“Estradiol”的意思、由来-开放百科全书

Estradiol is produced especially within the follicles of the ovaries, but also in other tissues including the testicles, the adrenal glands, fat, liver, the breasts, and the brain. Estradiol is produced in the body from cholesterol through a series of reactions and intermediates.^[10] The major pathway involves the formation of androstenedione, which is then converted by aromatase into estrone and is subsequently converted into estradiol. Alternatively, androstenedione can be converted into testosterone, which can then be converted into estradiol. Upon menopause in women, production of estrogens by the ovaries stops and estradiol levels decrease to very low levels.

In addition to its role as a natural hormone, estradiol is used as a medication, for instance in menopausal hormone therapy; for information on estradiol as a medication, see the estradiol (medication) article.

Biological function

Sexual development

The development of secondary sex characteristics in women is driven by estrogens, to be specific, estradiol.^[11]^[12] These changes are initiated at the time of puberty, most are enhanced during the reproductive years, and become less pronounced with declining estradiol support after menopause. Thus, estradiol produces breast development, and is responsible for changes in the body shape, affecting bones, joints, and fat deposition.^[11]^[12] In females, estradiol induces breast development, widening of the hips, a feminine fat distribution (with fat deposited particularly in the breasts, hips, thighs, and buttocks), and maturation of the vagina and vulva, whereas it mediates the pubertal growth spurt (indirectly via increased growth hormone secretion)^[13] and epiphyseal closure (thereby limiting final height) in both sexes.^[11]^[12]

Reproduction

Female reproductive system

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 produced by the growing follicles 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. The effect of estradiol, together with estrone and estriol, in pregnancy is less clear. They may promote uterine blood flow, myometrial growth, stimulate breast growth and at term, promote cervical softening and expression of myometrial oxytocin receptors.{{citation needed|date=February 2013}} In baboons, blocking of estrogen production leads to pregnancy loss, suggesting estradiol has a role in the maintenance of pregnancy. Research is investigating the role of estrogens in the process of initiation of labor. Actions of estradiol are required before the exposure of progesterone in the luteal phase.{{citation needed|date=February 2013}}

Male reproductive system

The effect of estradiol (and estrogens in general) upon male reproduction is complex. Estradiol is produced by action of aromatase mainly in the Leydig cells of the mammalian testis, but also by some germ cells and the Sertoli cells of immature mammals.^[14] It functions (in vitro) to prevent apoptosis of male sperm cells.^[15]

While some studies in the early 1990s claimed a connection between globally declining sperm counts and estrogen exposure in the environment,^[16] later studies found no such connection, nor evidence of a general decline in sperm counts.^[17]^[18]

Suppression of estradiol production in a subpopulation of subfertile men may improve the semen analysis.^[19]

Males with certain sex chromosome genetic conditions, such as Klinefelter's syndrome, will have a higher level of estradiol.^[20]

Skeletal system

Estradiol has a profound effect on bone. Individuals without it (or other estrogens) will become tall and eunuchoid, as epiphyseal closure is delayed or may not take place. Bone density, as well as joints, are also affected, resulting in early osteopenia and osteoporosis.^[21] Women past menopause experience an accelerated loss of bone mass due to a relative estrogen deficiency.^[22]

Skin health

The estrogen receptor, as well as the progesterone receptor, have been detected in the skin, including in keratinocytes and fibroblasts.^[23]^[24] At menopause and thereafter, decreased levels of female sex hormones result in atrophy, thinning, and increased wrinkling of the skin and a reduction in skin elasticity, firmness, and strength.^[23]^[24] These skin changes constitute an acceleration in skin aging and are the result of decreased collagen content, irregularities in the morphology of epidermal skin cells, decreased ground substance between skin fibers, and reduced capillaries and blood flow.^[23]^[24] The skin also becomes more dry during menopause, which is due to reduced skin hydration and surface lipids (sebum production).^[23] Along with chronological aging and photoaging, estrogen deficiency in menopause is one of the three main factors that predominantly influences skin aging.^[23]

Nervous system

Estrogens can be produced in the brain from steroid precursors. As antioxidants, they have been found to have neuroprotective function.^[25]

The positive and negative feedback loops of the menstrual cycle involve ovarian estradiol as the link to the hypothalamic-pituitary system to regulate gonadotropins.^[26] (See Hypothalamic–pituitary–gonadal axis.)

Estrogen is considered to play a significant role in women's mental health, with links suggested between the hormone level, mood and well-being. Sudden drops or fluctuations in, or long periods of sustained low levels of estrogen may be 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.^[27]^[28]

Recently, the volumes of sexually dimorphic brain structures in transgender women were found to change and approximate typical female brain structures when exposed to estrogen concomitantly with androgen deprivation over a period of months,^[29] suggesting that estrogen and/or androgens have a significant part to play in sex differentiation of the brain, both prenatally and later in life.

