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| Names | |
|---|---|
| IUPAC name 3-Hydroxyestra-1,3,5(10)-trien-17-one | |
| Systematic IUPAC name (3aS,3bR,9bS,11aS)-7-Hydroxy-11a-methyl-2,3,3a,3b,4,5,9b,10,11,11a-decahydro-1H-cyclopenta[a]phenanthren-1-one | |
| Other names Oestrone; E1 | |
| Identifiers | |
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3D model (JSmol) | |
| ChEBI | |
| ChEMBL | |
| ChemSpider |
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| ECHA InfoCard | 100.000.150 |
| KEGG |
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| UNII | |
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| Properties | |
| C18H22O2 | |
| Molar mass | 270.366 g/mol |
| Melting point | 254.5 |
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |
Estrone (E1), also spelledoestrone, is asteroid, a weakestrogen, and a minor femalesex hormone.[1] It is one of three majorendogenous estrogens, the others beingestradiol andestriol.[1] Estrone, as well as the other estrogens, aresynthesized fromcholesterol andsecreted mainly from thegonads, though they can also be formed fromadrenalandrogens inadipose tissue.[2] Relative to estradiol, both estrone and estriol have far weaker activity as estrogens.[1] Estrone can be converted into estradiol, and serves mainly as aprecursor ormetabolic intermediate of estradiol.[1][3] It is both a precursor andmetabolite of estradiol.[4][1]
In addition to its role as a natural hormone, estrone has been used as amedication, for instance inmenopausal hormone therapy; for information on estrone as a medication, see theestrone (medication) article.
Estrone is an estrogen, specifically anagonist of theestrogen receptorsERα andERβ.[1][5] It is a far lesspotent estrogen than is estradiol, and as such, is a relatively weak estrogen.[1][5][6] Given bysubcutaneous injection in mice, estradiol is about 10-fold more potent than estrone and about 100-fold more potent thanestriol.[7] According to one study, therelative binding affinities of estrone for the human ERα and ERβ were 4.0% and 3.5% of those estradiol, respectively, and therelative transactivational capacities of estrone at the ERα and ERβ were 2.6% and 4.3% of those of estradiol, respectively.[5] In accordance, the estrogenic activity of estrone has been reported to be approximately 4% of that of estradiol.[1] In addition to its low estrogenic potency, estrone, unlike estradiol and estriol, is not accumulated in estrogen target tissues.[1] Because estrone can betransformed into estradiol, most or all of the estrogenic potency of estronein vivo is actually due to conversion into estradiol.[1][8] As such, estrone is considered to be aprecursor orprohormone of estradiol.[3] In contrast to estradiol and estriol, estrone is not aligand of theG protein-coupled estrogen receptor (affinity >10,000 nM).[9]
Clinical research has confirmed the nature of estrone as a relatively inert precursor of estradiol.[1][10][11][12] Withoral administration of estradiol, the ratio of estradiol levels to estrone levels is about 5 times higher on average than under normalphysiological circumstances inpremenopausal women and withparenteral (non-oral)routes of estradiol.[1] Oral administration ofmenopausal replacement dosages of estradiol results in low,follicular phase levels of estradiol, whereas estrone levels resemble the high levels seen during thefirst trimester ofpregnancy.[1][13][14] In spite of markedly elevated levels of estrone with oral estradiol but not withtransdermal estradiol, clinical studies have shown that dosages of oral and transdermal estradiol achieving similar levels of estradiol possess equivalent and non-significantly differentpotency in terms of measures including suppression ofluteinizing hormone andfollicle-stimulating hormone levels, inhibition ofbone resorption, and relief ofmenopausal symptoms such ashot flashes.[1][10][11][12][15] In addition, estradiol levels were found to correlate with these effects, while estrone levels did not.[10][11] These findings confirm that estrone has very low estrogenic activity, and also indicate that estrone does not diminish the estrogenic activity of estradiol.[1][10][11][12] This contradicts somecell-freein-vitro research suggesting that high concentrations of estrone might be able topartiallyantagonize the actions of estradiol.[16][17][18]
| 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:[19][20][21][22][23][24][25][26][27] | |||||
Estrone isbiosynthesized fromcholesterol. The principal pathway involvesandrostenedione as anintermediate, with androstenedione beingtransformed into estrone by theenzymearomatase. This reaction occurs in both thegonads and in certain othertissues, particularlyadipose tissue, and estrone is subsequentlysecreted from these tissues.[2] In addition to aromatization of androstenedione, estrone is also formedreversibly from estradiol by the enzyme17β-hydroxysteroid dehydrogenase (17β-HSD) in various tissues, including theliver,uterus, andmammary gland.[1]
Mechanism of Action:
The way estrone works is by entering the cells of certain tissues in the body and attaching to nuclear receptors. This interaction then influences how genes are expressed, leading to various physiological responses in the body.[29]
Estrone is bound approximately 16% tosex hormone-binding globulin (SHBG) and 80% toalbumin in thecirculation,[1] with the remainder (2.0 to 4.0%) circulating freely or unbound.[30] It has about 24% of the relative binding affinity of estradiol for SHBG.[1] As such, estrone is relatively poorly bound to SHBG.[31]
