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| Names | |
|---|---|
| Pronunciation | /ˌɛstrəˈdaɪoʊl/ ⓘES-trə-DY-ohl[1][2] |
| IUPAC name Estra-1,3,5(10)-triene-3,17β-diol | |
| Systematic IUPAC name (1S,3aS,3bR,9bS,11aS)-11a-Methyl-2,3,3a,3b,4,5,9b,10,11,11a-decahydro-1H-cyclopenta[a]phenanthrene-1,7-diol | |
| Other names Oestradiol; E2; 17β-Estradiol; 17β-Oestradiol | |
| Identifiers | |
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3D model (JSmol) | |
| ChEBI | |
| ChEMBL | |
| ChemSpider |
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| DrugBank |
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| ECHA InfoCard | 100.000.022 |
| EC Number |
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| KEGG |
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| UNII | |
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| Properties | |
| C18H24O2 | |
| Molar mass | 272.38 g/mol |
| −186.6·10−6 cm3/mol | |
| Pharmacology | |
| G03CA03 (WHO) | |
| License data | |
| Oral,sublingual,intranasal,topical/transdermal,vaginal,intramuscular orsubcutaneous (as anester),subdermal implant | |
| Pharmacokinetics: | |
| Oral: <5%[3] | |
| ~98%:[3][4] •Albumin: 60% •SHBG: 38% • Free: 2% | |
| Liver (viahydroxylation,sulfation,glucuronidation) | |
| Oral: 13–20 hours[3] Sublingual: 8–18 hours[5] Topical (gel): 36.5 hours[6] | |
| Urine: 54%[3] Feces: 6%[3] | |
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |
Estradiol (E2), also calledoestrogen,oestradiol, is anestrogensteroid hormone and the majorfemalesex hormone. It is involved in the regulation of femalereproductive cycles such asestrous andmenstrual cycles. Estradiol is responsible for the development of femalesecondary sexual characteristics such as thebreasts,widening of the hips and afemale pattern of fat distribution. It is also important in the development and maintenance of femalereproductive tissues such as themammary glands,uterus andvagina duringpuberty,adulthood andpregnancy.[7] It also has important effects in many othertissues includingbone,fat,skin,liver, and thebrain.
Though estradiol levels in males are much lower than in females, estradiol has important roles in males as well. Apart from humans and othermammals, estradiol is also found in mostvertebrates andcrustaceans,insects,fish, and otheranimalspecies.[8][9]
Estradiol is produced within thefollicles of theovaries and in other tissues including thetesticles, theadrenal glands, fat,liver, the breasts, and the brain. Estradiol isproduced in the body fromcholesterol through a series ofreactions andintermediates.[10] The majorpathway involves the formation ofandrostenedione, which is then converted byaromatase intoestrone and is subsequently converted into estradiol. Alternatively, androstenedione can be converted intotestosterone, which can then be converted into estradiol. Uponmenopause in females, 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 amedication, for instance inmenopausal hormone therapy, andfeminizing hormone therapy fortransgender women and othergenderqueer individuals; for information on estradiol as a medication, see theestradiol (medication) article.
