Estradiol

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(New page: Estradiol Generally refers to the 17-beta-isomer of estradiol, an aromatized C18 steroid with hydroxyl group at 3-beta- and 17-beta-position. Estradiol-17-beta is the most potent form of m...)
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Estradiol
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[http://crdd.osdd.net/raghava/hmrbase/test_extract.php?db=arun&table=nphormonet&id=1061&show=SHOW-3D Show 3-D Structure]
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{{Drugbox|
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|IUPAC_name = (8R,9S,13S,14S,17S)-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol
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|synonyms = 17beta-Estradiol
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| CAS_number=50-28-2
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|  CASNo_Ref = {{cascite}}
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|  CAS_supplemental = <br/>57-91-0 (±) <!-- Also CAS verified -->
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| ChemSpiderID = 5554
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| ATC_prefix=G03
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| ATC_suffix=CA03
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| ATC_supplemental=
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| PubChem=5757
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| DrugBank=
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| chemical_formula= C<sup>18</sup>H<sup>24</sup>O<sup>2</sup>
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| molecular_weight = 272.38
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| smiles = Oc1ccc2c(CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]32)c1
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| melting point = 178.5
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| solubility = 3.6 mg/L 27<sup>o</sup>C EXP
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|half life = 36 hours
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| bioavailability= 97-99% is bound
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| metabolism = [[Liver]]
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| elimination_half-life= ~ 13 hours
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| excretion =  Urine
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| pregnancy_category = X ([[United States|USA]])
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| legal_status = S4 <small>(Au)</small>, POM <small>([[United Kingdom|UK]])</small>, ℞-only <small>(U.S.)</small>
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| routes_of_administration=Oral, transdermal
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}}
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'''Estradiol''' (17β-estradiol) (also '''oestradiol''') is a [[sex hormone]]. Mislabelled the "female" hormone, it is also present in males; it represents the major [[estrogen]] in humans. Estradiol has not only a critical impact on reproductive and sexual functioning, but also affects other organs including bone structure.
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Generally refers to the 17-beta-isomer of estradiol, an aromatized C18 steroid with hydroxyl group at 3-beta- and 17-beta-position. Estradiol-17-beta is the most potent form of mammalian estrogenic steroids. In humans, it is produced primarily by the cyclic ovaries and the PLACENTA. It is also produced by the adipose tissue of men and postmenopausal women. The 17-alpha-isomer of estradiol binds weakly to estrogen receptors (RECEPTORS, ESTROGEN) and exhibits little estrogenic activity in estrogen-responsive tissues. Various isomers can be synthesized.
Generally refers to the 17-beta-isomer of estradiol, an aromatized C18 steroid with hydroxyl group at 3-beta- and 17-beta-position. Estradiol-17-beta is the most potent form of mammalian estrogenic steroids. In humans, it is produced primarily by the cyclic ovaries and the PLACENTA. It is also produced by the adipose tissue of men and postmenopausal women. The 17-alpha-isomer of estradiol binds weakly to estrogen receptors (RECEPTORS, ESTROGEN) and exhibits little estrogenic activity in estrogen-responsive tissues. Various isomers can be synthesized.
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PUBCHEM 5757
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==PhysioChemical Properties==
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===Melting Point===
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178.5 EXP
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===log P===
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4.01 (none) EXP
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===Water Solubility===
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3.6 mg/L 27 EXP
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===Vapor Pressure===
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1.26E-08 mm Hg 25 EST
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===Henry's Law Constant===
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3.64E-11 atm-m3/mole 25 EST
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===Atmospheric OH Rate Constant===
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1.23E-10 cm3/molecule-sec 25 EST
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==Production==
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During the reproductive years, most estradiol in women is produced by the granulosa cells of the ovary|ovaries by the aromatization of androstenedione (produced in the theca folliculi cells} to estrone, followed by conversion of estrone to estradiol by 17β-hydroxysteroid reductase. Smaller amounts of estradiol are also produced by the adrenal cortex, and in me), by the testes.
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Estradiol is not only produced in the gonads: in both sexes, precursor hormones, specifically testosterone, are converted by [[aromaticity|aromatization]] to estradiol. In particular, [[adipose tissue|fat cells]] are active to convert precursors to estradiol, and will continue to do so even after menopause. Estradiol is also produced in the brain and in [[artery|arterial wall]]s.
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Therapeutic Indications
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==Mechanism of action==
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Estradiol enters cells freely and interacts with a cytoplasmic target [[cell receptor]]. When the [[estrogen receptor]] has bound its [[ligand]] it can enter the [[cell nucleus|nucleus]] of the target cell, and regulate [[gene transcription]] which leads to formation of [[messenger RNA]]. The mRNA interacts with [[ribosome]]s to produce specific proteins that express the effect of estradiol upon the target cell.
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    * Menopause
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Estradiol binds well to both estrogen receptors, ERα and ERβ, in contrast to certain other estrogens, notably medications that preferentially act on one of these receptors. These medications are called [[selective estrogen receptor modulator]]s, or SERMs.
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    * Osteoporosis
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KEGG Database(C00951,D00105)
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Estradiol is the most potent naturally-occurring estrogen.
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Pathway
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Androgen and estrogen metabolism
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Prostate cancer
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NEXT BIO Database
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Recently there has been speculation about a membrane estrogen receptor, ERX.
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Drug Type:  Small Molecule; Approved; Investigational
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==Metabolism==
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Pharmacology: Estradiol, the principal intracellular human estrogen, is substantially more active than its metabolites, estrone and estriol, at the cellular level.
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In plasma, estradiol is largely bound to [[sex hormone binding globulin]], also to [[albumin]], -only a fraction is free and biologically active. Deactivation includes conversion to less active estrogens such as [[estrone]] and [[estriol]]. Estriol is the major urinary metabolite. Estradiol is conjugated in the liver by sulfate and glucuronide formation and as such  excreted via the kidneys. Some of the watersoluble conjugates are excreted via the bile duct, and partly reabsorbed after [[hydrolysis]]  from the intestinal tract. This [[enterohepatic circulation]] contributes to maintaining estradiol levels.