There is also evidence the programming of adult male sexual behavior in many vertebrates is largely dependent on estradiol produced during prenatal life and early infancy.^[30] It is not yet known whether this process plays a significant role in human sexual behavior, although evidence from other mammals tends to indicate a connection.^[31]

Estrogen has been found to increase the secretion of oxytocin and to increase the expression of its receptor, the oxytocin receptor, in the brain.^[32] In women, a single dose of estradiol has been found to be sufficient to increase circulating oxytocin concentrations.^[33]

Gynecological cancers

Estradiol has been tied to the development and progression of cancers such as breast cancer, ovarian cancer and endometrial cancer. Estradiol affects target tissues mainly by interacting with two nuclear receptors called estrogen receptor α (ERα) and estrogen receptor β (ERβ).^[34]^[35] One of the functions of these estrogen receptors is the modulation of gene expression. Once estradiol binds to the ERs, the receptor complexes then bind to specific DNA sequences, possibly causing damage to the DNA and an increase in cell division and DNA replication. Eukaryotic cells respond to damaged DNA by stimulating or impairing G1, S, or G2 phases of the cell cycle to initiate DNA repair. As a result, cellular transformation and cancer cell proliferation occurs.^[36]

Other functions

Estradiol has complex effects on the liver. It affects the production of multiple proteins, including lipoproteins, binding proteins, and proteins responsible for blood clotting.{{citation needed|date=February 2013}} In high amounts, estradiol can lead to cholestasis, for instance cholestasis of pregnancy.

Certain gynecological conditions are dependent on estrogen, such as endometriosis, leiomyomata uteri, and uterine bleeding.{{Citation needed|date=February 2013}}

Estrogen affects certain blood vessels. Improvement in arterial blood flow has been demonstrated in coronary arteries.^[37]

Biological activity

Estradiol acts primarily as an agonist of the estrogen receptor (ER), a nuclear steroid hormone receptor. There are two subtypes of the ER, ERα and ERβ, and estradiol potently binds to and activates both of these receptors. The result of ER activation is a modulation of gene transcription and expression in ER-expressing cells, which is the predominant mechanism by which estradiol mediates its biological effects in the body. Estradiol also acts as an agonist of membrane estrogen receptors (mERs), such as GPER (GPR30), a recently discovered non-nuclear receptor for estradiol, via which it can mediate a variety of rapid, non-genomic effects.^[38] Unlike the case of the ER, GPER appears to be selective for estradiol, and shows very low affinities for other endogenous estrogens, such as estrone and estriol.^[39] Additional mERs besides GPER include ER-X, ERx, and G_q-mER.^[40]^[41]

ERα/ERβ are in inactive state trapped in multimolecular chaperone complexes organized around the heat shock protein 90 (HSP90), containing p23 protein, and immunophilin, and located in majority in cytoplasm and partially in nucleus. In the E2 classical pathway or estrogen classical pathway, estradiol enters the cytoplasm, where it interacts with ERs. Once bound E2, ERs dissociate from the molecular chaperone complexes and become competent to dimerize, migrate to nucleus, and to bind to specific DNA sequences (estrogen response element, ERE), allowing for gene transcription which can take place over hours and days.

Given by subcutaneous injection in mice, estradiol is about 10-fold more potent than estrone and about 100-fold more potent than estriol.^[42]^[43]^[44] As such, estradiol is the main estrogen in the body, although the roles of estrone and estriol as estrogens are said not to be negligible.^[44]

Biochemistry

Biosynthesis

Estradiol, like other steroid hormones, is derived from cholesterol. After side chain cleavage and using the Δ⁵ or the Δ⁴- pathway, androstenedione is the key intermediary. A portion of the androstenedione is converted to testosterone, which in turn undergoes conversion to estradiol by aromatase. In an alternative pathway, androstenedione is aromatized to estrone, which is subsequently converted to estradiol via 17β-hydroxysteroid dehydrogenase (17β-HSD).^[46]

During the reproductive years, most estradiol in women is produced by the granulosa cells of the ovaries by the aromatization of androstenedione (produced in the theca folliculi cells) to estrone, followed by conversion of estrone to estradiol by 17β-HSD. Smaller amounts of estradiol are also produced by the adrenal cortex, and, in men, by the testes.{{mcn|date=February 2019}}

Estradiol is not produced in the gonads only, in particular, fat cells produce active precursors to estradiol, and will continue to do so even after menopause.^[47] Estradiol is also produced in the brain and in arterial walls.

