17α-Estradiol
Names
IUPAC name
Estra-1,3,5(10)-triene-3,17α-diol
Systematic IUPAC name
(1R,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
17α-E2; Alpha-Estradiol; Alfatradiol; 17-Epiestradiol; β-Estradiol (obsolete, misleading)[1]
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
ECHA InfoCard 100.000.322
UNII
  • InChI=1S/C18H24O2/c1-18-9-8-14-13-5-3-12(19)10-11(13)2-4-15(14)16(18)6-7-17(18)20/h3,5,10,14-17,19-20H,2,4,6-9H2,1H3/t14-,15-,16+,17-,18+/m1/s1
  • C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@H]2O)CCC4=C3C=CC(=C4)O
Properties
C18H24O2
Molar mass 272.388 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

17α-Estradiol (also known as 17α-E2, 17-epiestradiol, alfatradiol, or estra-1,3,5(10)-triene-3,17α-diol) is a minor and weak endogenous steroidal estrogen that is related to 17β-estradiol (better known simply as estradiol).[2] It is the C17 epimer of estradiol.[2] It has approximately 100-fold lower estrogenic potency than 17β-estradiol.[3] The compound shows preferential affinity for the ERα over the ERβ.[2][4] Although 17α-estradiol is far weaker than 17β-estradiol as an agonist of the nuclear estrogen receptors, it has been found to bind to and activate the brain-expressed ER-X with a greater potency than that of 17β-estradiol, suggesting that it may be the predominant endogenous ligand for the receptor.[5]