The development ofsecondary sex characteristics in women is driven by estrogens, to be specific, estradiol.[11][12] These changes are initiated at the time ofpuberty, most are enhanced during the reproductive years, and become less pronounced with declining estradiol support aftermenopause. Thus, estradiol producesbreast development, and is responsible for changes in thebody shape, affecting bones, joints, andfat deposition.[11][12] In females, estradiol induces breast development,widening of the hips, afeminine fat distribution (with fat deposited particularly in the breasts, hips, thighs, and buttocks), and maturation of thevagina andvulva, whereas it mediates thepubertal growth spurt (indirectly via increasedgrowth hormone secretion)[13] andepiphyseal closure (thereby limitingfinal height) in both sexes.[11][12]
In the female, estradiol acts as a growth hormone for tissue of the reproductive organs, supporting the lining of thevagina, the cervical glands, theendometrium, and the lining of the fallopian tubes. It enhances growth of themyometrium. Estradiol appears necessary to maintainoocytes in theovary. During themenstrual cycle, estradiol produced by the growing follicles triggers, via a positive feedback system, the hypothalamic-pituitary events that lead to theluteinizing hormone surge, inducing ovulation. In the luteal phase, estradiol, in conjunction withprogesterone, prepares the endometrium forimplantation. Duringpregnancy, estradiol increases due toplacental production. The effect of estradiol, together withestrone andestriol, inpregnancy is less clear. They may promote uterine blood flow, myometrial growth, stimulate breast growth and at term, promote cervical softening and expression of myometrialoxytocin receptors.[citation needed] 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 oflabor. Actions of estradiol are required before the exposure of progesterone in the luteal phase.[citation needed]
The effect of estradiol (and estrogens in general) upon male reproduction is complex. Estradiol is produced by action ofaromatase mainly in theLeydig cells of themammaliantestis, but also by somegerm cells and theSertoli cells of immature mammals.[14] It functions (in vitro) to preventapoptosis of malesperm cells.[15]While some studies in the early 1990s claimed a connection between globally decliningsperm 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 thesemen analysis.[19]
Males with certainsex chromosomegenetic conditions, such asKlinefelter's syndrome, will have a higher level of estradiol.[20]
Estradiol has a profound effect on bone. Individuals without it (or other estrogens) will become tall andeunuchoid, asepiphyseal closure is delayed or may not take place.[21]Bone density is also affected, resulting in earlyosteopenia andosteoporosis.[22] Low levels of estradiol may also predict fractures, with post-menopausal women having the highest incidence ofbone fracture.[23] Women past menopause experience an accelerated loss of bone mass due to a relative estrogen deficiency.[24]
Theestrogen receptor, as well as theprogesterone receptor, have been detected in theskin, including inkeratinocytes andfibroblasts.[25][26] Atmenopause and thereafter, decreased levels of femalesex hormones result inatrophy, thinning, and increasedwrinkling of the skin and a reduction in skinelasticity, firmness, and strength.[25][26] These skin changes constitute an acceleration inskin aging and are the result of decreasedcollagen content, irregularities in themorphology ofepidermalskin cells, decreasedground substance betweenskin fibers, and reducedcapillaries andblood flow.[25][26] The skin also becomes moredry during menopause, which is due to reduced skinhydration andsurface lipids (sebum production).[25] Along with chronological aging and photoaging, estrogen deficiency in menopause is one of the three main factors that predominantly influences skin aging.[25]
Hormone replacement therapy consisting of systemic treatment with estrogen alone or in combination with a progestogen, has well-documented and considerable beneficial effects on the skin of postmenopausal women.[25][26] These benefits include increased skin collagen content, skin thickness and elasticity, and skin hydration and surface lipids.[25][26] Topical estrogen has been found to have similar beneficial effects on the skin.[25] In addition, a study has found that topical 2% progesterone cream significantly increases skin elasticity and firmness and observably decreases wrinkles in peri- and postmenopausal women.[26] Skin hydration and surface lipids, on the other hand, did not significantly change with topical progesterone.[26] These findings suggest that progesterone, like estrogen, also has beneficial effects on the skin, and may be independently protective against skin aging.[26]
Estrogens can be produced in thebrain from steroid precursors. Asantioxidants, they have been found to haveneuroprotective function.[27]
The positive and negativefeedback loops of themenstrual cycle involve ovarian estradiol as the link to the hypothalamic-pituitary system to regulategonadotropins.[28]
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.[29][30]
The volumes ofsexually dimorphic brain structures intransgender women were found to change and approximate typical female brain structures when exposed to estrogen concomitantly with androgen deprivation over a period of months,[31] suggesting that estrogen and/or androgens have a significant part to play in sex differentiation of the brain, bothprenatally 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.[32] 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.[33]
Estrogen has been found to increase thesecretion of oxytocin and to increase theexpression of itsreceptor, theoxytocin receptor, in thebrain.[34] In women, a single dose of estradiol has been found to be sufficient to increase circulating oxytocin concentrations.[35]
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 twonuclear receptors calledestrogen receptor α (ERα) andestrogen receptor β (ERβ).[36][37] One of the functions of these estrogen receptors is the modulation ofgene expression. Once estradiol binds to the ERs, the receptor complexes then bind to specificDNA sequences, possibly causing damage to the DNA and an increase in cell division andDNA replication.Eukaryotic cells respond to damaged DNA by stimulating or impairing G1, S, or G2 phases of the cell cycle to initiateDNA repair. As a result, cellular transformation and cancer cell proliferation occurs.[38]
Estrogen affects certainblood vessels. Improvement in arterial blood flow has been demonstrated incoronary arteries.[39] 17-beta-estradiol (E2) is considered the most potent estrogen found in humans. E2 influences vascular function, apoptosis, and damage during cardiac ischemia and reperfusion. E2 can protect the heart and individual cardiac myocytes from injuries related to ischemia. After a heart attack or long periods of hypertension, E2 inhibits the adverse effects of pathologic remodeling of the heart.[40]
Duringpregnancy, high levels of estrogens, namely estradiol, increasecoagulation and the risk ofvenous thromboembolism.