In men, approximately 15 to 25% of circulating estradiol is produced in the testicles.^[48]^[49] The rest is synthesized via peripheral aromatization of testosterone into estradiol and of androstenedione into estrone (which is then transformed into estradiol via peripheral 17β-HSD).^[48]^[49] This peripheral aromatization occurs predominantly in adipose tissue, but also occurs in other tissues such as bone, liver, and the brain.^[48] Approximately 40 to 50 µg of estradiol is produced per day in men.^[48]

Distribution

In plasma, estradiol is largely bound to SHBG, and also to albumin. Only a fraction of 2.21% (± 0.04%) is free and biologically active, the percentage remaining constant throughout the menstrual cycle.^[50]

Metabolism

Inactivation of estradiol includes conversion to less-active estrogens, such as estrone and estriol. Estriol is the major urinary metabolite.{{Citation needed|date=December 2016}} Estradiol is conjugated in the liver to form estrogen conjugates like estradiol sulfate, estradiol glucuronide and, as such, excreted via the kidneys. Some of the water-soluble conjugates are excreted via the bile duct, and partly reabsorbed after hydrolysis from the intestinal tract. This enterohepatic circulation contributes to maintaining estradiol levels.

Estradiol is also metabolized via hydroxylation into catechol estrogens. In the liver, it is non-specifically metabolized by CYP1A2, CYP3A4, and CYP2C9 via 2-hydroxylation into 2-hydroxyestradiol, and by CYP2C9, CYP2C19, and CYP2C8 via 17β-hydroxy dehydrogenation into estrone,^[51] with various other cytochrome P450 (CYP) enzymes and metabolic transformations also being involved.^[52]

Estradiol is additionally conjugated with an ester into lipoidal estradiol forms like estradiol palmitate and estradiol stearate to a certain extent; these esters are stored in adipose tissue and may act as a very long-lasting reservoir of estradiol.^[53]^[54]

Excretion

Estradiol is excreted in the form of glucuronide and sulfate estrogen conjugates in urine.

Levels

Levels of estradiol in premenopausal women are highly variable throughout the menstrual cycle and reference ranges widely vary from source to source.^[56] Estradiol levels are minimal and according to most laboratories range from 20 to 80 pg/mL during the early to mid follicular phase (or the first week of the menstrual cycle, also known as menses).^[57]^[85] Levels of estradiol gradually increase during this time and through the mid to late follicular phase (or the second week of the menstrual cycle) until the pre-ovulatory phase.^[56]^[57] At the time of pre-ovulation (a period of about 24 to 48 hours), estradiol levels briefly surge and reach their highest concentrations of any other time during the menstrual cycle.^[56] Circulating levels are typically between 130 and 200 pg/mL at this time, but in some women may be as high as 300 to 400 pg/mL, and the upper limit of the reference range of some laboratories are even greater (for instance, 750 pg/mL).^[56]^[57]^[58]^[59]^[60] Following ovulation (or mid-cycle) and during the latter half of the menstrual cycle or the luteal phase, estradiol levels plateau and fluctuate between around 100 and 150 pg/mL during the early and mid luteal phase, and at the time of the late luteal phase, or a few days before menstruation, reach a low of around 40 pg/mL.^[56]^[85] The mean integrated levels of estradiol during a full menstrual cycle have variously been reported by different sources as 80, 120, and 150 pg/mL.^[61]^[62]^[63] Although contradictory reports exist, one study found mean integrated estradiol levels of 150 pg/mL in younger women whereas mean integrated levels ranged from 50 to 120 pg/mL in older women.^[63]

During the reproductive years of the human female, levels of estradiol are somewhat higher than that of estrone, except during the early follicular phase of the menstrual cycle; thus, estradiol may be considered the predominant estrogen during human female reproductive years in terms of absolute serum levels and estrogenic activity.{{citation needed|date=June 2014}} During pregnancy, estriol becomes the predominant circulating estrogen, and this is the only time at which estetrol occurs in the body, while during menopause, estrone predominates (both based on serum levels).{{citation needed|date=June 2014}} The estradiol produced by male humans, from testosterone, is present at serum levels roughly comparable to those of postmenopausal women (14–55 versus <35 pg/mL, respectively).{{citation needed|date=June 2014}} It has also been reported that if concentrations of estradiol in a 70-year-old man are compared to those of a 70-year-old woman, levels are approximately 2- to 4-fold higher in the man.^[64]

Measurement

In women, serum estradiol is measured in a clinical laboratory and 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.

Ranges

Individual laboratory results should always been interpreted using the ranges provided by the laboratory that performed the test.

In the normal menstrual cycle, estradiol levels measure typically <50 pg/ml at menstruation, rise with follicular development (peak: 200 pg/ml), 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 toward term. The source of these estrogens is the placenta, which aromatizes prohormones produced in the fetal adrenal gland.