Estrone isconjugated intoestrogen conjugates such asestrone sulfate andestrone glucuronide bysulfotransferases andglucuronidases, and can also behydroxylated bycytochrome P450 enzymes intocatechol estrogens such as2-hydroxyestrone and4-hydroxyestrone or intoestriol.[1] Both of these transformations take place predominantly in theliver.[1] Estrone can also be reversibly converted into estradiol by 17β-HSD.[1] Theblood half-life of estrone is about 10 to 70 minutes and is similar to that of estradiol.[32][33]
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Estrone isexcreted inurine in the form ofestrogen conjugates such asestrone sulfate.[1] Following an intravenous injection oflabeled estrone in women, almost 90% is excreted in urine andfeces within 4 to 5 days.[32]Enterohepatic recirculation causes a delay in excretion of estrone.[32]
It is one of the three primary types of estrogen and is produced in various parts of the body, including the placenta, ovaries, and peripheral tissues.[34]
| Sex | Sex hormone | Reproductive phase | Blood production rate | Gonadal secretion rate | Metabolic clearance rate | Reference range (serum levels) | |
|---|---|---|---|---|---|---|---|
| Molar concentration | Mass concentration | ||||||
| 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. | |||||||
Toxicity:
When estrone is used too much or taken in large amounts, it can cause toxicity, leading to symptoms like nausea and vomiting. Estrone should be stored in its original package or container to maintain its quality and effectiveness.[34]
Estrone, also known as estra-1,3,5(10)-trien-3-ol-17-one, is anaturally occurringestranesteroid withdouble bonds at the C1, C3, and C5 positions, ahydroxyl group at the C3 position, and aketonegroup at the C17 position. The nameestrone was derived from the chemical termsestrin (estra-1,3,5(10)-triene) andketone.
Thechemical formula of estrone is C18H22O2 and itsmolecular weight is 270.366 g/mol. It is a white, odorless,solidcrystallinepowder, with amelting point of 254.5 °C (490 °F) and aspecific gravity of 1.23.[35][36] Estrone iscombustible at high temperatures, with the productscarbon monoxide (CO) andcarbon dioxide (CO2).[35]
Estrone has been available as aninjected estrogen for medical use, for instance inhormone therapy formenopausal symptoms, but it is now mostly no longer marketed.[37]
Estrone, as part of hormone replacement therapy (HRT), is frequently used to treat symptoms caused by estrogen deficiency in peri and post-menopausal women. This therapy aims to enhance overall health and relieve menopausal symptoms related to estrogen imbalance. Additionally, estrone and other estrogens are used to prevent osteoporosis in postmenopausal women who are at high risk of fractures and cannot tolerate alternative medications. Estrogens are absorbed efficiently by the body and subsequently inactivated in the liver, making them effective in HRT and osteoporosis prevention.[34]
The use of estrone has severalcontraindications, some examples including:hypersensitivity, history of some cancers, stroke,venous thromboembolism (VTE), and those currently pregnant or breastfeeding. Estrogens hold aboxed warning to be used at the lowest effective dose and for the shortest possible treatment period if used alone or with another hormone in the progestogen class.[38]
Estrone is contraindicated for those that have or are suspected of havingbreast cancer. The use of estrogens hold a boxed warning with breast cancer for post-menopausal women as this can increase the risk of developing invasive breast cancer.[39] Those with breast cancer become at a greater risk ofhypercalcemia andbone metastases when taking estrogens.[40] Post-menopausal women with breast cancer can be seen to developfrailty syndrome when there are changes in blood hormonal levels, including an increased level of estrone. Estrone, the major type of estrogen produced in post-menopausal women, was seen in greater concentrations from standard levels in those that were categorized as prefrail and in those that classified as frail.[41]
The risk of VTE is increased in those that use estrogens, those that currently have or have a history with VTE are at a greater risk of reoccurring VTE with the usage of estrogens.[39][42] The use of estrogens within three weeks postpartum may increase the risk of developing a VTE.[43] Risk of developing initial VTE is also increased with familial history, genetic mutations:factor V Leiden andprothrombin-G20210A, and pregnancy-postpartum with the use of estrogens.[44]
The use of estrogens may affect the ability to breastfeed and can change the composition of breastmilk. Estrogens have been used to suppress lactation which can result in a reduced total duration of lactation and reduced volume or inability to produce breastmilk. Composition of breastmilk produced was also seen to be different resulting in a reduced concentration of proteins in the milk. Babies of mothers that were taking estrogens while breastfeeding were seen to experience slower weight gain.[43]
Some common side effects seen with the usage of estrogens include: breast swelling, breast tenderness, vaginal itching, abnormal uterine bleeding, weight gain, hair loss,jaundice, andanaphylaxis.[45]
Someadverse effects seen with the usage of estrogens include: increased risk of venous thromboembolism (VTE), stroke, breast cancer,hypertension, andvaginitis.[45][38]