| Absolute incidence of first VTE per 10,000 person–years during pregnancy and the postpartum period | ||||||||
|---|---|---|---|---|---|---|---|---|
| Swedish data A | Swedish data B | English data | Danish data | |||||
| Time period | N | Rate (95% CI) | N | Rate (95% CI) | NФВяы | Rate (95% CI) | N | Rate (95% CI) |
| Outside pregnancy | 1105 | 4.2 (4.0–4.4) | 1015 | 3.8 (?) | 1480 | 3.2 (3.0–3.3) | 2895 | 3.6 (3.4–3.7) |
| Antepartum | 995 | 20.5 (19.2–21.8) | 690 | 14.2 (13.2–15.3) | 156 | 9.9 (8.5–11.6) | 491 | 10.7 (9.7–11.6) |
| Trimester 1 | 207 | 13.6 (11.8–15.5) | 172 | 11.3 (9.7–13.1) | 23 | 4.6 (3.1–7.0) | 61 | 4.1 (3.2–5.2) |
| Trimester 2 | 275 | 17.4 (15.4–19.6) | 178 | 11.2 (9.7–13.0) | 30 | 5.8 (4.1–8.3) | 75 | 5.7 (4.6–7.2) |
| Trimester 3 | 513 | 29.2 (26.8–31.9) | 340 | 19.4 (17.4–21.6) | 103 | 18.2 (15.0–22.1) | 355 | 19.7 (17.7–21.9) |
| Around delivery | 115 | 154.6 (128.8–185.6) | 79 | 106.1 (85.1–132.3) | 34 | 142.8 (102.0–199.8) | – | |
| Postpartum | 649 | 42.3 (39.2–45.7) | 509 | 33.1 (30.4–36.1) | 135 | 27.4 (23.1–32.4) | 218 | 17.5 (15.3–20.0) |
| Early postpartum | 584 | 75.4 (69.6–81.8) | 460 | 59.3 (54.1–65.0) | 177 | 46.8 (39.1–56.1) | 199 | 30.4 (26.4–35.0) |
| Late postpartum | 65 | 8.5 (7.0–10.9) | 49 | 6.4 (4.9–8.5) | 18 | 7.3 (4.6–11.6) | 319 | 3.2 (1.9–5.0) |
| Incidence rate ratios (IRRs) of first VTE during pregnancy and the postpartum period | ||||||||
| Swedish data A | Swedish data B | English data | Danish data | |||||
| Time period | IRR* (95% CI) | IRR* (95% CI) | IRR (95% CI)† | IRR (95% CI)† | ||||
| Outside pregnancy | Reference (i.e., 1.00) | |||||||
| Antepartum | 5.08 (4.66–5.54) | 3.80 (3.44–4.19) | 3.10 (2.63–3.66) | 2.95 (2.68–3.25) | ||||
| Trimester 1 | 3.42 (2.95–3.98) | 3.04 (2.58–3.56) | 1.46 (0.96–2.20) | 1.12 (0.86–1.45) | ||||
| Trimester 2 | 4.31 (3.78–4.93) | 3.01 (2.56–3.53) | 1.82 (1.27–2.62) | 1.58 (1.24–1.99) | ||||
| Trimester 3 | 7.14 (6.43–7.94) | 5.12 (4.53–5.80) | 5.69 (4.66–6.95) | 5.48 (4.89–6.12) | ||||
| Around delivery | 37.5 (30.9–44.45) | 27.97 (22.24–35.17) | 44.5 (31.68–62.54) | – | ||||
| Postpartum | 10.21 (9.27–11.25) | 8.72 (7.83–9.70) | 8.54 (7.16–10.19) | 4.85 (4.21–5.57) | ||||
| Early postpartum | 19.27 (16.53–20.21) | 15.62 (14.00–17.45) | 14.61 (12.10–17.67) | 8.44 (7.27–9.75) | ||||
| Late postpartum | 2.06 (1.60–2.64) | 1.69 (1.26–2.25) | 2.29 (1.44–3.65) | 0.89 (0.53–1.39) | ||||
| Notes: Swedish data A = Using any code for VTE regardless of confirmation. Swedish data B = Using only algorithm-confirmed VTE. Early postpartum = First 6 weeks after delivery. Late postpartum = More than 6 weeks after delivery. * = Adjusted for age and calendar year. † = Unadjusted ratio calculated based on the data provided.Source:[41] | ||||||||