Medical use

Estradiol is used as a medication, primarily in hormone therapy for menopausal symptoms as well as transgender hormone replacement therapy.^[118]

Chemistry

Estradiol is an estrane steroid.^[69] It is also known as 17β-estradiol (to distinguish it from 17α-estradiol) or as estra-1,3,5(10)-triene-3,17β-diol. It has two hydroxyl groups, one at the C3 position and the other at the 17β position, as well as three double bonds in the A ring. Due to its two hydroxyl groups, estradiol is often abbreviated as E2. The structurally related estrogens, estrone (E1), estriol (E3), and estetrol (E4) have one, three, and four hydroxyl groups, respectively.

History

The discovery of estrogen is usually credited to the American scientists Edgar Allen and Edward A. Doisy.^[70]^[71] In 1923, they observed that injection of fluid from porcine ovarian follicles produced pubertal- and estrus-type changes (including vaginal, uterine, and mammary gland changes and sexual receptivity) in sexually immature, ovariectomized mice and rats.^[70]^[71]^[72] These findings demonstrated the existence of a hormone which is produced by the ovaries and is involved in sexual maturation and reproduction.^[70]^[71]^[72] At the time of its discovery, Allen and Doisy did not name the hormone, and simply referred to it as an "ovarian hormone" or "follicular hormone";^[71] others referred to it variously as feminin, folliculin, menformon, thelykinin, and emmenin.^[73]^[74] In 1926, Parkes and Bellerby coined the term estrin to describe the hormone on the basis of it inducing estrus in animals.^[75]^[73] Estrone was isolated and purified independently by Allen and Doisy and German scientist Adolf Butenandt in 1929, and estriol was isolated and purified by Marrian in 1930; they were the first estrogens to be identified.^[71]^[76]^[77]

Estradiol, the most potent of the three major estrogens, was the last of the three to be identified.^[71]^[75] It was discovered by Schwenk and Hildebrant in 1933, who synthesized it via reduction of estrone.^[71] Estradiol was subsequently isolated and purified from sow ovaries by Doisy in 1935, with its chemical structure determined simultaneously,^[78] and was referred to variously as dihydrotheelin, dihydrofolliculin, and dihydroxyestrin.^[71]^[79] In 1935, the name estradiol and the term estrogen were formally established by the Sex Hormone Committee of the Health Organization of the League of Nations; this followed the names estrone (which was initially called theelin, progynon, folliculin, and ketohydroxyestrin) and estriol (initially called theelol and trihydroxyestrin) having been established in 1932 at the first meeting of the International Conference on the Standardization of Sex Hormones in London.^[75]^[80] Following its discovery, a partial synthesis of estradiol from cholesterol was developed by Inhoffen and Hohlweg in 1940, and a total synthesis was developed by Anner and Miescher in 1948.^[71]

Society and culture

Etymology

The name estradiol derives from estra-, Gk. {{lang|grc|οἶστρος}} (oistros, literally meaning "verve or inspiration"),^[81] which refers to the estrane steroid ring system, and -diol, a chemical term and suffix indicating that the compound is a type of alcohol bearing two hydroxyl groups.