Affinities of estrogen receptor ligands for the ERα and ERβ
LigandOther namesRelative binding affinities (RBA, %)aAbsolute binding affinities (Ki, nM)aAction
ERαERβERαERβ
EstradiolE2; 17β-Estradiol1001000.115 (0.04–0.24)0.15 (0.10–2.08)Estrogen
EstroneE1; 17-Ketoestradiol16.39 (0.7–60)6.5 (1.36–52)0.445 (0.3–1.01)1.75 (0.35–9.24)Estrogen
EstriolE3; 16α-OH-17β-E212.65 (4.03–56)26 (14.0–44.6)0.45 (0.35–1.4)0.7 (0.63–0.7)Estrogen
EstetrolE4; 15α,16α-Di-OH-17β-E24.03.04.919Estrogen
Alfatradiol17α-Estradiol20.5 (7–80.1)8.195 (2–42)0.2–0.520.43–1.2Metabolite
16-Epiestriol16β-Hydroxy-17β-estradiol7.795 (4.94–63)50 ? ?Metabolite
17-Epiestriol16α-Hydroxy-17α-estradiol55.45 (29–103)79–80 ? ?Metabolite
16,17-Epiestriol16β-Hydroxy-17α-estradiol1.013 ? ?Metabolite
2-Hydroxyestradiol2-OH-E222 (7–81)11–352.51.3Metabolite
2-Methoxyestradiol2-MeO-E20.0027–2.01.0 ? ?Metabolite
4-Hydroxyestradiol4-OH-E213 (8–70)7–561.01.9Metabolite
4-Methoxyestradiol4-MeO-E22.01.0 ? ?Metabolite
2-Hydroxyestrone2-OH-E12.0–4.00.2–0.4 ? ?Metabolite
2-Methoxyestrone2-MeO-E1<0.001–<1<1 ? ?Metabolite
4-Hydroxyestrone4-OH-E11.0–2.01.0 ? ?Metabolite
4-Methoxyestrone4-MeO-E1<1<1 ? ?Metabolite
16α-Hydroxyestrone16α-OH-E1; 17-Ketoestriol2.0–6.535 ? ?Metabolite
2-Hydroxyestriol2-OH-E32.01.0 ? ?Metabolite
4-Methoxyestriol4-MeO-E31.01.0 ? ?Metabolite
Estradiol sulfateE2S; Estradiol 3-sulfate<1<1 ? ?Metabolite
Estradiol disulfateEstradiol 3,17β-disulfate0.0004 ? ? ?Metabolite
Estradiol 3-glucuronideE2-3G0.0079 ? ? ?Metabolite
Estradiol 17β-glucuronideE2-17G0.0015 ? ? ?Metabolite
Estradiol 3-gluc. 17β-sulfateE2-3G-17S0.0001 ? ? ?Metabolite
Estrone sulfateE1S; Estrone 3-sulfate<1<1>10>10Metabolite
Estradiol benzoateEB; Estradiol 3-benzoate10 ? ? ?Estrogen
Estradiol 17β-benzoateE2-17B11.332.6 ? ?Estrogen
Estrone methyl etherEstrone 3-methyl ether0.145 ? ? ?Estrogen
ent-Estradiol1-Estradiol1.31–12.349.44–80.07 ? ?Estrogen
Equilin7-Dehydroestrone13 (4.0–28.9)13.0–490.790.36Estrogen
Equilenin6,8-Didehydroestrone2.0–157.0–200.640.62Estrogen
17β-Dihydroequilin7-Dehydro-17β-estradiol7.9–1137.9–1080.090.17Estrogen
17α-Dihydroequilin7-Dehydro-17α-estradiol18.6 (18–41)14–320.240.57Estrogen
17β-Dihydroequilenin6,8-Didehydro-17β-estradiol35–6890–1000.150.20Estrogen
17α-Dihydroequilenin6,8-Didehydro-17α-estradiol20490.500.37Estrogen
Δ8-Estradiol8,9-Dehydro-17β-estradiol68720.150.25Estrogen
Δ8-Estrone8,9-Dehydroestrone19320.520.57Estrogen
EthinylestradiolEE; 17α-Ethynyl-17β-E2120.9 (68.8–480)44.4 (2.0–144)0.02–0.050.29–0.81Estrogen
MestranolEE 3-methyl ether ?2.5 ? ?Estrogen
MoxestrolRU-2858; 11β-Methoxy-EE35–435–200.52.6Estrogen
Methylestradiol17α-Methyl-17β-estradiol7044 ? ?Estrogen
DiethylstilbestrolDES; Stilbestrol129.5 (89.1–468)219.63 (61.2–295)0.040.05Estrogen
HexestrolDihydrodiethylstilbestrol153.6 (31–302)60–2340.060.06Estrogen
DienestrolDehydrostilbestrol37 (20.4–223)56–4040.050.03Estrogen
Benzestrol (B2)–114 ? ? ?Estrogen
ChlorotrianiseneTACE1.74 ?15.30 ?Estrogen
TriphenylethyleneTPE0.074 ? ? ?Estrogen
TriphenylbromoethyleneTPBE2.69 ? ? ?Estrogen
