production leads to an increase in the total number of mutant cells that exist. These cells are at increased risk of becoming cancerous, so the chances that cancer may actually develop are increased.

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