Estradiol has complex effects on theliver. It affects the production of multipleproteins, includinglipoproteins, binding proteins, and proteins responsible forblood clotting.[citation needed] In high amounts, estradiol can lead tocholestasis, for instancecholestasis of pregnancy.
Certain gynecological conditions are dependent on estrogen, such asendometriosis,leiomyomata uteri, anduterine bleeding.[citation needed]
Estradiol acts primarily as anagonist of theestrogen receptor (ER), anuclearsteroid hormone receptor. There are two subtypes of the ER,ERα andERβ, and estradiol potently binds to and activates both of these receptors. The result of ER activation is a modulation ofgene transcription andexpression in ER-expressingcells, which is the predominant mechanism by which estradiol mediates its biological effects in the body. Estradiol also acts as an agonist ofmembrane estrogen receptors (mERs), such asGPER (GPR30), a recently discovered non-nuclear receptor for estradiol, via which it can mediate a variety of rapid, non-genomic effects.[42] Unlike the case of the ER, GPER appears to beselective for estradiol, and shows very lowaffinities for other endogenous estrogens, such as estrone andestriol.[43] Additional mERs besides GPER includeER-X,ERx, andGq-mER.[44][45]
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 thecytoplasm, 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 bysubcutaneous injection in mice, estradiol is about 10-fold more potent than estrone and about 100-fold more potent than estriol.[46][47][48] 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.[48]
| Estrogen | ERTooltip Estrogen receptorRBATooltip relative binding affinity (%) | Uterine weight (%) | Uterotrophy | LHTooltip Luteinizing hormone levels (%) | SHBGTooltip Sex hormone-binding globulinRBATooltip relative binding affinity (%) |
|---|---|---|---|---|---|
| Control | – | 100 | – | 100 | – |
| Estradiol (E2) | 100 | 506 ± 20 | +++ | 12–19 | 100 |
| Estrone (E1) | 11 ± 8 | 490 ± 22 | +++ | ? | 20 |
| Estriol (E3) | 10 ± 4 | 468 ± 30 | +++ | 8–18 | 3 |
| Estetrol (E4) | 0.5 ± 0.2 | ? | Inactive | ? | 1 |
| 17α-Estradiol | 4.2 ± 0.8 | ? | ? | ? | ? |
| 2-Hydroxyestradiol | 24 ± 7 | 285 ± 8 | +b | 31–61 | 28 |
| 2-Methoxyestradiol | 0.05 ± 0.04 | 101 | Inactive | ? | 130 |
| 4-Hydroxyestradiol | 45 ± 12 | ? | ? | ? | ? |
| 4-Methoxyestradiol | 1.3 ± 0.2 | 260 | ++ | ? | 9 |
| 4-Fluoroestradiola | 180 ± 43 | ? | +++ | ? | ? |
| 2-Hydroxyestrone | 1.9 ± 0.8 | 130 ± 9 | Inactive | 110–142 | 8 |
| 2-Methoxyestrone | 0.01 ± 0.00 | 103 ± 7 | Inactive | 95–100 | 120 |
| 4-Hydroxyestrone | 11 ± 4 | 351 | ++ | 21–50 | 35 |