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Mechanism of Action: Estradiol enters target cells freely (e.g., female organs, breasts, hypothalamus, pituitary) and interacts with a target cell receptor. When the estrogen receptor has bound its ligand it can enter the nucleus of the target cell, and regulate gene transcription which leads to formation of messenger RNA. The mRNA interacts with ribosomes to produce specific proteins that express the effect of estradiol upon the target cell. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins and suppress follicle-stimulating hormone (FSH) from the anterior pituitary.
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Indication: For the treatment of urogenital symptoms associated with post-menopausal atrophy of the vagina (such as dryness, burning, pruritus and dyspareunia) and/or the lower urinary tract (urinary urgency and dysuria).
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Half Life: 36 hours
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==Measurement==
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Serum estradiol measurement in women reflects primarily the activity of the ovaries. As such they are useful in the detection of baseline estrogen in women with [[amenorrhea]] or menstrual dysfunction and to detect the state of hypoestrogenicity and [[menopause]]. Furthermore, estrogen monitoring during fertility therapy assesses follicular growth and is useful in monitoring the treatment. Estrogen-producing tumors will demonstrate persistent high levels of estradiol and other estrogens. In [[precocious puberty]] estradiol levels are inappropriately increased.
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SCORE = Number of Parameters (out of 4) Satisfying Lipinski’s “Rule of Five”
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In the normal [[menstrual cycle]] estradiol levels measure typically <50 ng/ml at menstruation, rise with follicular development, drop briefly at ovulation, and rise again during the luteal phase for a  second peak. At the end of the luteal phase estradiol levels drop to their menstrual levels unless there is a pregnancy.
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Lipinski’s “Rule of Five” Prediction for a Compound’s ABSORPTION OR PERMEABILITY PROPERTIES
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During [[pregnancy]] estrogen levels including estradiol rise steadily towards term. The source of these estrogens is the [[placenta]] that aromatizes prohormones produced in the fetal adrenal gland.
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4 GOOD
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3 INDETERMINATE
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2 INDETERMINATE
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1 INDETERMINATE
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0 POOR
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==Effects==
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===Female reproduction===
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In the female, estradiol acts as a growth hormone for tissue of the reproductive organs, supporting the lining of the [[vagina]], the cervical glands, the [[endometrium]] and the lining of the fallopian tubes. It enhances growth of the [[myometrium]]. Estradiol appears necessary to maintain [[oocyte]]s in the [[ovary]]. During the [[menstrual cycle]], estradiol that is produced by the growing follicle triggers, via a positive feedback system, the hypothalamic-pituitary events that lead to the [[luteinizing hormone]] surge, inducing ovulation. In the luteal phase estradiol, in conjunction with [[progesterone]], prepares the endometrium for [[implantation]]. During [[pregnancy]] estradiol increases due to [[placenta]]l production. In baboons, blocking of estrogen production leads to pregnancy loss suggesting that estradiol has a role in the maintenance of pregnancy. Research is investigating the role of estrogens in the process of initiation of [[Childbirth|labor]].
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Reference Article
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===Sexual development===
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Ref1
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The development of [[secondary sex characteristics]] in women is driven by estrogens, specifically estradiol. These changes are initiated at the time of  puberty, most enhanced during the reproductive years, and become less pronounced with declining estradiol support after the menopause.  Thus, estradiol enhances breast development, and is responsible for changes in the body shape affecting bones, joints, fat deposition. Fat structure and skin composition are modified by estradiol.
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Virtual and biomolecular screening converge on a selective agonist for GPR30
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Cristian G Bologa1,7, Chetana M Revankar2,3,7, Susan M Young3, Bruce S Edwards3,4, Jeffrey B Arterburn5, Alexander S Kiselyov6, Matthew A Parker6, Sergey E Tkachenko6, Nikolay P Savchuck6, Larry A Sklar3,4, Tudor I Oprea1 & Eric R Prossnitz2,3
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===Male reproduction===
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The effect of estradiol (and estrogens) upon male reproduction is complex. Estradiol is produced in the [[Sertoli cell]]s of the testes. There is evidence that estradiol is to prevent [[apoptosis]] of male germ cells. <ref>Pentikäinen V, Erkkilä K, Suomalainen L, Parvinen M, Dunkel L. Estradiol Acts as a Germ Cell Survival Factor in the Human Testis ''in vitro''.
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The Journal of Clinical Endocrinology & Metabolism 2006;85:2057-67 PMID 10843196</ref>
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Estrogen is a hormone critical in the development, normal physiology and pathophysiology1 of numerous human tissues2. The effects of estrogen have traditionally been solely ascribed to estrogen receptor alpha (ERalpha) and more recently ERbeta, members of the soluble, nuclear ligand–activated family of transcription factors3. We have recently shown that the seven-transmembrane G protein–coupled receptor GPR30 binds estrogen with high affinity and resides in the endoplasmic reticulum, where it activates multiple intracellular signaling pathways4. To differentiate between the functions of ERalpha or ERbeta and GPR30, we used a combination of virtual and biomolecular screening to isolate compounds that selectively bind to GPR30. Here we describe the identification of the first GPR30-specific agonist, G-1 (1), capable of activating GPR30 in a complex environment of classical and new estrogen receptors. The development of compounds specific to estrogen receptor family members provides the opportunity to increase our understanding of these receptors and their contribution to estrogen biology.
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Several studies have noted that [[sperm count]]s have been declining in many parts of the world and it has been postulated that this may be related to estrogen exposure in the environment.<ref> Sharpe RM, Skakkebaek NE. Are oestrogens involved in falling sperm counts and disorders of the male reproductive tract?  Lancet. 1993 May 29;341(8857):1392-5. PMID 8098802 </ref> Suppression of estradiol production in a subpopulation of subfertile men may improve the semen analysis.<ref>Raman JD, Schlegel PN.  Aromatase Inhibitors for Male Infertility. Journal of Urology. (2002), 167:  624-629. PMID 11792932</ref>
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Ref2
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Males with sex chromosome genetic conditions such as [[Klinefelters Syndrome]] will have a higher level of estradiol.
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Drugs Fut 2006, 31(1): 65
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ISSN 0377-8282
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Copyright 2006 Prous Science
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CCC: 0377-8282
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DOI: 10.1358/dof.2006.031.01.959122
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Structure-function similarity between vitamin D3 and estrogens: Scope for effective drug design for vitamin D3 and estrogen dependent disorders
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Ray, S., Gupta, A.
