Estradiol

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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.

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 1 Production 2 Mechanism of action 3 Metabolism 4 Measurement 5 Effects 5.1 Female reproduction 5.2 Sexual development 5.3 Male reproduction 5.4 Bone 5.5 Liver 5.6 Brain 5.7 Blood vessels 5.8 Oncogene 5.9 Pregnancy 6 Role in sex differentiation of the brain 7 Estradiol medication 8 Therapy 8.1 Hormone replacement therapy 8.2 Estrogen and Mood 8.3 Blocking estrogens 8.4 Hormonal contraception 8.5 List of estradiol medications 9 Contraindications 10 Side effects 11 References

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.

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.

Half Life: 36 hours Drug Type: Small Molecule; Approved; Investigational

Pharmacology: Estradiol, the principal intracellular human estrogen, is substantially more active than its metabolites, estrone and estriol, at the cellular level. 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).

Estradiol is the most potent naturally-occurring estrogen.

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

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.

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.

Effects

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.

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.

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.

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.

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.

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>

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>

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.

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.

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.

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

Therapy

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.

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.

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>

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.

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.

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>

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

KEGG Database(C00951,D00105) Pathway Androgen and estrogen metabolism Prostate cancer

List of PDB files having estradiol as a Ligand:

MMDB ID	PDB ID	Reference
14139	1QKT	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
14140	1QKU	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
17807	1JGL	Lamminmaki U, Kankare JACrystal structure of a recombinant anti-estradiol Fab fragment in complex with 17beta -estradiolJ. Biol. Chem. v276, p.36687-36694
18390	1G50	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
18412	1JNN	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
20338	1GWR	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
20905	1LHU	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
25056	1PCG	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
35805	2D06	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
43057	2J7X	Structure Of Estradiol-Bound Estrogen Receptor Beta Lbd In Complex With Lxxll Motif From Ncoa5. 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
47760	1A52	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
47957	1AQU	Kakuta Y, Pedersen LG, Carter CW, Negishi M, Pedersen LCCrystal structure of estrogen sulphotransferaseNat. Struct. Biol. v4, p.904-908
49701	1IOL	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
55024	1A27	Mazza C, Breton R, Housset D, Fontecilla-Camps JCUnusual charge stabilization of NADP+ in 17beta-hydroxysteroid dehydrogenaseJ. Biol. Chem. v273, p.8145-8152
56114	1FDS	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
56115	1FDT	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
56116	1FDW	Mazza C, Breton R, Housset D, Fontecilla-Camps JCUnusual charge stabilization of NADP+ in 17beta-hydroxysteroid dehydrogenaseJ. Biol. Chem. v273, p.8145-8152
60515	2OCF	Rajan SS, Kuruvilla SM, Sharma SK, Kim Y, Huang J, Koide A, Koide S, Joachimiak A, Greene GL, 2006/12/20
8897	1ERE	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

Physiochemical properties of Estradiol:

Physical Property	Value	Units	Temp (deg C)	Source
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

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.

Lipinski’s “Rule of Five” for Estradiol

4	3	2	1	0
GOOD	INDETERMINATE	INDETERMINATE	INDETERMINATE	POOR

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