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Ian Gans Bio 421 Estrogen: molecular properties and function Estrogen is one of the major sex hormones in vertebrates, synthesized primarily in the gonads of both males and females. Estrogen is also synthesized by some insects‐ illuminating the fact that its evolutionary history is an ancient one1. Estrogen is the primary human female sex hormone, and thus it is found at its highest levels in healthy women of reproductive age, for whom the hormone regulates reproductive cycles as well as development of secondary sex traits such as growth of breast tissue as well as the storage of fat. To a lesser degree estrogen is also involved in the sexual development of men. Male sex drive, while primarily dependent on androgens such as testosterone, requires the presence of estrogen, as does the maturation of sperm cells. Estrogen is a member of the steroid family of molecules, meaning it is a lipophilic molecule containing the steroid nucleus of four carbon rings made up of 17 carbon atoms2. The singular term “estrogen” is actually a little misleading, as the term estrogen actually refers to a family of related molecules that, in humans, includes estrone, estradiol, and estriol. These molecules differ structurally by having either a hydroxyl and a ketone group or two or three hydroxyl groups added to their common steroid nucleus, and these structural differences lead to varying chemical potencies. Estradiol, also known as E2, is the most potent of the three, and is the most abundant estrogen during the reproductive years of a woman’s life. In most cases when people refer to estrogen they are referring to estradiol. Estriol, or E3, the weakest of the three, is the most abundant estrogen in a woman’s body during pregnancy, and estrone, or E1, is the most abundant during menopause. The synthesis of natural estrogen steroids begins with cholesterol and proceeds through a number of catalytic steps before ending with the conversion of either testosterone or androstenedione (both androgens, or masculinizing hormones) by the enzyme aromatase into estradiol or estrone respectively. Either of these estrogens may then by further modified into estriol. In addition to the estrogens normally produced by mammals, numerous substances have been found which behave like estrogen, although this does not necessarily mean they have similar chemical structures. These substances are known as xenoestrogens (xeno being latin for foreign). Some plants synthesize estrogenic chemicals, and these are called phytoestrogens. When these plants are commonly consumed these estrogens may also be referred to as dietary estrogens. It is theorized that some plants, such as cereal grains and legumes, evolved the synthesis of these estrogenic compounds as a defense mechanism to control the male fertility and thus the population of herbivores in their ecosystem3. The broad category of xenoestrogens also includes synthetic substances. Some of these substances are pharmaceuticals, such as birth control or the breast cancer drug tamoxifen. Others are widely used industrial chemicals like the pesticide DDT or the plastic additive BPA used in water bottles and to line aluminum cans, or the plastic softening agents called phthalates which are found in vinyl, car seats, cosmetics and more. Alarming studies have found that the ubiquitous use of such chemicals over the past several decades has led to hormonal disruption of wildlife species. Certain populations of fish, exposed to these chemicals via runoff from human settlement, seem to have suffered significant consequences, with the results being fewer reproductive cycles for females, and lowered sperm concentration and motility in males, and even significant numbers of fish suffering partial sex reversals or being born intersex. In this negative context, xenoestrogens fall into a larger category of chemicals known as endocrine disruptors‐ chemicals that have the ability to disrupt or affect the function of the endocrine system. In humans, there is debate over what effects these chemicals, which we encounter everyday in our environment, are having. Some say the environmental concentration is too low to have any effect, while others argue that xenoestrogens can be linked to breast cancer, prostate cancer, problems with fetal brain development, early onset of puberty in girls, falling sperm counts in men, and more. Because estrogens (and steroids in general) are non‐polar molecules, they are able to freely pass through cell membranes. Within cells, estrogen is synthesized in the hydrophobic environment of the smooth endoplasmic reticulum. Cholesterol endosomes fuse with the ER, and the cholesterol is then converted by a series of enzymes into estrogen, which is released with no storage occurring in the cell. As it is a lipoid molecule, there is no gene that codes for estrogen. The genes necessary for estrogen production are those that code for the oxidases involved in its synthesis. Also because of its lipid nature, when estrogen is transported in the blood, it is bound to a sex hormone binding globulin (SHBG) in order to prevent its removal from circulation by the liver and kidneys. Estrogen is produced primarily in the gonads. However, liver, breast, adrenal and fat cells also contribute to estrogen production and these contributions become more important in women after menopause. The production of estrogens is regulated by circulating gonadotrophins (GTH), which are in turn controlled by the HPG axis (Hypothalamus‐Pituitary‐Gonads)4. Estrogen’s main receptor is found in the nucleus of target cells. It is a member of the nuclear family of receptors, and causes genomic actions within the target cell.5 Due to it’s steroidal nature, estrogen molecules can freely diffuse into the nucleus, where they bind to these receptors. Chaperone proteins (also referred to as heat‐shock proteins), help to maintain the unoccupied receptor’s shape. These chaperone proteins dissociate from receptor molecules once they are occupied by estrogen. The structure of each estrogen receptor includes an 80 amino acid sequence comprising two peptide loops called zinc fingers. The dissociation of the chaperone proteins exposes these zinc fingers. An occupied estrogen receptor will phosphorylate and form a homodimer with another occupied receptor molecule, becoming a ligand‐activated transcription factor. The combined four zinc fingers of this transcription factor can then bind to a promoter region of DNA known as a Hormone Response Element (HRE). More specifically in estrogen’s case this promoter region is called an Estrogen Response Element (ERE). Additional nuclear adaptor proteins are then recruited to the promoter site, causing interaction with RNA polymerase and resulting in RNA transcription (and thus gene expression). The estrogen receptor (ER) molecule is thought to have evolved from an ancestral Estrogen‐Related Receptor (ERR), which can still be found in some more primitive vertebrates6. A gene duplication event then allowed the estrogen receptor to evolve. A second gene duplication event allowed the ER to diverge further into ER alpha and beta receptors, which have differing affinities for different estrogens, as well as different tissue distributions, with beta receptors not being present in the liver and the alpha receptor not being present in the gastrointestinal tract. Because the alpha receptor is less selective in what it will bind with, it is this receptor which most xenoestrogens bind with, as well as many drugs such as the birth control drug ethinyl estradiol (EE2) and the breast cancer drug Tamoxifen. Estrogenic pharmaceuticals (and xenoestrogens in general) can have either agonistic or antagonistic effects. In the case of the birth control drug EE2, the drug binds to the receptor and mimics natural estrogen, manipulating its level and that of interrelated hormones in order to prevent ovulation. Tamoxifen, on the other hand, has antagonistic behavior in breast tissue, where it blocks estrogen receptors without activating them7. Preventing the receptors from binding with estrogen in turn inhibits the growth of some types of breast cancer cells which require estrogen to grow. In addition to its nuclear receptor, estrogen also has been found to have membrane bound receptors in some cells. In one such case, estradiol binds to a G Protein Coupled Receptor (GPCR) in the membrane, which in turn activates a cascade of other proteins within the cell, culminating in the release of intracellular Ca++ ions, inducing exocytosis by the cell of other hormones or secretory proteins. This method of hormonal action is called the second messenger system (extracellular estrogen being the first messenger, and internal cellular proteins being the second). The results of this pathway differ from those of the standard genomic pathway, but may occur more rapidly than the genomic pathway which typically requires hours. 1. http://en.wikipedia.org/wiki/Estrogen 2. textbook, page 65 3. http://en.wikipedia.org/wiki/Xenoestrogen 4. textbook, page 318 5. text, page 74 6. text, page 77 7. http://en.wikipedia.org/wiki/Tamoxifen