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31. ^{{cite journal | vauthors = Simerly RB | title = Wired for reproduction: organization and development of sexually dimorphic circuits in the mammalian forebrain | journal = Annual Review of Neuroscience | volume = 25 | pages = 507–36 | date = 27 March 2002 | pmid = 12052919 | doi = 10.1146/annurev.neuro.25.112701.142745 | url = http://www.healthsystem.virginia.edu/internet/neuroscience/BehavioralNeuroscience/Simerley-EFR-1-4.pdf | format = pdf }}
32. ^{{cite book | first1 = Irwin | last1 = Goldstein | first2 = Cindy M. | last2 = Meston | first3 = Susan | last3 = Davis | first4 = Abdulmaged | last4 = Traish | name-list-format = vanc | title = Women's Sexual Function and Dysfunction: Study, Diagnosis and Treatment|url=https://books.google.com/books?id=3J7TnwpbZQwC&pg=PA205|date=17 November 2005|publisher=CRC Press|isbn=978-1-84214-263-9|pages=205–}}
33. ^{{cite journal | vauthors = Acevedo-Rodriguez A, Mani SK, Handa RJ | title = Oxytocin and Estrogen Receptor β in the Brain: An Overview | journal = Frontiers in Endocrinology | volume = 6 | pages = 160 | year = 2015 | pmid = 26528239 | pmc = 4606117 | doi = 10.3389/fendo.2015.00160 }}
34. ^{{cite journal | vauthors = Bulzomi P, Bolli A, Galluzzo P, Leone S, Acconcia F, Marino M | title = Naringenin and 17beta-estradiol coadministration prevents hormone-induced human cancer cell growth | journal = IUBMB Life | volume = 62 | issue = 1 | pages = 51–60 | date = January 2010 | pmid = 19960539 | doi = 10.1002/iub.279 }}
35. ^{{cite journal | vauthors = Sreeja S, Santhosh Kumar TR, Lakshmi BS, Sreeja S | title = Pomegranate extract demonstrate a selective estrogen receptor modulator profile in human tumor cell lines and in vivo models of estrogen deprivation | journal = The Journal of Nutritional Biochemistry | volume = 23 | issue = 7 | pages = 725–32 | date = July 2012 | pmid = 21839626 | doi = 10.1016/j.jnutbio.2011.03.015 }}
36. ^{{cite journal | vauthors = Thomas CG, Strom A, Lindberg K, Gustafsson JA | title = Estrogen receptor beta decreases survival of p53-defective cancer cells after DNA damage by impairing G₂/M checkpoint signaling | journal = Breast Cancer Research and Treatment | volume = 127 | issue = 2 | pages = 417–27 | date = June 2011 | pmid = 20623183 | doi = 10.1007/s10549-010-1011-z }}
37. ^{{cite journal | vauthors = Collins P, Rosano GM, Sarrel PM, Ulrich L, Adamopoulos S, Beale CM, McNeill JG, Poole-Wilson PA | title = 17 beta-Estradiol attenuates acetylcholine-induced coronary arterial constriction in women but not men with coronary heart disease | journal = Circulation | volume = 92 | issue = 1 | pages = 24–30 | date = July 1995 | pmid = 7788912 | doi = 10.1161/01.CIR.92.1.24 }}
38. ^{{cite journal | vauthors = Prossnitz ER, Barton M | title = Estrogen biology: new insights into GPER function and clinical opportunities | journal = Molecular and Cellular Endocrinology | volume = 389 | issue = 1–2 | pages = 71–83 | date = May 2014 | pmid = 24530924 | pmc = 4040308 | doi = 10.1016/j.mce.2014.02.002 }}
39. ^{{vcite2 journal | vauthors = Prossnitz ER, Arterburn JB, Sklar LA | title = GPR30: A G protein-coupled receptor for estrogen | journal = Mol. Cell. Endocrinol. | volume = 265–266 | issue = | pages = 138–42 | year = 2007 | pmid = 17222505 | pmc = 1847610 | doi = 10.1016/j.mce.2006.12.010 | url = }}
40. ^{{cite journal | vauthors = Soltysik K, Czekaj P | title = Membrane estrogen receptors - is it an alternative way of estrogen action? | journal = Journal of Physiology and Pharmacology | volume = 64 | issue = 2 | pages = 129–42 | date = April 2013 | pmid = 23756388 | doi = }}
41. ^{{cite journal | vauthors = Micevych PE, Kelly MJ | title = Membrane estrogen receptor regulation of hypothalamic function | journal = Neuroendocrinology | volume = 96 | issue = 2 | pages = 103–10 | year = 2012 | pmid = 22538318 | pmc = 3496782 | doi = 10.1159/000338400 }}
42. ^{{cite book|author=A. Labhart|title=Clinical Endocrinology: Theory and Practice|url=https://books.google.com/books?id=DAgJCAAAQBAJ&pg=PA548|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-96158-8|pages=548–}}
43. ^{{cite book|author=Susan Tucker Blackburn|title=Maternal, Fetal, & Neonatal Physiology: A Clinical Perspective|url=https://books.google.com/books?id=2y6zOSQcn14C&pg=PA43|year=2007|publisher=Elsevier Health Sciences|isbn=978-1-4160-2944-1|pages=43–}}