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Vitamin D3 and estradiol are essential hormones that are formed in the body from the same source cholesterol. Whereas vitamin D3 is required mainly for calcium regulation and bone formation, estradiol regulates the reproductive cycle in women and maintains female characteristics. Both hormones are involved in various other functions in the body and act through their respective receptors which belong to the nuclear receptor superfamily. This article discusses the major role of vitamin D3 and estradiol in disorders such as osteoporosis, cancer and calcium regulation. Their functional similarity may be due to their participation at different junctures of the same mechanistic pathway or else a crosstalk between the two hormones and their opposite receptors. This suggests the possibility of designing effective drugs that would interact with both vitamin D3 and estrogen receptors for the treatment of vitamin D3 and estrogen-dependent disorders.
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MMDB ID: 14139
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===Bone===
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PDB ID: 1QKT
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There is ample evidence that estradiol has a profound effect on bone. Individuals without estradiol (or other estrogens) will become tall and eunuchoid as epiphysieal closure is delayed or may not take place. Bone structure is affected resulting in early osteopenia and osteoporosis. <ref>Carani C, Qin K, Simoni M, Faustini-Fustini M, Serpente S, Boyd J, Korach KS, Simpson ER. Effect of Testosterone and Estradiol in a Man with Aromatase Deficiency. New England Journal of Medicine Volume 337:91-95  July 10, 1997  PMID 9211678</ref>  Also, women past menopause experience an accelerated loss of bone mass due to a relative estrogen deficiency.
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MMDB ID: 14140
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PDB ID: 1QKU
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Reference: Gangloff M, Ruff M, Eiler S, Duclaud S, Wurtz JM, Moras DCrystal structure of a mutant hERalpha ligand-binding domain reveals key structural features for the mechanism of partial agonismJ. Biol. Chem. v276, p.15059-15065
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The crystal structure of a triple cysteine to serine mutant ERalpha ligand-binding domain (LBD), complexed with estradiol, shows that despite the presence of a tightly bound agonist ligand, the protein exhibits an antagonist-like conformation, similar to that observed in raloxifen and 4-hydroxytamoxifen-bound structures....
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MMDB ID: 17807
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===Liver===
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PDB ID: 1JGL
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Estradiol has complex effects on the liver. It can lead to [[cholestasis]]. It affects the production of multiple proteins including [[lipoprotein]]s, binding proteins, and proteins responsible for [[blood clotting]].
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Reference: Lamminmaki U, Kankare JACrystal structure of a recombinant anti-estradiol Fab fragment in complex with 17beta -estradiolJ. Biol. Chem. v276, p.36687-36694
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The crystal structure of a Fab fragment of an anti-17beta-estradiol antibody 57-2 was determined in the absence and presence of the steroid ligand, 17beta-estradiol (E2), at 2.5 and 2.15-A resolutions, respectively. The antibody binds the steroid in a deep hydrophobic pocket formed at the interface between the variable domains....
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MMDB ID: 18390
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===Brain===
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PDB ID: 1G50
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Estrogens can be produced in the brain from steroid precursors. As [[antioxidants]], they have been found to have neuroprotective function.<ref>Behl C, Widmann M, Trapp T, Holsboer F. 17-beta estradiol protects neurons from oxidative stress-induced cell death ''in vitro''. Biochem Biophys Res Commun. 1995 Nov 13;216(2):473-82. PMID 7488136 </ref>
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Reference: Eiler S, Gangloff M, Duclaud S, Moras D, Ruff MOverexpression, purification, and crystal structure of native ER alpha LBDProtein Expr. Purif. v22, p.165-173
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The positive and negative [[feedback loop]] of the [[menstrual cycle]] involve ovarian estradiol  as the link to the hypothalamic-pituitary system to regulate [[gonadotropin]]s.
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Several crystal structures of human estrogen receptor alpha ligand-binding domain (hERalpha LBD) complexed with agonist or antagonist molecules have previously been solved. The proteins had been modified in cysteine residues (carboxymethylation) or renatured in urea to circumvent aggregation and denaturation problems. In this work, high-level protein expression and purification together with crystallization screening procedure yielded high amounts of soluble protein without renaturation or modifications steps....
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MMDB ID: 18412
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Estrogen is considered to play a significant role in women’s mental health.  A conceptual model of how estrogen affects mood was suggested by Douma et al 2005 based on their extensive literature review relating activity of endogenous, bio-identical and synthetic estrogen with mood and well-being. They concluded that the sudden estrogen withdrawal, fluctuating estrogen, and periods of sustained estrogen low levels correlated with significant mood lowering.  Clinical recovery from depression postpartum, perimenopause, and postmenopause was shown to be effective after levels of estrogen were stabilized and/or restored.<ref>Douma SL, Husband C., O’Donnell, M.E., Barwin B.N., Woodend AK. Estrogen-related Mood Disorders Reproductive Life Cycle Factors.Advances in Nursing Science(2005), 28: No. 4:147-160.</ref>
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PDB ID: 1JNN
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<ref>Lasiuk GC,.The Effects of Estradiol on Central Serotonergic Systems and Its Relationship to Mood in Women. Biological Research for Nursing. (2007), 9: No. 2:364-375. DOI: 10.1177/1099500407605600</ref>
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Reference: Monnet C, Bettsworth F, Stura EA, Le Du MH, Menez R, Derrien L, Zinn-Justin S, Gilquin B, Sibai G, Battail-Poirot N, Jolivet M, Menez A, Arnaud M, Ducancel F, Charbonnier JBHighly specific anti-estradiol antibodies: structural characterisation and binding diversityJ. Mol. Biol. v315, p.699-712
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Subtle modulation of antibody-binding properties by protein engineering often lies with an accurate structural and energetic description of how an antigen is recognised. Thus, with the intent to increase the affinity and add a bias in favour of natural estradiol compared with its chemically modified immunogen, we have determined the crystal structure of two anti-estradiol monoclonal antibodies, 10G6D6 and 17E12E5....
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MMDB ID: 20338
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===Blood vessels===
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PDB ID: 1GWR
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Estrogen affects certain blood vessels. Improvement in arterial blood flow has been demonstrated in [[coronary artery|coronary arteries]].<ref>Collins P, Rosano GM, Sarrel PM, Ulrich L, Adamopoulos S, Beale CM, McNeill JG, Poole-Wilson PA. 17 beta-Estradiol attenuates acetylcholine-induced coronary arterial constriction in women but not men with coronary heart disease. Circulation. 1995 Jul 1;92(1):24-30 PMID 7788912 </ref>
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Reference: Warnmark A, Treuter E, Gustafsson JA, Hubbard RE, Brzozowski AM, Pike ACInteraction of transcriptional intermediary factor 2 nuclear receptor box peptides with the coactivator binding site of estrogen receptor alphaJ. Biol. Chem. v277, p.21862-21868
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The activation function 2/ligand-dependent interaction between nuclear receptors and their coregulators is mediated by a short consensus motif, the so-called nuclear receptor (NR) box. Nuclear receptors exhibit distinct preferences for such motifs depending both on the bound ligand and on the NR box sequence. To better understand the structural basis of motif recognition, we characterized the interaction between estrogen receptor alpha and the NR box regions of the p160 coactivator TIF2....
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MMDB ID: 20905
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===Oncogene===
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PDB ID: 1LHU
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Estrogen is suspected to activate certain [[oncogenes]], as it supports certain cancers, notably [[breast cancer]] and cancer of the [[uterine lining]]. In addition there are several benign gynecologic conditions that are dependent on estrogen such as [[endometriosis]], [[leiomyoma]]ta uteri, and uterine bleeding.