| 4-Methoxyestrone | 0.13 ± 0.04 | 338 | ++ | 65–92 | 12 |
| 16α-Hydroxyestrone | 2.8 ± 1.0 | 552 ± 42 | +++ | 7–24 | <0.5 |
| 2-Hydroxyestriol | 0.9 ± 0.3 | 302 | +b | ? | ? |
| 2-Methoxyestriol | 0.01 ± 0.00 | ? | Inactive | ? | 4 |
| Notes: Values are mean ± SD or range.ERRBA =Relative binding affinity toestrogen receptors of ratuterinecytosol. Uterine weight = Percentage change in uterine wet weight ofovariectomized rats after 72 hours with continuous administration of 1 μg/hour viasubcutaneously implantedosmotic pumps.LH levels =Luteinizing hormone levels relative to baseline of ovariectomized rats after 24 to 72 hours of continuous administration via subcutaneous implant.Footnotes:a =Synthetic (i.e., notendogenous).b = Atypical uterotrophic effect which plateaus within 48 hours (estradiol's uterotrophy continues linearly up to 72 hours).Sources: See template. | |||||
Estradiol, like othersteroid hormones, is derived fromcholesterol. Afterside 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 isaromatized toestrone, which is subsequently converted to estradiol via17β-hydroxysteroid dehydrogenase (17β-HSD).[50]
During the reproductive years, most estradiol in women is produced by thegranulosa 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 theadrenal cortex, and, in men, by the testes.[medical citation needed]
Estradiol is not produced in thegonads only; in particular,fat cells produce active precursors to estradiol, and will continue to do so even after menopause.[51] Estradiol is also produced in thebrain and inarterial walls.
In men, approximately 15 to 25% of circulating estradiol is produced in thetesticles.[52][53] 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).[52][53] This peripheral aromatization occurs predominantly inadipose tissue, but also occurs in othertissues such asbone,liver, and thebrain.[52] Approximately 40 to 50 μg of estradiol is produced per day in men.[52]
In plasma, estradiol is largely bound to SHBG andalbumin. Only about 2.21% (± 0.04%) of estradiol is free and biologically active. The percentage remains constant throughout themenstrual cycle.[54]
Metabolic pathways of estradiol in humans   |
Inactivation of estradiol includes conversion to less-active estrogens, such as estrone and estriol. Estriol is the major urinarymetabolite.[citation needed] Estradiol isconjugated in theliver to formestrogen conjugates likeestradiol sulfate,estradiol glucuronide and, as such, excreted via thekidneys. Some of the water-soluble conjugates are excreted via thebile duct, and partly reabsorbed afterhydrolysis from theintestinal tract. Thisenterohepatic circulation contributes to maintaining estradiol levels.