TamoxifenICI-46,4743 (0.1–47)3.33 (0.28–6)3.4–9.692.5SERM
Afimoxifene4-Hydroxytamoxifen; 4-OHT100.1 (1.7–257)10 (0.98–339)2.3 (0.1–3.61)0.04–4.8SERM
Toremifene4-Chlorotamoxifen; 4-CT ? ?7.14–20.315.4SERM
ClomifeneMRL-4125 (19.2–37.2)120.91.2SERM
CyclofenilF-6066; Sexovid151–152243 ? ?SERM
NafoxidineU-11,000A30.9–44160.30.8SERM
Raloxifene–41.2 (7.8–69)5.34 (0.54–16)0.188–0.5220.2SERM
ArzoxifeneLY-353,381 ? ?0.179 ?SERM
LasofoxifeneCP-336,15610.2–16619.00.229 ?SERM
OrmeloxifeneCentchroman ? ?0.313 ?SERM
Levormeloxifene6720-CDRI; NNC-460,0201.551.88 ? ?SERM
OspemifeneDeaminohydroxytoremifene0.82–2.630.59–1.22 ? ?SERM
Bazedoxifene– ? ?0.053 ?SERM
EtacstilGW-56384.3011.5 ? ?SERM
ICI-164,384–63.5 (3.70–97.7)1660.20.08Antiestrogen
FulvestrantICI-182,78043.5 (9.4–325)21.65 (2.05–40.5)0.421.3Antiestrogen
PropylpyrazoletriolPPT49 (10.0–89.1)0.120.4092.8ERα agonist
16α-LE216α-Lactone-17β-estradiol14.6–570.0890.27131ERα agonist
16α-Iodo-E216α-Iodo-17β-estradiol30.22.30 ? ?ERα agonist
MethylpiperidinopyrazoleMPP110.05 ? ?ERα antagonist
DiarylpropionitrileDPN0.12–0.256.6–1832.41.7ERβ agonist
8β-VE28β-Vinyl-17β-estradiol0.3522.0–8312.90.50ERβ agonist
PrinaberelERB-041; WAY-202,0410.2767–72 ? ?ERβ agonist
ERB-196WAY-202,196 ?180 ? ?ERβ agonist
ErteberelSERBA-1; LY-500,307 ? ?2.680.19ERβ agonist
SERBA-2– ? ?14.51.54ERβ agonist
Coumestrol–9.225 (0.0117–94)64.125 (0.41–185)0.14–80.00.07–27.0Xenoestrogen
Genistein–0.445 (0.0012–16)33.42 (0.86–87)2.6–1260.3–12.8Xenoestrogen
Equol–0.2–0.2870.85 (0.10–2.85) ? ?Xenoestrogen
Daidzein–0.07 (0.0018–9.3)0.7865 (0.04–17.1)2.085.3Xenoestrogen
Biochanin A–0.04 (0.022–0.15)0.6225 (0.010–1.2)1748.9Xenoestrogen
Kaempferol–0.07 (0.029–0.10)2.2 (0.002–3.00) ? ?Xenoestrogen
Naringenin–0.0054 (<0.001–0.01)0.15 (0.11–0.33) ? ?Xenoestrogen
8-Prenylnaringenin8-PN4.4 ? ? ?Xenoestrogen
Quercetin–<0.001–0.010.002–0.040 ? ?Xenoestrogen
Ipriflavone–<0.01<0.01 ? ?Xenoestrogen
Miroestrol–0.39 ? ? ?Xenoestrogen
Deoxymiroestrol–2.0 ? ? ?Xenoestrogen
β-Sitosterol–<0.001–0.0875<0.001–0.016 ? ?Xenoestrogen
Resveratrol–<0.001–0.0032 ? ? ?Xenoestrogen
α-Zearalenol–48 (13–52.5) ? ? ?Xenoestrogen
β-Zearalenol–0.6 (0.032–13) ? ? ?Xenoestrogen
Zeranolα-Zearalanol48–111 ? ? ?Xenoestrogen
Taleranolβ-Zearalanol16 (13–17.8)140.80.9Xenoestrogen
ZearalenoneZEN7.68 (2.04–28)9.45 (2.43–31.5) ? ?Xenoestrogen
ZearalanoneZAN0.51 ? ? ?Xenoestrogen
Bisphenol ABPA0.0315 (0.008–1.0)0.135 (0.002–4.23)19535Xenoestrogen
EndosulfanEDS<0.001–<0.01<0.01 ? ?Xenoestrogen
KeponeChlordecone0.0069–0.2 ? ? ?Xenoestrogen
o,p'-DDT–0.0073–0.4 ? ? ?Xenoestrogen
p,p'-DDT–0.03 ? ? ?Xenoestrogen
Methoxychlorp,p'-Dimethoxy-DDT0.01 (<0.001–0.02)0.01–0.13 ? ?Xenoestrogen
HPTEHydroxychlor; p,p'-OH-DDT1.2–1.7 ? ? ?Xenoestrogen
TestosteroneT; 4-Androstenolone<0.0001–<0.01<0.002–0.040>5000>5000Androgen
DihydrotestosteroneDHT; 5α-Androstanolone0.01 (<0.001–0.05)0.0059–0.17221–>500073–1688Androgen
Nandrolone19-Nortestosterone; 19-NT0.010.2376553Androgen
DehydroepiandrosteroneDHEA; Prasterone0.038 (<0.001–0.04)0.019–0.07245–1053163–515Androgen