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Reference: Grishkovskaya I, Avvakumov GV, Hammond GL, Catalano MG, Muller YASteroid ligands bind human sex hormone-binding globulin in specific orientations and produce distinct changes in protein conformationJ. Biol. Chem. v277, p.32086-32093
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The amino-terminal laminin G-like domain of human sex hormone-binding globulin (SHBG) contains a single high affinity steroid-binding site. Crystal structures of this domain in complex with several different steroid ligands have revealed that estradiol occupies the SHBG steroid-binding site in an opposite orientation when compared with 5 alpha-dihydrotestosterone or C19 androgen metabolites (5 alpha-androstan-3 beta,17 beta-diol and 5 alpha-androstan-3 beta,17 alpha-diol) or the synthetic progestin levonorgestrel....
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MMDB ID: 25056
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===Pregnancy===
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PDB ID: 1PCG
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The effect of estradiol, together with [[estrone]] and [[estriol]], in [[pregnancy]] is less clear. They may promote uterine blood flow, myometrial growth, sitmulate breast growth and at term, promote cervical softening and expression of myometrial [[oxytocin]] receptors.
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Reference: Leduc AM, Trent JO, Wittliff JL, Bramlett KS, Briggs SL, Chirgadze NY, Wang Y, Burris TP, Spatola AFHelix-stabilized cyclic peptides as selective inhibitors of steroid receptor-coactivator interactionsProc. Natl. Acad. Sci. U. S. A. v100, p.11273-11278
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The interaction between nuclear receptors and coactivators provides an arena for testing whether protein-protein interactions may be inhibited by small molecule drug candidates. We provide evidence that a short cyclic peptide, containing a copy of the LXXLL nuclear receptor box pentapeptide, binds tightly and selectively to estrogen receptor alpha....
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MMDB ID: 35805
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==Role in [[sex differentiation]] of the brain==
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PDB ID: 2D06
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One of the fascinating twists to mammalian sex differentiation is that estradiol is one of the two active metabolites of testosterone in males (the other being [[dihydrotestosterone]]), and since fetuses of both sexes are exposed to similarly high levels of maternal estradiol, this source cannot have a significant impact on prenatal sex differentiation. Estradiol cannot be transferred readily from the circulation into the brain, while testosterone can, thus sex differentiation can be caused by the testosterone in the brain of most male mammals, including humans, aromatizing in significant amounts into estradiol. There is also now evidence that the programming of adult male sexual behavior in animals is largely dependent on estradiol produced in the central nervous system during prenatal life and early infancy from testosterone. <ref>{{cite journal | last = Harding | first = Prof. Cheryl F. | title = Hormonal Modulation of Singing: Hormonal Modulation of the Songbird Brain and Singing Behavior | journal = Ann. N.Y. Acad. Sci. | volume = 1016 | pages = 524–539 | publisher = The New York Academy of Sciences | month = June | year = 2004 | url = http://www.annalsnyas.org/content/vol1016/issue1/index.dtl | doi = 10.1196/annals.1298.030 | accessdate = 2007-03-07}}</ref> However, it is not yet known whether this process plays a minimal or significant part in human sexual behaviors although evidence from other mammals tends to indicate that it does. <ref>{{cite journal | last = Simerly | first = Richard B. | title = Wired for reproduction: organization and development of sexually dimorphic circuits in the mammalian forebrain | journal = Annual Rev. Neurosci. | volume = 25 | pages =507–536 | date = 2002-03-27 | url = http://www.healthsystem.virginia.edu/internet/neuroscience/BehavioralNeuroscience/Simerley-EFR-1-4.pdf | doi = 10.1146/annurev.neuro.25.112701.142745 | pmid = 12052919 | format = pdf | accessdate = 2007-03-07}}</ref>
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Reference: Gamage NU, Tsvetanov S, Duggleby RG, McManus ME, Martin JLThe structure of human SULT1A1 crystallized with estradiol. An insight into active site plasticity and substrate inhibition with multi-ring substratesJ. Biol. Chem. v280, p.41482-41486
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Human SULT1A1 belongs to the supergene family of sulfotransferases (SULTs) involved in the sulfonation of xeno- and endobiotics. The enzyme is also one of the SULTs responsible for metabolic activation of mutagenic and carcinogenic compounds and therefore is implicated in various cancer forms. Further, it is not well understood how substrate inhibition takes place with rigid fused multiring substrates such as 17beta-estradiol (E2) at high substrate concentrations when subcellular fractions or recombinant enzymes are used....
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MMDB ID: 43057
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Recently, it was discovered that volumes of [[Sexual dimorphism|sexually dimorphic]] brain structures in phenotypical males changed to approximate those of typical female brain structures when exposed to estradiol over a period of months. <ref name="eje-utrecht">{{cite journal| author = Hulshoff, Cohen-Kettenis et al. | year = 2006 | month = July | title = Changing your sex changes your brain: influences of testosterone and estrogen on adult human brain structure | url = http://www.eje-online.org/cgi/content/abstract/155/suppl_1/S107 | journal = European Journal of Endocrinology | issue = 155 | pages = 107–114 | doi = 10.1530/eje.1.02248 | id = {{ISSN|0804-4643}} | | volume = 155}}</ref> This would suggest that estradiol has a significant part to play in sex differentiation of the brain, both pre-natal and throughout life.
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PDB ID: 2J7X
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Description Structure Of Estradiol-Bound Estrogen Receptor Beta Lbd In Complex With Lxxll Motif From Ncoa5.
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Deposition: Pike ACW, Brzozowski AM, Hubbard RE, Walton J, Bonn T, - A, Thorsell G, Engstrom O, Ljunggren J, Gustaffson J-A, Carlquist M, 2006/10/17
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MMDB ID: 47760
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==Estradiol medication==
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PDB ID: 1A52
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Estrogen is marketed in a number of  ways to address issues of [[hypoestrogenism]]. Thus there are oral, transdermal, topical, injectable,  and vaginal preparations. Furthermore, the estradiol molecule may be linked to an [[alkyl]] group at C3 position to facilitate the administration. Such modifications give rise to '''estradiol acetate''' (oral and vaginal applications) and to '''estradiol cyprionate''' (injectable).
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Reference: Tanenbaum DM, Wang Y, Williams SP, Sigler PBCrystallographic comparison of the estrogen and progesterone receptor's ligand binding domainsProc. Natl. Acad. Sci. U. S. A. v95, p.5998-6003
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The 2.8-A crystal structure of the complex formed by estradiol and the human estrogen receptor-alpha ligand binding domain (hERalphaLBD) is described and compared with the recently reported structure of the progesterone complex of the human progesterone receptor ligand binding domain, as well as with similar structures of steroid/nuclear receptor LBDs solved elsewhere....
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MMDB ID: 47957
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Oral preparations are not necessarily predictably absorbed and subject to a first pass through the liver where they can be metabolized and also initiate unwanted side effects. Thus, alternative routes of administration have been developed that bypass the liver before primary target organs are hit. Transdermal and transvaginal routes are not subject to the initial liver passage.
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PDB ID: 1AQU
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Reference: Kakuta Y, Pedersen LG, Carter CW, Negishi M, Pedersen LCCrystal structure of estrogen sulphotransferaseNat. Struct. Biol. v4, p.904-908