Estradiol is also metabolized viahydroxylation intocatechol estrogens. In the liver, it is non-specifically metabolized byCYP1A2,CYP3A4, andCYP2C9 via 2-hydroxylation into2-hydroxyestradiol, and byCYP2C9,CYP2C19, andCYP2C8 via 17β-hydroxy dehydrogenation intoestrone,[55] with various othercytochrome P450 (CYP)enzymes andmetabolic transformations also being involved.[56]
Estradiol is additionallyconjugated with anester intolipoidal estradiol forms likeestradiol palmitate andestradiol stearate to a certain extent; these esters are stored inadipose tissue and may act as a very long-lasting reservoir of estradiol.[57][58]
Estradiol isexcreted in the form ofglucuronide andsulfateestrogen conjugates inurine. Following anintravenous injection oflabeled estradiol in women, almost 90% is excreted in urine andfeces within 4 to 5 days.[59][60]Enterohepatic recirculation causes a delay in excretion of estradiol.[59]
Levels of estradiol in premenopausal women are highly variable throughout the menstrual cycle and reference ranges widely vary from source to source.[62] 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).[63][64] 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.[62][63] 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.[62] 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).[62][63][65][66][67] 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.[62][64] 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.[64][68][69] 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.[69]
During the reproductive years of human females, 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] 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] The estradiol produced by male humans, from testosterone, is present at serum levels roughly comparable to those ofpostmenopausal women (14–55 versus <35 pg/mL, respectively).[citation needed] 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.[70]
| Group | E2 (prod) | E2 (levels) | E1 (levels) | Ratio |
|---|---|---|---|---|
| Pubertal girlsa Tanner stage I (childhood) Tanner stage II (ages 8–12) Tanner stage III (ages 10–13) Tanner stage IV (ages 11–14) Tanner stage V (ages 12–15) Follicular (days 1–14) Luteal (days 15–28) | ? ? ? ? ? ? | 9 (<9–20) pg/mL 15 (<9–30) pg/mL 27 (<9–60) pg/mL 55 (16–85) pg/mL 50 (30–100) pg/mL 130 (70–300) pg/mL | 13 (<9–23) pg/mL 18 (10–37) pg/mL 26 (17–58) pg/mL 36 (23–69) pg/mL 44 (30–89) pg/mL 75 (39–160) pg/mL | ? ? ? ? ? ? |
| Prepubertal boys | ? | 2–8 pg/mL | ? | ? |
| Premenopausal women Early follicular phase (days 1–4) Mid follicular phase (days 5–9) Late follicular phase (days 10–14) Luteal phase (days 15–28) Oral contraceptive (anovulatory) | 30–100 μg/day 100–160 μg/day 320–640 μg/day 300 μg/day ? | 40–60 pg/mL 60–100 pg/mL 200–400 pg/mL 190 pg/mL 12–50 pg/mL | 40–60 pg/mL ? 170–200 pg/mL 100–150 pg/mL ? | 0.5–1 ? 1–2 1.5 ? |
| Postmenopausal women | 18 μg/day | 5–20 pg/mL | 30–70 pg/mL | 0.3–0.8 |
| Pregnant women First trimester (weeks 1–12) Second trimester (weeks 13–26) Third trimester (weeks 27–40) | ? ? ? | 1,000–5,000 pg/mL 5,000–15,000 pg/mL 10,000–40,000 pg/mL | ? ? ? | ? ? ? |
| Mena | 20–60 μg/day | 27 (20–55) pg/mL | 20–90 pg/mL | 0.4–0.6 |
| Footnotes:a = Format is "mean value (range)" or just "range".Sources:[71][72][73][74][75][61][76] | ||||
In women, serum estradiol is measured in aclinical laboratory and reflects primarily the activity of the ovaries. The Estradiol blood test measures the amount of estradiol in the blood.[77] It is used to check the function of the ovaries, placenta, adrenal glands.[77] This can detect baseline estrogen in women withamenorrhea 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. Inprecocious puberty, estradiol levels are inappropriately increased.
Individual laboratory results should always be interpreted using the ranges provided by the laboratory that performed the test.
| Patient type | Lower limit | Upper limit | Unit |
|---|---|---|---|
| Adult male | 50[78] | 200[78] | pmol/L |
| 14 | 55 | pg/mL | |
| Adult female (follicular phase, day 5) | 70[78] 95%PI (standard) | 500[78] 95% PI | pmol/L |
| 110[79] 90%PI (used indiagram) | 220[79] 90% PI | ||
| 19(95% PI) | 140(95% PI) | pg/mL | |
| 30(90% PI) | 60(90% PI) | ||
| Adult female (preovulatory peak) | 400[78] | 1500[78] | pmol/L |
| 110 | 410 | pg/mL | |
| Adult female (luteal phase) | 70[78] | 600[78] | pmol/L |
| 19 | 160 | pg/mL | |
| Adult female – free (not protein bound) | 0.5[80][original research?] | 9[80][original research?] | pg/mL |
| 1.7[80][original research?] | 33[80][original research?] | pmol/L | |
| Post-menopausal female | N/A[78] | < 130[78] | pmol/L |
| N/A | < 35 | pg/mL |
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 theplacenta, which aromatizesprohormones produced in the fetal adrenal gland.