44. ^¹{{cite book|author=John E. Hall|title=Guyton and Hall Textbook of Medical Physiology E-Book|url=https://books.google.com/books?id=krLSCQAAQBAJ&pg=PA1043|date=31 May 2015|publisher=Elsevier Health Sciences|isbn=978-0-323-38930-3|pages=1043–}}
45. ^{{cite journal |last1=Häggström |first1=Mikael |last2=Richfield |first2=David | name-list-format = vanc | year=2014 |title=Diagram of the pathways of human steroidogenesis|journal=WikiJournal of Medicine|volume=1|issue=1|doi=10.15347/wjm/2014.005|issn=2002-4436}}
46. ^{{cite book | first1 = Walter F. | last1 = Boron | first2 = Emile L. | last2 = Boulpaep | name-list-format = vanc |title=Medical Physiology: A Cellular And Molecular Approach |publisher=Elsevier/Saunders |year=2003 |page=1300 |isbn=978-1-4160-2328-9}}
47. ^{{Cite book|last1=Mutschler|first1=Ernst|last2=Schäfer-Korting|first2=Monika | name-list-format = vanc | title = Arzneimittelwirkungen|language=German|location=Stuttgart|publisher=Wissenschaftliche Verlagsgesellschaft|year=2001|edition=8|pages=434, 444|isbn=978-3-8047-1763-3}}
48. ^¹²³{{cite book|author=Shlomo Melmed|title=Williams Textbook of Endocrinology|url=https://books.google.com/books?id=YZ8_CwAAQBAJ&pg=PA710|date=1 January 2016|publisher=Elsevier Health Sciences|isbn=978-0-323-29738-7|pages=710–}}
49. ^¹{{cite book| first1 = Robert | last1 = Marcus | first2 = David | last2 = Feldman | first3 = David W. | last3 = Dempster | first4 = Marjorie | last4 = Luckey | first5 = Jane A. | last5 = Cauley | name-list-format = vanc |title=Osteoporosis|url=https://books.google.com/books?id=b1FtazykqzMC&pg=PA331|date=13 June 2013|publisher=Academic Press|isbn=978-0-12-398252-0|pages=331–}}
50. ^{{cite journal | vauthors = Wu CH, Motohashi T, Abdel-Rahman HA, Flickinger GL, Mikhail G | title = Free and protein-bound plasma estradiol-17 beta during the menstrual cycle | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 43 | issue = 2 | pages = 436–45 | date = August 1976 | pmid = 950372 | doi = 10.1210/jcem-43-2-436 }}
51. ^{{cite journal | vauthors = Cheng ZN, Shu Y, Liu ZQ, Wang LS, Ou-Yang DS, Zhou HH | title = Role of cytochrome P450 in estradiol metabolism in vitro | journal = Acta Pharmacologica Sinica | volume = 22 | issue = 2 | pages = 148–54 | date = February 2001 | pmid = 11741520 | doi = }}
52. ^{{cite journal | vauthors = Lee AJ, Cai MX, Thomas PE, Conney AH, Zhu BT | title = Characterization of the oxidative metabolites of 17beta-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms | journal = Endocrinology | volume = 144 | issue = 8 | pages = 3382–98 | date = August 2003 | pmid = 12865317 | doi = 10.1210/en.2003-0192 }}
53. ^{{cite book| first1 = Michael | last1 = Oettel | first2 = Ekkehard | last2 = Schillinger | name-list-format = vanc |title=Estrogens and Antiestrogens I: Physiology and Mechanisms of Action of Estrogens and Antiestrogens|url=https://books.google.com/books?id=0BfrCAAAQBAJ&pg=PA235|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-58616-3|pages=235–237}}
54. ^{{cite book| first1 = Michael | last1 = Oettel | first2 = Ekkehard | last2 = Schillinger | name-list-format = vanc |title=Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen|url=https://books.google.com/books?id=wBvyCAAAQBAJ&pg=PA268|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-60107-1|pages=268, 271}}
55. ^http://www.ilexmedical.com/files/PDF/Estradiol_ARC.pdf
56. ^¹²³⁴{{cite book | first1 = Jill B. | last1 = Becker | first2 = Karen J. | last2 = Berkley | first3 = Nori | last3 = Geary | first4 = Elizabeth | last4 = Hampson|authorlink5=James P. Herman | first5 = James P. | last5 = Herman | first6 = Elizabeth | last6 = Young | name-list-format = vanc |title=Sex Differences in the Brain: From Genes to Behavior|url=https://books.google.com/books?id=IeaLXPWsbuAC&pg=PA64|date=4 December 2007|publisher=Oxford University Press|isbn=978-0-19-804255-6|pages=64–|quote=Estradiol levels are minimal during the earliest days of the follicular phase, but increasing concentrations are released into the general circulation as the follicle matures. The highest levels are reached about 24 to 48 hours before the LH peak. In fact, the pre-ovulatory peak in estradiol represents its highest concentration during the entire menstrual cycle. Serum concentrations at this time are typically about 130-200 pg/mL, but concentrations as high as 300-400 pg/mL can be achieved in some women. Following a transient fall in association with ovulation, estradiol secretion is restored by production from the corpus luteum during the luteal phase. Plateau levels of around 100-150 pg/mL (Abraham, 1978; Thorneycroft et al., 1971) are most often seen during the period from -10 to -5 days before the onset of menses. With the regression of the corpus luteum, estradiol levels fall, gradually in some women and precipitously in others, during the last few days of the luteal phase. This ushers in the onset of menses, the sloughing of the endometrium. Serum estradiol during menses is approximately 30-50 pg/mL. (Source.)}}