5-AndrostenediolA5; Androstenediol6173.60.9Androgen
4-Androstenediol–0.50.62319Androgen
4-AndrostenedioneA4; Androstenedione<0.01<0.01>10000>10000Androgen
3α-Androstanediol3α-Adiol0.070.326048Androgen
3β-Androstanediol3β-Adiol3762Androgen
Androstanedione5α-Androstanedione<0.01<0.01>10000>10000Androgen
Etiocholanedione5β-Androstanedione<0.01<0.01>10000>10000Androgen
Methyltestosterone17α-Methyltestosterone<0.0001 ? ? ?Androgen
Ethinyl-3α-androstanediol17α-Ethynyl-3α-adiol4.0<0.07 ? ?Estrogen
Ethinyl-3β-androstanediol17α-Ethynyl-3β-adiol505.6 ? ?Estrogen
ProgesteroneP4; 4-Pregnenedione<0.001–0.6<0.001–0.010 ? ?Progestogen
NorethisteroneNET; 17α-Ethynyl-19-NT0.085 (0.0015–<0.1)0.1 (0.01–0.3)1521084Progestogen
Norethynodrel5(10)-Norethisterone0.5 (0.3–0.7)<0.1–0.221453Progestogen
Tibolone7α-Methylnorethynodrel0.5 (0.45–2.0)0.2–0.076 ? ?Progestogen
Δ4-Tibolone7α-Methylnorethisterone0.069–<0.10.027–<0.1 ? ?Progestogen
3α-Hydroxytibolone–2.5 (1.06–5.0)0.6–0.8 ? ?Progestogen
3β-Hydroxytibolone–1.6 (0.75–1.9)0.070–0.1 ? ?Progestogen
Footnotes: a = (1) Binding affinity values are of the format "median (range)" (# (#–#)), "range" (#–#), or "value" (#) depending on the values available. The full sets of values within the ranges can be found in the Wiki code. (2) Binding affinities were determined via displacement studies in a variety of in-vitro systems with labeled estradiol and human ERα and ERβ proteins (except the ERβ values from Kuiper et al. (1997), which are rat ERβ). Sources: See template page.
Selected biological properties of endogenous estrogens in rats
EstrogenERTooltip Estrogen receptor RBATooltip relative binding affinity (%)Uterine weight (%)UterotrophyLHTooltip Luteinizing hormone levels (%)SHBGTooltip Sex hormone-binding globulin RBATooltip relative binding affinity (%)
Control–100–100–
Estradiol (E2)100506 ± 20+++12–19100
Estrone (E1)11 ± 8490 ± 22+++ ?20
Estriol (E3)10 ± 4468 ± 30+++8–183
Estetrol (E4)0.5 ± 0.2 ?Inactive ?1
17α-Estradiol4.2 ± 0.8 ? ? ? ?
2-Hydroxyestradiol24 ± 7285 ± 8+b31–6128
2-Methoxyestradiol0.05 ± 0.04101Inactive ?130
4-Hydroxyestradiol45 ± 12 ? ? ? ?
4-Methoxyestradiol1.3 ± 0.2260++ ?9
4-Fluoroestradiola180 ± 43 ?+++ ? ?
2-Hydroxyestrone1.9 ± 0.8130 ± 9Inactive110–1428
2-Methoxyestrone0.01 ± 0.00103 ± 7Inactive95–100120
4-Hydroxyestrone11 ± 4351++21–5035
4-Methoxyestrone0.13 ± 0.04338++65–9212
16α-Hydroxyestrone2.8 ± 1.0552 ± 42+++7–24<0.5
2-Hydroxyestriol0.9 ± 0.3302+b ? ?
2-Methoxyestriol0.01 ± 0.00 ?Inactive ?4
Notes: Values are mean ± SD or range. ER RBA = Relative binding affinity to estrogen receptors of rat uterine cytosol. Uterine weight = Percentage change in uterine wet weight of ovariectomized rats after 72 hours with continuous administration of 1 μg/hour via subcutaneously implanted osmotic 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., not endogenous). b = Atypical uterotrophic effect which plateaus within 48 hours (estradiol's uterotrophy continues linearly up to 72 hours). Sources: See template.