| Sex | Sex hormone | Reproductive phase | Blood production rate | Gonadal secretion rate | Metabolic clearance rate | Reference range (serum levels) | |
|---|---|---|---|---|---|---|---|
| SI units | Non-SI units | ||||||
| Men | Androstenedione | – | 2.8 mg/day | 1.6 mg/day | 2200 L/day | 2.8–7.3 nmol/L | 80–210 ng/dL |
| Testosterone | – | 6.5 mg/day | 6.2 mg/day | 950 L/day | 6.9–34.7 nmol/L | 200–1000 ng/dL | |
| Estrone | – | 150 μg/day | 110 μg/day | 2050 L/day | 37–250 pmol/L | 10–70 pg/mL | |
| Estradiol | – | 60 μg/day | 50 μg/day | 1600 L/day | <37–210 pmol/L | 10–57 pg/mL | |
| Estrone sulfate | – | 80 μg/day | Insignificant | 167 L/day | 600–2500 pmol/L | 200–900 pg/mL | |
| Women | Androstenedione | – | 3.2 mg/day | 2.8 mg/day | 2000 L/day | 3.1–12.2 nmol/L | 89–350 ng/dL |
| Testosterone | – | 190 μg/day | 60 μg/day | 500 L/day | 0.7–2.8 nmol/L | 20–81 ng/dL | |
| Estrone | Follicular phase | 110 μg/day | 80 μg/day | 2200 L/day | 110–400 pmol/L | 30–110 pg/mL | |
| Luteal phase | 260 μg/day | 150 μg/day | 2200 L/day | 310–660 pmol/L | 80–180 pg/mL | ||
| Postmenopause | 40 μg/day | Insignificant | 1610 L/day | 22–230 pmol/L | 6–60 pg/mL | ||
| Estradiol | Follicular phase | 90 μg/day | 80 μg/day | 1200 L/day | <37–360 pmol/L | 10–98 pg/mL | |
| Luteal phase | 250 μg/day | 240 μg/day | 1200 L/day | 699–1250 pmol/L | 190–341 pg/mL | ||
| Postmenopause | 6 μg/day | Insignificant | 910 L/day | <37–140 pmol/L | 10–38 pg/mL | ||
| Estrone sulfate | Follicular phase | 100 μg/day | Insignificant | 146 L/day | 700–3600 pmol/L | 250–1300 pg/mL | |
| Luteal phase | 180 μg/day | Insignificant | 146 L/day | 1100–7300 pmol/L | 400–2600 pg/mL | ||
| Progesterone | Follicular phase | 2 mg/day | 1.7 mg/day | 2100 L/day | 0.3–3 nmol/L | 0.1–0.9 ng/mL | |
| Luteal phase | 25 mg/day | 24 mg/day | 2100 L/day | 19–45 nmol/L | 6–14 ng/mL | ||
Notes and sources Notes: "Theconcentration of a steroid in the circulation is determined by the rate at which it is secreted from glands, the rate of metabolism of precursor or prehormones into the steroid, and the rate at which it is extracted by tissues and metabolized. Thesecretion rate of a steroid refers to the total secretion of the compound from a gland per unit time. Secretion rates have been assessed by sampling the venous effluent from a gland over time and subtracting out the arterial and peripheral venous hormone concentration. Themetabolic clearance rate of a steroid is defined as the volume of blood that has been completely cleared of the hormone per unit time. Theproduction rate of a steroid hormone refers to entry into the blood of the compound from all possible sources, including secretion from glands and conversion of prohormones into the steroid of interest. At steady state, the amount of hormone entering the blood from all sources will be equal to the rate at which it is being cleared (metabolic clearance rate) multiplied by blood concentration (production rate = metabolic clearance rate × concentration). If there is little contribution of prohormone metabolism to the circulating pool of steroid, then the production rate will approximate the secretion rate."Sources: See template. | |||||||
Estradiol is used as amedication, primarily inhormone therapy formenopausalsymptoms as well asfeminizing hormone therapy for trans individuals.[82]
Estradiol is anestranesteroid.[82] It is also known as 17β-estradiol (to distinguish it from17α-estradiol) or as estra-1,3,5(10)-triene-3,17β-diol. It has twohydroxyl groups, one at the C3 position and the other at the 17β position, as well as threedouble bonds in the Aring. Due to its two hydroxyl groups, estradiol is often abbreviated as E2. The structurally related estrogens, estrone (E1), estriol (E3), andestetrol (E4) have one, three, and four hydroxyl groups, respectively.