57. ^¹²{{cite book | first1 =Jerome Frank | last1 = Strauss | first2 = Robert L. | last2 = Barbieri | name-list-format = vanc |title=Yen and Jaffe's Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management|url=https://books.google.com/books?id=NudwnhxY8kYC&pg=PA807|year=2009|publisher=Elsevier Health Sciences|isbn=978-1-4160-4907-4|pages=807–|quote=In most laboratories, serum estradiol levels range from 20 to 80 pg/mL during the early to midfollicular phase of the menstrual cycle and peak at 200 to 500 pg/mL during the preovulatory surge. During the midluteal phase, serum estradiol levels range from 60 to 200 pg/mL.}}
58. ^{{cite book | first1 = J. Larry | last1 = Jameson | first2 = Leslie J. | last2 = De Groot | name-list-format = vanc | title=Endocrinology: Adult and Pediatric | url = https://books.google.com/books?id=W4dZ-URK8ZoC&pg=PA2812|date=18 May 2010|publisher=Elsevier Health Sciences|isbn=978-1-4557-1126-0|pages=2812–|quote=Midcycle: 150-750 pg/mL}}
59. ^{{cite book | first1 = Ian D. | last1 = Hay | first2 = John A. H. | last2 = Wass | name-list-format = vanc |title=Clinical Endocrine Oncology|url=https://books.google.com/books?id=fGio-5vtqqkC&pg=PA623|date=26 January 2009|publisher=John Wiley & Sons|isbn=978-1-4443-0023-9|pages=623–|quote=Mid-cycle: 110-330 pg/mL}}
60. ^{{cite book|author=Robert F. Dons|title=Endocrine and Metabolic Testing Manual|url=https://books.google.com/books?id=w8jGxo_xoI4C&pg=SA8-PA8|date=12 July 1994|publisher=CRC Press|isbn=978-0-8493-7657-3|pages=8–|quote=Ovulatory: 200-400 pg/mL}}
61. ^¹²{{cite book | vauthors = Christian C, von Schoultz B| title = Hormone Replacement Therapy: Standardized or Individually Adapted Doses?|url=https://books.google.com/books?id=apU4AfUqSGwC&pg=PA60|date=15 March 1994|publisher=CRC Press|isbn=978-1-85070-545-1|pages=60–|quote=Plasma levels of estradiol range from 40 to 80 pg/ml during the 1st week of the ovarian cycle (early follicular phase) and from 80 to 300 pg/ml during the 2nd week (mid- and late follicular phase including periovulatory peak). Then during the 3rd and 4th weeks, estradiol fluctuates between 100 and 150 pg/ml (early and mid-luteal phase) to 40 pg/ml a few days before menstruation (late luteal phase). The mean integrated estradiol level during a full 28-day normal cycle is around 80 pg/ml.}}
62. ^{{cite book | vauthors = Notelovitz M, van Keep PA |title=The Climacteric in Perspective: Proceedings of the Fourth International Congress on the Menopause, held at Lake Buena Vista, Florida, October 28 – November 2, 1984|url=https://books.google.com/books?id=VM0hBQAAQBAJ&pg=PA397|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-009-4145-8|pages=397–|quote=[...] following the menopause, circulating estradiol levels decrease from a premenopausal mean of 120 pg/ml to only 13 pg/ml.}}
63. ^¹{{cite book | first1 = Eugenio E. | last1 = Müller | first2 = Robert M. | last2 = MacLeod | name-list-format = vanc | title = Neuroendocrine Perspectives |url=https://books.google.com/books?id=TUXtBwAAQBAJ&pg=PA121|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-1-4612-3554-5|pages=121–|quote=[...] [premenopausal] mean [estradiol] concentration of 150 pg/ml [...]}}
64. ^{{cite journal | vauthors = Sayed Y, Taxel P | title = The use of estrogen therapy in men | journal = Current Opinion in Pharmacology | volume = 3 | issue = 6 | pages = 650–4 | date = December 2003 | pmid = 14644018 | doi = }}
65. ^¹²³⁴⁵⁶⁷⁸⁹GPNotebook — reference range (oestradiol) Retrieved on 27 September 2009
66. ^¹Values taken from day 1 after LH surge in: {{cite journal | vauthors = Stricker R, Eberhart R, Chevailler MC, Quinn FA, Bischof P, Stricker R | title = Establishment of detailed reference values for luteinizing hormone, follicle stimulating hormone, estradiol, and progesterone during different phases of the menstrual cycle on the Abbott ARCHITECT analyzer | journal = Clinical Chemistry and Laboratory Medicine | volume = 44 | issue = 7 | pages = 883–7 | year = 2006 | pmid = 16776638 | doi = 10.1515/CCLM.2006.160 }} as PDF