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The structure of estrogen sulphotransferase has been solved in the presence of inactive cofactor PAP and substrate 17 beta-estradiol. This structure reveals structural similarities between cytosolic sulphotransferases and nucleotide kinases.
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MMDB ID: 49701
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A more profound alteration is [[ethinylestradiol]], the most common estrogen ingredient in [[combined oral contraceptive pill]]s
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PDB ID: 1IOL
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Reference: Azzi A, Rehse PH, Zhu DW, Campbell RL, Labrie F, Lin SXCrystal structure of human estrogenic 17 beta-hydroxysteroid dehydrogenase complexed with 17 beta-estradiolNat. Struct. Biol. v3, p.665-668
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MMDB ID: 55024
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==Therapy==
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PDB ID: 1A27
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===Hormone replacement therapy===
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Reference: Mazza C, Breton R, Housset D, Fontecilla-Camps JCUnusual charge stabilization of NADP+ in 17beta-hydroxysteroid dehydrogenaseJ. Biol. Chem. v273, p.8145-8152
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If severe side effects of low levels of estradiol in a woman's blood are experienced (commonly at the beginning of [[menopause]] or after [[oophorectomy]]), [[hormone replacement therapy]] may be prescribed. Often such therapy is combined with a [[progestin]].  
-
Type 1 17beta-hydroxysteroid dehydrogenase (17beta-HSD1), a member of the short chain dehydrogenase reductase (SDR) family, is responsible for the synthesis of 17beta-estradiol, the biologically active estrogen involved in the genesis and development of human breast cancers. Here, we report the crystal structures of the H221L 17beta-HSD1 mutant complexed to NADP+ and estradiol and the H221L mutant/NAD+ and a H221Q mutant/estradiol complexes....
+
-
MMDB ID: 56114
+
Estrogen therapy may be used in treatment of [[infertility]] in women when there is a need to develop sperm-friendly [[cervix|cervical]] mucus or an appropriate uterine lining.  
-
PDB ID: 1FDS
+
-
Reference: Breton R, Housset D, Mazza C, Fontecilla-Camps JCThe structure of a complex of human 17beta-hydroxysteroid dehydrogenase with estradiol and NADP+ identifies two principal targets for the design of inhibitorsStructure v4, p.905-915
+
-
BACKGROUND: The steroid hormone 17beta-estradiol is important in the genesis and development of human breast cancer. Its intracellular concentration is regulated by 17beta-hydroxysteroid dehydrogenase, which catalyzes the reversible reduction of estrone to 17beta-estradiol. This enzyme is thus an important target for inhibitor design....
+
-
MMDB ID: 56115
+
Estrogen therapy is also used to maintain female hormone levels in [[male-to-female transsexual]]s.
-
PDB ID: 1FDT
+
===Estrogen and Mood===
-
Reference: Breton R, Housset D, Mazza C, Fontecilla-Camps JCThe structure of a complex of human 17beta-hydroxysteroid dehydrogenase with estradiol and NADP+ identifies two principal targets for the design of inhibitorsStructure v4, p.905-915
+
Estrogen is considered to play a significant role in women’s mental health.  A conceptual model of how estrogen affects mood was suggested by Douma et al 2005 based on their extensive literature review relating activity of endogenous, bio-identical and synthetic estrogen with mood and well-being.    They concluded the sudden estrogen withdrawal, fluctuating estrogen, and periods of sustained estrogen low levels correlated with significant mood lowering. Clinical recovery from depression postpartum, perimenopause, and postmenopause was shown to be affective after levels of estrogen were stabilized and/or restored.
-
BACKGROUND: The steroid hormone 17beta-estradiol is important in the genesis and development of human breast cancer. Its intracellular concentration is regulated by 17beta-hydroxysteroid dehydrogenase, which catalyzes the reversible reduction of estrone to 17beta-estradiol. This enzyme is thus an important target for inhibitor design....
+
-
MMDB ID: 56116
+
===Blocking estrogens===
-
PDB ID: 1FDW
+
Inducing a state of hypoestrogenism may be beneficial in certain situations where estrogens are contributing to unwanted effects, e.g, certain forms of [[breast cancer]], [[gynecomastia]], and premature [[bone maturation|closure of epiphyses]]. Estrogen levels can be reduced by inhibiting production using gonadotropin- releasing factor agonists ([[GnRH agonist]]s) or blocking the aromatase enzyme using an [[aromatase inhibitor]], or estrogen effects can be reduced with estrogen antagonists such as [[tamoxifen]]. Flaxseed is known to reduce estradiol.<ref>{{cite book | first=Andrew | last= Chevallier | year= 2000 | title=Encyclopedia of Herbal Medicine: The Definitive Home Reference Guide to 550 Key Herbs with all their Uses as Remedies for Common Ailments | chapter= | editor=Gillian Emerson-Roberts | others= | pages= | publisher= DK Publishing | isbn=0-7894-6783-6 | url= | authorlink= }}</ref>
-
Reference: Mazza C, Breton R, Housset D, Fontecilla-Camps JCUnusual charge stabilization of NADP+ in 17beta-hydroxysteroid dehydrogenaseJ. Biol. Chem. v273, p.8145-8152
+
-
Type 1 17beta-hydroxysteroid dehydrogenase (17beta-HSD1), a member of the short chain dehydrogenase reductase (SDR) family, is responsible for the synthesis of 17beta-estradiol, the biologically active estrogen involved in the genesis and development of human breast cancers. Here, we report the crystal structures of the H221L 17beta-HSD1 mutant complexed to NADP+ and estradiol and the H221L mutant/NAD+ and a H221Q mutant/estradiol complexes....
+
-
MMDB ID: 60515
+
===Hormonal contraception===
-
PDB ID: 2OCF
+
A synthetic form of estradiol, called [[ethinylestradiol]] is a major component of hormonal contraceptive devices. Combined forms of [[hormonal contraception]] contain [[ethinylestradiol]] and a [[progestin]], which both contribute to the inhibition of [[GnRH]], [[Luteinizing hormone|LH]], and [[FSH]]. The inhibition of these [[hormones]] accounts for the ability of these [[birth control]] methods to prevent ovulation and thus prevent pregnancy. Other types of hormonal birth control contain only [[progestins]] and no [[ethinylestradiol]].
-
Description Human Estrogen Receptor Alpha Ligand-Binding Domain In Complex With Estradiol And The E2#23 Fn3 Monobody.
+
-
Deposition: Rajan SS, Kuruvilla SM, Sharma SK, Kim Y, Huang J, Koide A, Koide S, Joachimiak A, Greene GL, 2006/12/20
+
-
MMDB ID: 8897
+
===List of estradiol medications===
-
PDB ID: 1ERE
+
The following are marketed versions of estradiol:
-
Reference: Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, Engstrom O, Ohman L, Greene GL, Gustafsson JA, Carlquist MMolecular basis of agonism and antagonism in the oestrogen receptorNature v389, p.753-758
+
* Oral versions: Estrace, Activella (also contains a progestin), estradiol acetate, Progynova, estrofem
-
Oestrogens are involved in the growth, development and homeostasis of a number of tissues. The physiological effects of these steroids are mediated by a ligand-inducible nuclear transcription factor, the oestrogen receptor (ER). Hormone binding to the ligand-binding domain (LBD) of the ER initiates a series of molecular events culminating in the activation or repression of target genes....
+
* Transdermal preparation: Alora, Climara, Vivelle, Vivelle-Dot, Menostar, Estraderm TTS
 +
* Ointments: Estrasorb Topical, Estrogel, Elestrin
 +
* Injection: Estradiol cypionate: Lunelle monthly injection, Estradiol valerate
 +
* Vaginal ointment: Estrace Vaginal Cream, Premarin Cream
 +
* Vaginal ring: Estring (estradiol acetate), Femring
-
Physical Property  Value  Units  Temp (deg C)  Source
+
Estradiol is also part of conjugated estrogen preparations, including [[Premarin]] but is not the major ingredient (Premarin consists of hundreds of estrogen derivatives due to its natural source...'''pre'''gnant '''mar'''e ur'''in'''e.
-
Melting Point 178.5 deg C   EXP
+
-
log P (octanol-water) 4.01 (none)   EXP
+
-
Water Solubility 3.6 mg/L 27 EXP
+
-
Vapor Pressure 1.26E-08 mm Hg 25 EST
+
-
Henry's Law Constant 3.64E-11 atm-m3/mole 25 EST
+
-
Atmospheric OH Rate Constant 1.23E-10 cm3/molecule-sec 25 EST
+
-
Organism Test Type Route Reported Dose (Normalized Dose) Effect Source
+
==Contraindications==
-
rat LD subcutaneous > 300mg/kg (300mg/kg)   Iyakuhin Kenkyu. Study of Medical Supplies. Vol. 26, Pg. 740, 1995.
+
Estradiol should not be given to women who are pregnant or are breastfeeding, women with unexplained uterine bleeding, certain forms of cancer, or prone to blood clotting disorders. The medication is to be kept away from children. Detailed prescription information is available <ref>[http://warnerchilcott.com/pdfs/pi/pi_estrace_wc_imprint.pdf Estrace/Estradiol patient information leaflet] - Warner Chilcott (manufacturer)</ref>
 +
 