Product insert information, accompanying commercial perscription estradiol, indicates it causes depression.In a randomized, double-blind, placebo-controlled study, estradiol was shown to have gender-specific effects on fairness sensitivity. Overall, when the division of a given amount of money was framed as either fair or unfair in a modified version of theultimatum game, estradiol increased the acceptance rate of fair-framed proposals among men and decreased it among women. However, among the placebo-group "the mere belief of receiving estradiol treatment significantly increased the acceptance of unfair-framed offers in both sexes", indicating that so-called "environmental" factors played a role in organising the responses towards these presentations of theultimatum game.[83]
The discovery of estrogen is usually credited to theAmericanscientistsEdgar Allen andEdward A. Doisy.[84][85] In 1923, they observed that injection of fluid fromporcineovarian follicles producedpubertal- andestrus-type changes (includingvaginal,uterine, andmammary gland changes andsexual receptivity) insexually immature,ovariectomized mice and rats.[84][85][86] These findings demonstrated the existence of ahormone which is produced by theovaries and is involved insexual maturation andreproduction.[84][85][86] 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";[85] others referred to it variously asfeminin,folliculin,menformon,thelykinin, andemmenin.[87][88] In 1926, Parkes and Bellerby coined the termestrin to describe the hormone on the basis of it inducingestrus in animals.[89][87]Estrone was isolated and purified independently by Allen and Doisy andGerman scientistAdolf Butenandt in 1929, andestriol was isolated and purified by Marrian in 1930; they were the first estrogens to be identified.[85][90][91]
Estradiol, the most potent of the three major estrogens, was the last of the three to be identified.[85][89] It was discovered by Schwenk and Hildebrant in 1933, whosynthesized it viareduction of estrone.[85] Estradiol was subsequently isolated and purified from sow ovaries by Doisy in 1935, with itschemical structure determined simultaneously,[92] and was referred to variously asdihydrotheelin,dihydrofolliculin,dihydrofollicular hormone, anddihydroxyestrin.[85][93][94] In 1935, the nameestradiol and the termestrogen were formally established by the Sex Hormone Committee of the Health Organization of theLeague 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 inLondon.[89][95] Following its discovery, apartial synthesis of estradiol fromcholesterol was developed by Inhoffen and Hohlweg in 1940, and atotal synthesis was developed by Anner and Miescher in 1948.[85]
The nameestradiol derives fromestra-,Gk.οἶστρος (oistros, literally meaning "verve or inspiration"),[96] which refers to theestranesteroidring system, and-diol, a chemical term and suffix indicating that the compound is a type ofalcohol bearing twohydroxylgroups.
{{cite book}}:ISBN / Date incompatibility (help)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.)
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.
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.
Midcycle: 150-750 pg/mL
Mid-cycle: 110-330 pg/mL
Ovulatory: 200-400 pg/mL
[...] following the menopause, circulating estradiol levels decrease from a premenopausal mean of 120 pg/mL to only 13 pg/mL.
[...] [premenopausal] mean [estradiol] concentration of 150 pg/mL [...]