Estrone was the firststeroid hormone to be discovered.[46][47] It was discovered in 1929 independently by theAmerican scientistsEdward Doisy andEdgar Allen and theGermanbiochemistAdolf Butenandt, although Doisy and Allen isolated it two months before Butenandt.[46][48][49] They isolated andpurified estrone incrystalline form from theurine ofpregnant women.[48][49][50] Doisy and Allen named ittheelin, while Butenandt named itprogynon and subsequently referred to it asfolliculin in his second publication on the substance.[49][51] Butenandt was later awarded theNobel Prize in 1939 for the isolation of estrone and his work onsex hormones in general.[50][52] Themolecular formula of estrone was known by 1931,[53] and itschemical structure had been determined by Butenandt by 1932.[49][48] Following the elucidation of its structure, estrone was additionally referred to asketohydroxyestrin oroxohydroxyestrin,[54][55] and the nameestrone, on the basis of its C17ketone group, was formally established in 1932 at the first meeting of the International Conference on the Standardization of Sex Hormones in London.[56][57]
Apartial synthesis of estrone fromergosterol was accomplished byRussell Earl Marker in 1936, and was the firstchemical synthesis of estrone.[58][59] An alternative partial synthesis of estrone fromcholesterol by way ofdehydroepiandrosterone (DHEA) was developed byHans Herloff Inhoffen andWalter Hohlweg in 1939 or 1940,[58] and atotal synthesis of estrone was achieved by Anner and Miescher in 1948.[57]
Approval
The FDA has approved estrone based on its safety and effectiveness as per the rules outlined in sections 505 of the Federal Food, Drug, and Cosmetic Act.[34]
When Allen and Doisy heard about the [Ascheim-Zondek test for the diagnosis of pregnancy], they realized there was a rich and easily handled source of hormones in urine from which they could develop a potent extract. [...] Allen and Doisy's research was sponsored by the committee, while that of their main rival, Adolt Butenandt (b. 1903) of the University of Gottingen was sponsored by a German pharmaceutical firm. In 1929, both terms announced the isolation of a pure crystal female sex hormone, estrone, in 1929, although Doisy and Allen did so two months earlier than Butenandt.27 By 1931, estrone was being commercially produced by Parke Davis in this country, and Schering-Kahlbaum in Germany. Interestingly, when Butenandt (who shared the Nobel Prize for chemistry in 1939) isolated estrone and analyzed its structure, he found that it was a steroid, the first hormone to be classed in this molecular family.[permanent dead link]
The first steroid hormone was isolated from the urine of pregnant women by Adolf Butenandt in 1929 (estrone; see Fig. 1) (Butenandt 1931).
[Doisy] focused his research on the isolation of female sex hormones from hundreds of gallons of human pregnancy urine based on the discovery by Ascheim and Zondeck in 1927 that the urine of pregnant women possessed estrogenic activity [9]. In the summer of 1929, Doisy succeeded in the isolated of estrone (named by him theelin), simultaneously with but independent of Adolf Butenandt of the University of Gottingen in Germany. Doisy presented his results on the crystallization of estrone at the XIII International Physiological Congress in Boston in August 1929 [10].
Adolt Friedrich Johann Butenandt was awarded the Nobel Prize in chemistry in 1939 "for his work on sex hormones"; [...] In 1929 Butenandt isolated estrone [...] in pure crystalline form. [...] Both Butenandt and Edward Doisy isolated estrone simultaneously but independently in 1929. [...] Butenandt took a big step forward in the history of biochemistry when he isolated estrone from the urine of pregnant women. [...] He named it "progynon" in his first publication, and then "folliculine", [...] By 1932, [...] he could determine its chemical structure, [...]
Rational chemical studies of human sex hormones began in 1929 with Adolph Butenandt's isolation of pure crystalline estrone, the follicular hormone, from the urine of pregnant women. [...] Butenandt and Ruzicka shared the 1939 Nobel Prize in chemistry.
E. A. Doisy and A. Butenandt reported almost at the same time on the isolation of an estrogen-active substance in crystalline form from the urine of pregnant women. N. K. Adam suggested that this substance be named estrone because of the C-17-ketone group present (1933).
In 1929 the first estrogen, a steroid called "estrone," was isolated and purified by Doisy; he later won a Nobel Prize for this work.
In 1926, Sir Alan S. Parkes and C.W Bellerby coined the basic word "estrin" to designate the hormone or hormones that induce estrus in animals, the time when female mammals are fertile and receptive to males. [...] The terminology was extended to include the principal estrogens in humans, estrone, estradiol, and estriol, in 1932 at the first meeting of the International Conference on the Standardization of Sex Hormones in London, [...]
The structure of the estrogenic hormones was stated by Butenandt, Thayer, Marrian, and Hazlewood in 1930 and 1931 (see Butenandt 1980). Following the proposition of the Marrian group, the estrogenic hormones were given the trivial names of estradiol, estrone, and estriol. At the first meeting of the International Conference on the Standardization of Sex Hormones, in London (1932), a standard preparation of estrone was established. [...] The partial synthesis of estradiol and estrone from cholesterol and dehydroepiandrosterone was accomplished by Inhoffen and Howleg (Berlin 1940); the total synthesis was achieved by Anner and Miescher (Basel, 1948).