 +
==Side effects==
 +
Side effects of estradiol therapy may include uterine bleeding, breast tenderness, nausea and vomiting, [[chloasma]], cholestasis, and [[migraine]] headaches.
 +
 
 +
Therapeutic Indications
 +
* Menopause
 +
* Osteoporosis
 +
 
 +
==Toxicity==
 +
 
 +
{| border="1;width:100%; height:200px;style=text-align:center"
 +
|+'''Toxicity:'''
 +
|-
 +
! style="background:white; color:blue" |Organism  
 +
! style="background:white; color:blue" |Test Type
 +
! style="background:white; color:blue" |Route
 +
! style="background:white; color:blue" |Reported Dose (Normalized Dose)
 +
! style="background:white; color:blue" |Effect
 +
! style="background:white; color:blue" |Source
 +
|-
 +
|rat
 +
|LD
 +
|subcutaneous
 +
|> 300mg/kg (300mg/kg)  
 +
|  
 +
|Iyakuhin Kenkyu. Study of Medical Supplies. Vol. 26, Pg. 740, 1995.
 +
|-
 +
|}
 +
==See also==
 +
*[[Estrogen insensitivity syndrome]]
 +
*[[Hormone replacement therapy]]
 +
*[[Gender]]
 +
*[[Androgen]]
 +
*[[Oral contraceptive formulations]]
 +
*[[Phytoestrogens]], the family of plant chemicals which can act on estradiol receptive tissue in mammals, although the exact mechanism at hand is unclear.
 +
 
 +
[[category:hormones]]
 +
[[Category:Estrogens]]
 +
[[Category:Phenols]]
 +
 
 +
==References==
 +
*Virtual and biomolecular screening converge on a selective agonist for GPR30
 +
 
 +
Cristian G Bologa1,7, Chetana M Revankar2,3,7, Susan M Young3, Bruce S Edwards3,4, Jeffrey B Arterburn5, Alexander S Kiselyov6, Matthew A Parker6, Sergey E Tkachenko6, Nikolay P Savchuck6, Larry A Sklar3,4, Tudor I Oprea1 & Eric R Prossnitz2,3
 +
 
 +
*Structure-function similarity between vitamin D3 and estrogens: Scope for effective drug design for vitamin D3 and estrogen dependent disorders
 +
Ray, S., Gupta, A.
 +
Drugs Fut 2006, 31(1): 65
 +
ISSN 0377-8282
 +
Copyright 2006 Prous Science
 +
CCC: 0377-8282
 +
DOI: 10.1358/dof.2006.031.01.959122

Current revision

Show 3-D Structure

Estradiol
Systematic (IUPAC) name
(8R,9S,13S,14S,17S)-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol
Identifiers
CAS number 50-28-2
57-91-0 (±)
ATC code G03CA03
PubChem 5757
ChemSpider 5554
Chemical data
Formula C18H24O2
Mol. mass 272.38
SMILES eMolecules & PubChem
Synonyms 17beta-Estradiol
Physical data
Solubility in water 3.6 mg/L 27oC EXP mg/mL
Pharmacokinetic data
Bioavailability 97-99% is bound
Metabolism Liver
Half life ~ 13 hours
Excretion Urine
Therapeutic considerations
Pregnancy cat.

X (USA)

Legal status

S4 (Au), POM (UK), ℞-only (U.S.)

Routes Oral, transdermal

Estradiol (17β-estradiol) (also oestradiol) is a sex hormone. Mislabelled the "female" hormone, it is also present in males; it represents the major estrogen in humans. Estradiol has not only a critical impact on reproductive and sexual functioning, but also affects other organs including bone structure.

Generally refers to the 17-beta-isomer of estradiol, an aromatized C18 steroid with hydroxyl group at 3-beta- and 17-beta-position. Estradiol-17-beta is the most potent form of mammalian estrogenic steroids. In humans, it is produced primarily by the cyclic ovaries and the PLACENTA. It is also produced by the adipose tissue of men and postmenopausal women. The 17-alpha-isomer of estradiol binds weakly to estrogen receptors (RECEPTORS, ESTROGEN) and exhibits little estrogenic activity in estrogen-responsive tissues. Various isomers can be synthesized.

Contents

[edit] PhysioChemical Properties

[edit] Melting Point

178.5 EXP

[edit] log P

4.01 (none) EXP

[edit] Water Solubility

3.6 mg/L 27 EXP

[edit] Vapor Pressure

1.26E-08 mm Hg 25 EST

[edit] Henry's Law Constant

3.64E-11 atm-m3/mole 25 EST

[edit] Atmospheric OH Rate Constant

1.23E-10 cm3/molecule-sec 25 EST

[edit] Production

During the reproductive years, most estradiol in women is produced by the granulosa cells of the ovary|ovaries by the aromatization of androstenedione (produced in the theca folliculi cells} to estrone, followed by conversion of estrone to estradiol by 17β-hydroxysteroid reductase. Smaller amounts of estradiol are also produced by the adrenal cortex, and in me), by the testes. Estradiol is not only produced in the gonads: in both sexes, precursor hormones, specifically testosterone, are converted by aromatization to estradiol. In particular, fat cells are active to convert precursors to estradiol, and will continue to do so even after menopause. Estradiol is also produced in the brain and in arterial walls.

[edit] Mechanism of action

Estradiol enters cells freely and interacts with a cytoplasmic target cell receptor. When the estrogen receptor has bound its ligand it can enter the nucleus of the target cell, and regulate gene transcription which leads to formation of messenger RNA. The mRNA interacts with ribosomes to produce specific proteins that express the effect of estradiol upon the target cell.

Estradiol binds well to both estrogen receptors, ERα and ERβ, in contrast to certain other estrogens, notably medications that preferentially act on one of these receptors. These medications are called selective estrogen receptor modulators, or SERMs.

Estradiol is the most potent naturally-occurring estrogen.

Recently there has been speculation about a membrane estrogen receptor, ERX.

[edit] Metabolism

In plasma, estradiol is largely bound to sex hormone binding globulin, also to albumin, -only a fraction is free and biologically active. Deactivation includes conversion to less active estrogens such as estrone and estriol. Estriol is the major urinary metabolite. Estradiol is conjugated in the liver by sulfate and glucuronide formation and as such excreted via the kidneys. Some of the watersoluble conjugates are excreted via the bile duct, and partly reabsorbed after hydrolysis from the intestinal tract. This enterohepatic circulation contributes to maintaining estradiol levels.