67. ^¹²³Total amount multiplied by 0.022 according to 2.2% presented in: {{cite journal | vauthors = Wu CH, Motohashi T, Abdel-Rahman HA, Flickinger GL, Mikhail G | title = Free and protein-bound plasma estradiol-17 beta during the menstrual cycle | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 43 | issue = 2 | pages = 436–45 | date = August 1976 | pmid = 950372 | doi = 10.1210/jcem-43-2-436 }}{{Original research inline|date=June 2014}}
68. ^{{cite journal|year=2014|title=Reference ranges for estradiol, progesterone, luteinizing hormone and follicle-stimulating hormone during the menstrual cycle|journal=WikiJournal of Medicine|volume=1|issue=1|doi=10.15347/wjm/2014.001|issn=2002-4436|last1=Häggström|first1=Mikael}}
69. ^¹{{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 Suppl 1 | issue = | pages = 3–63 | date = August 2005 | pmid = 16112947 | doi = 10.1080/13697130500148875 }}
70. ^¹²{{cite book | first1 = D. Lynn | last1 = Loriaux | first2 = Lynn | last2 = Loriaux | name-list-format = vanc |title=A Biographical History of Endocrinology|url=https://books.google.com/books?id=pkWhCwAAQBAJ&pg=PA345|date=14 March 2016|publisher=John Wiley & Sons|isbn=978-1-119-20246-2|pages=345–}}
71. ^¹²³⁴⁵⁶⁷⁸{{cite book | first1 = Christian | last1 = Lauritzen | first2 = John W. W. | last2 = Studd | name-list-format = vanc |title=Current Management of the Menopause|url=https://books.google.com/books?id=WD7S7677xUUC&pg=PA44|date=22 June 2005|publisher=CRC Press|isbn=978-0-203-48612-2|pages=44–}}
72. ^¹{{cite journal |last1=Allen |first1=Edgar |last2=Doisy |first2=Edward A. | name-list-format = vanc | title = An Ovarian Hormone | journal = Journal of the American Medical Association |volume=81 |issue=10 |year=1923 |pages=819 |issn=0002-9955 |doi=10.1001/jama.1923.02650100027012 }}
73. ^¹{{cite book | vauthors = Gruhn JG, Kazer RR |title=Hormonal Regulation of the Menstrual Cycle: The Evolution of Concepts|url=https://books.google.com/books?id=lFn0BwAAQBAJ&pg=PA69|date=11 November 2013|publisher=Springer Science & Business Media|isbn=978-1-4899-3496-3|pages=69–73}}
74. ^{{cite journal|last1=Newerla|first1=Gerhard J.|title=The History of the Discovery and Isolation of the Female Sex Hormones|journal=New England Journal of Medicine|volume=230|issue=20|year=1944|pages=595–604|issn=0028-4793|doi=10.1056/NEJM194405182302001}}
75. ^¹²{{cite book | first1 = Marc A. | last1 = Fritz | first2 = Leon | last2 = Speroff | name-list-format = vanc |title=Clinical Gynecologic Endocrinology and Infertility|url=https://books.google.com/books?id=KZLubBxJEwEC&pg=PA750|date=28 March 2012|publisher=Lippincott Williams & Wilkins|isbn=978-1-4511-4847-3|pages=750–}}
76. ^{{cite book|author=Fritz F. Parl|title=Estrogens, Estrogen Receptor and Breast Cancer|url=https://books.google.com/books?id=v7ai5Mz9TZQC&pg=PA4|year=2000|publisher=IOS Press|isbn=978-0-9673355-4-4|pages=4–}}
77. ^{{cite book | first1 = Alan C. | last1 = Sartorelli | first2 = David G. | last2 = Johns | name-list-format = vanc |title=Antineoplastic and Immunosuppressive Agents|url=https://books.google.com/books?id=aU_oCAAAQBAJ&pg=PA104|date=27 November 2013|publisher=Springer Science & Business Media|isbn=978-3-642-65806-8|pages=104–}}
78. ^{{cite book | first1 = Donna | last1 = Shoupe | first2 = Florence P. | last2 = Haseltine | name-list-format = vanc |title=Contraception|url=https://books.google.com/books?id=cpDhBwAAQBAJ&pg=PA2|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-1-4612-2730-4|pages=2–}}
79. ^{{cite journal | vauthors = MacCorquodale DW, Thayer SA, Doisy EA |title=The Crystalline Ovarian Follicular Hormone|journal=Experimental Biology and Medicine|volume=32|issue=7|year=1935|pages=1182|issn=1535-3702|doi=10.3181/00379727-32-8020P}}
80. ^{{cite book|author=Anne Fausto-Sterling|title=Sexing the Body: Gender Politics and the Construction of Sexuality|url=https://books.google.com/books?id=c3lhYfZzIXkC&pg=PA189|year=2000|publisher=Basic Books|isbn=978-0-465-07714-4|pages=189–}}
81. ^{{cite web|url=http://www.perseus.tufts.edu/hopper/morph?l=oistros&la=greek|title=Greek Word Study Tool: oistros|publisher=Perseus Digital Library|access-date=28 December 2011}}