[edit] Measurement

Serum estradiol measurement in women reflects primarily the activity of the ovaries. As such they are useful in the detection of baseline estrogen in women with amenorrhea or menstrual dysfunction and to detect the state of hypoestrogenicity and menopause. Furthermore, estrogen monitoring during fertility therapy assesses follicular growth and is useful in monitoring the treatment. Estrogen-producing tumors will demonstrate persistent high levels of estradiol and other estrogens. In precocious puberty estradiol levels are inappropriately increased.

In the normal menstrual cycle estradiol levels measure typically <50 ng/ml at menstruation, rise with follicular development, drop briefly at ovulation, and rise again during the luteal phase for a second peak. At the end of the luteal phase estradiol levels drop to their menstrual levels unless there is a pregnancy.

During pregnancy estrogen levels including estradiol rise steadily towards term. The source of these estrogens is the placenta that aromatizes prohormones produced in the fetal adrenal gland.

[edit] Effects

[edit] Female reproduction

In the female, estradiol acts as a growth hormone for tissue of the reproductive organs, supporting the lining of the vagina, the cervical glands, the endometrium and the lining of the fallopian tubes. It enhances growth of the myometrium. Estradiol appears necessary to maintain oocytes in the ovary. During the menstrual cycle, estradiol that is produced by the growing follicle triggers, via a positive feedback system, the hypothalamic-pituitary events that lead to the luteinizing hormone surge, inducing ovulation. In the luteal phase estradiol, in conjunction with progesterone, prepares the endometrium for implantation. During pregnancy estradiol increases due to placental production. In baboons, blocking of estrogen production leads to pregnancy loss suggesting that estradiol has a role in the maintenance of pregnancy. Research is investigating the role of estrogens in the process of initiation of labor.

[edit] Sexual development

The development of secondary sex characteristics in women is driven by estrogens, specifically estradiol. These changes are initiated at the time of puberty, most enhanced during the reproductive years, and become less pronounced with declining estradiol support after the menopause. Thus, estradiol enhances breast development, and is responsible for changes in the body shape affecting bones, joints, fat deposition. Fat structure and skin composition are modified by estradiol.

[edit] Male reproduction

The effect of estradiol (and estrogens) upon male reproduction is complex. Estradiol is produced in the Sertoli cells of the testes. There is evidence that estradiol is to prevent apoptosis of male germ cells. <ref>Pentikäinen V, Erkkilä K, Suomalainen L, Parvinen M, Dunkel L. Estradiol Acts as a Germ Cell Survival Factor in the Human Testis in vitro. The Journal of Clinical Endocrinology & Metabolism 2006;85:2057-67 PMID 10843196</ref>

Several studies have noted that sperm counts have been declining in many parts of the world and it has been postulated that this may be related to estrogen exposure in the environment.<ref> Sharpe RM, Skakkebaek NE. Are oestrogens involved in falling sperm counts and disorders of the male reproductive tract? Lancet. 1993 May 29;341(8857):1392-5. PMID 8098802 </ref> Suppression of estradiol production in a subpopulation of subfertile men may improve the semen analysis.<ref>Raman JD, Schlegel PN. Aromatase Inhibitors for Male Infertility. Journal of Urology. (2002), 167: 624-629. PMID 11792932</ref>

Males with sex chromosome genetic conditions such as Klinefelters Syndrome will have a higher level of estradiol.

[edit] Bone

There is ample evidence that estradiol has a profound effect on bone. Individuals without estradiol (or other estrogens) will become tall and eunuchoid as epiphysieal closure is delayed or may not take place. Bone structure is affected resulting in early osteopenia and osteoporosis. <ref>Carani C, Qin K, Simoni M, Faustini-Fustini M, Serpente S, Boyd J, Korach KS, Simpson ER. Effect of Testosterone and Estradiol in a Man with Aromatase Deficiency. New England Journal of Medicine Volume 337:91-95 July 10, 1997 PMID 9211678</ref> Also, women past menopause experience an accelerated loss of bone mass due to a relative estrogen deficiency.

[edit] Liver

Estradiol has complex effects on the liver. It can lead to cholestasis. It affects the production of multiple proteins including lipoproteins, binding proteins, and proteins responsible for blood clotting.

[edit] Brain

Estrogens can be produced in the brain from steroid precursors. As antioxidants, they have been found to have neuroprotective function.<ref>Behl C, Widmann M, Trapp T, Holsboer F. 17-beta estradiol protects neurons from oxidative stress-induced cell death in vitro. Biochem Biophys Res Commun. 1995 Nov 13;216(2):473-82. PMID 7488136 </ref> The positive and negative feedback loop of the menstrual cycle involve ovarian estradiol as the link to the hypothalamic-pituitary system to regulate gonadotropins.

Estrogen is considered to play a significant role in women’s mental health. A conceptual model of how estrogen affects mood was suggested by Douma et al 2005 based on their extensive literature review relating activity of endogenous, bio-identical and synthetic estrogen with mood and well-being. They concluded that the sudden estrogen withdrawal, fluctuating estrogen, and periods of sustained estrogen low levels correlated with significant mood lowering. Clinical recovery from depression postpartum, perimenopause, and postmenopause was shown to be effective after levels of estrogen were stabilized and/or restored.<ref>Douma SL, Husband C., O’Donnell, M.E., Barwin B.N., Woodend AK. Estrogen-related Mood Disorders Reproductive Life Cycle Factors.Advances in Nursing Science(2005), 28: No. 4:147-160.</ref> <ref>Lasiuk GC,.The Effects of Estradiol on Central Serotonergic Systems and Its Relationship to Mood in Women. Biological Research for Nursing. (2007), 9: No. 2:364-375. DOI: 10.1177/1099500407605600</ref>

[edit] Blood vessels

Estrogen affects certain blood vessels. Improvement in arterial blood flow has been demonstrated in coronary arteries.<ref>Collins P, Rosano GM, Sarrel PM, Ulrich L, Adamopoulos S, Beale CM, McNeill JG, Poole-Wilson PA. 17 beta-Estradiol attenuates acetylcholine-induced coronary arterial constriction in women but not men with coronary heart disease. Circulation. 1995 Jul 1;92(1):24-30 PMID 7788912 </ref>

[edit] Oncogene

Estrogen is suspected to activate certain oncogenes, as it supports certain cancers, notably breast cancer and cancer of the uterine lining. In addition there are several benign gynecologic conditions that are dependent on estrogen such as endometriosis, leiomyomata uteri, and uterine bleeding.

[edit] Pregnancy

The effect of estradiol, together with estrone and estriol, in pregnancy is less clear. They may promote uterine blood flow, myometrial growth, sitmulate breast growth and at term, promote cervical softening and expression of myometrial oxytocin receptors.

[edit] Role in sex differentiation of the brain

One of the fascinating twists to mammalian sex differentiation is that estradiol is one of the two active metabolites of testosterone in males (the other being dihydrotestosterone), and since fetuses of both sexes are exposed to similarly high levels of maternal estradiol, this source cannot have a significant impact on prenatal sex differentiation. Estradiol cannot be transferred readily from the circulation into the brain, while testosterone can, thus sex differentiation can be caused by the testosterone in the brain of most male mammals, including humans, aromatizing in significant amounts into estradiol. There is also now evidence that the programming of adult male sexual behavior in animals is largely dependent on estradiol produced in the central nervous system during prenatal life and early infancy from testosterone. <ref>Harding, Prof. Cheryl F. (June 2004). "Hormonal Modulation of Singing: Hormonal Modulation of the Songbird Brain and Singing Behavior". Ann. N.Y. Acad. Sci. 1016: 524–539. The New York Academy of Sciences. doi:10.1196/annals.1298.030. Retrieved on 2007-03-07.</cite> </ref> However, it is not yet known whether this process plays a minimal or significant part in human sexual behaviors although evidence from other mammals tends to indicate that it does. <ref><cite style="font-style:normal">Simerly, Richard B. (2002-03-27). "Wired for reproduction: organization and development of sexually dimorphic circuits in the mammalian forebrain" (pdf). Annual Rev. Neurosci. 25: 507–536. doi:10.1146/annurev.neuro.25.112701.142745. PMID 12052919. Retrieved on 2007-03-07.</cite> </ref>

Recently, it was discovered that volumes of sexually dimorphic brain structures in phenotypical males changed to approximate those of typical female brain structures when exposed to estradiol over a period of months. <ref name="eje-utrecht"><cite style="font-style:normal">Hulshoff, Cohen-Kettenis et al. (July 2006). "Changing your sex changes your brain: influences of testosterone and estrogen on adult human brain structure". European Journal of Endocrinology 155 (155): 107–114. doi:10.1530/eje.1.02248. Template:ISSN.</cite> </ref> This would suggest that estradiol has a significant part to play in sex differentiation of the brain, both pre-natal and throughout life.

[edit] Estradiol medication

Estrogen is marketed in a number of ways to address issues of hypoestrogenism. Thus there are oral, transdermal, topical, injectable, and vaginal preparations. Furthermore, the estradiol molecule may be linked to an alkyl group at C3 position to facilitate the administration. Such modifications give rise to estradiol acetate (oral and vaginal applications) and to estradiol cyprionate (injectable).

Oral preparations are not necessarily predictably absorbed and subject to a first pass through the liver where they can be metabolized and also initiate unwanted side effects. Thus, alternative routes of administration have been developed that bypass the liver before primary target organs are hit. Transdermal and transvaginal routes are not subject to the initial liver passage.

A more profound alteration is ethinylestradiol, the most common estrogen ingredient in combined oral contraceptive pills

[edit] Therapy

[edit] Hormone replacement therapy

If severe side effects of low levels of estradiol in a woman's blood are experienced (commonly at the beginning of menopause or after oophorectomy), hormone replacement therapy may be prescribed. Often such therapy is combined with a progestin.

Estrogen therapy may be used in treatment of infertility in women when there is a need to develop sperm-friendly cervical mucus or an appropriate uterine lining.

Estrogen therapy is also used to maintain female hormone levels in male-to-female transsexuals.

[edit] Estrogen and Mood

Estrogen is considered to play a significant role in women’s mental health. A conceptual model of how estrogen affects mood was suggested by Douma et al 2005 based on their extensive literature review relating activity of endogenous, bio-identical and synthetic estrogen with mood and well-being. They concluded the sudden estrogen withdrawal, fluctuating estrogen, and periods of sustained estrogen low levels correlated with significant mood lowering. Clinical recovery from depression postpartum, perimenopause, and postmenopause was shown to be affective after levels of estrogen were stabilized and/or restored.

[edit] Blocking estrogens

Inducing a state of hypoestrogenism may be beneficial in certain situations where estrogens are contributing to unwanted effects, e.g, certain forms of breast cancer, gynecomastia, and premature closure of epiphyses. Estrogen levels can be reduced by inhibiting production using gonadotropin- releasing factor agonists (GnRH agonists) or blocking the aromatase enzyme using an aromatase inhibitor, or estrogen effects can be reduced with estrogen antagonists such as tamoxifen. Flaxseed is known to reduce estradiol.<ref>Template:Cite book</ref>

[edit] Hormonal contraception

A synthetic form of estradiol, called ethinylestradiol is a major component of hormonal contraceptive devices. Combined forms of hormonal contraception contain ethinylestradiol and a progestin, which both contribute to the inhibition of GnRH, LH, and FSH. The inhibition of these hormones accounts for the ability of these birth control methods to prevent ovulation and thus prevent pregnancy. Other types of hormonal birth control contain only progestins and no ethinylestradiol.

[edit] List of estradiol medications

The following are marketed versions of estradiol:

  • Oral versions: Estrace, Activella (also contains a progestin), estradiol acetate, Progynova, estrofem
  • Transdermal preparation: Alora, Climara, Vivelle, Vivelle-Dot, Menostar, Estraderm TTS
  • Ointments: Estrasorb Topical, Estrogel, Elestrin
  • Injection: Estradiol cypionate: Lunelle monthly injection, Estradiol valerate
  • Vaginal ointment: Estrace Vaginal Cream, Premarin Cream
  • Vaginal ring: Estring (estradiol acetate), Femring

Estradiol is also part of conjugated estrogen preparations, including Premarin but is not the major ingredient (Premarin consists of hundreds of estrogen derivatives due to its natural source...pregnant mare urine.

[edit] Contraindications

Estradiol should not be given to women who are pregnant or are breastfeeding, women with unexplained uterine bleeding, certain forms of cancer, or prone to blood clotting disorders. The medication is to be kept away from children. Detailed prescription information is available <ref>Estrace/Estradiol patient information leaflet - Warner Chilcott (manufacturer)</ref>

[edit] Side effects

Side effects of estradiol therapy may include uterine bleeding, breast tenderness, nausea and vomiting, chloasma, cholestasis, and migraine headaches.

Therapeutic Indications

  • Menopause
  • Osteoporosis

[edit] Toxicity

Toxicity:
Organism Test Type Route Reported Dose (Normalized Dose) Effect Source
rat LD subcutaneous > 300mg/kg (300mg/kg) Iyakuhin Kenkyu. Study of Medical Supplies. Vol. 26, Pg. 740, 1995.

[edit] See also

[edit] References

  • Virtual and biomolecular screening converge on a selective agonist for GPR30

Cristian G Bologa1,7, Chetana M Revankar2,3,7, Susan M Young3, Bruce S Edwards3,4, Jeffrey B Arterburn5, Alexander S Kiselyov6, Matthew A Parker6, Sergey E Tkachenko6, Nikolay P Savchuck6, Larry A Sklar3,4, Tudor I Oprea1 & Eric R Prossnitz2,3

  • Structure-function similarity between vitamin D3 and estrogens: Scope for effective drug design for vitamin D3 and estrogen dependent disorders

Ray, S., Gupta, A. Drugs Fut 2006, 31(1): 65 ISSN 0377-8282 Copyright 2006 Prous Science CCC: 0377-8282 DOI: 10.1358/dof.2006.031.01.959122

Retrieved from "http://140949.jxltd.asia/drugpedia/index.php/Estradiol"