Biosynthesis

17α-Estradiol is produced from epitestosterone by aromatase at locations not fully characterized (known to include the brain). Where and how epitestosterone is made is not fully understood. Conversion between 17α-estradiol and estrone seems to occur, but the enzymes remain unidentified.[5]

Occurrence

17α-E2 is found in mice brain, regardless of age and sex, at concentrations much higher than 17β-E2. Gonadectomized and/or adrenalectomized mice continue to have high brain levels of 17α-E2.[5]

17α-E2 poorly binds α-fetoprotein, unlike 17β-E2.[5]

17α-E2 is excreted in urine. It was initially discovered in pregnant mare urine (see conjugated estrogens).[5] In a 2022 study, all six tested human urine samples contained detectable amounts of 17α-E2.[6]

Function

As mentioned before, 17α-estradiol binds to ERα and ERβ with moderate affinity but very low activity. It binds to the brain-localized ER-X with significant activity and may play a neuroprotective role.[5]

In the uterus, 17α-estradiol causes smooth muscle relaxation via a nongenomic pathway, similarly to 17β-estradiol; the effect is weaker with no antagonization. It antagonizes the hypertrophic response of 17β-estradiol, probably by acting as an antiestrogen by virtue of its very low activity.[7]

Aging

Supplementation with 17α-Estradiol increases the median lifespan of male mice by 19%, while not affecting female lifespan. This treatment does not lead to feminization of male mice.[8] 17α-Estradiol furthermore alleviates age-related metabolic and inflammatory dysfunction[9] and improves glucose tolerance[10] in male mice. The exact reason for this sex-specific increase in lifespan is unknown, however, the effect on male lifespan is gone in castrated mice, suggesting that the metabolic response to 17α-Estradiol requires the presence of male gonadal hormones.[11] Whether these results are translatable to humans is currently unknown.

See also

References

  1. ↑ J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 897–. ISBN 978-1-4757-2085-3.
  2. 1 2 3 Zhu BT, Han GZ, Shim JY, Wen Y, Jiang XR (2006). "Quantitative structure-activity relationship of various endogenous estrogen metabolites for human estrogen receptor alpha and beta subtypes: Insights into the structural determinants favoring a differential subtype binding". Endocrinology. 147 (9): 4132–50. doi:10.1210/en.2006-0113. PMID 16728493.
  3. ↑ Ralph M. Trüeb, Won-Soo Lee (13 February 2014). Male Alopecia: Guide to Successful Management. Springer Science & Business Media. pp. 93–. ISBN 978-3-319-03233-7.
  4. ↑ Kuiper GG, Carlsson B, Grandien K, Enmark E, Häggblad J, Nilsson S, Gustafsson JA (1997). "Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta". Endocrinology. 138 (3): 863–70. doi:10.1210/endo.138.3.4979. PMID 9048584.
  5. 1 2 3 4 5 6 Toran-Allerand CD, Tinnikov AA, Singh RJ, Nethrapalli IS (2005). "17alpha-estradiol: a brain-active estrogen?". Endocrinology. 146 (9): 3843–50. doi:10.1210/en.2004-1616. PMID 15947006.
  6. ↑ Tang Z, Liu ZH, Wang H, Dang Z (10 July 2022). "17α-Estradiol, an ignored endogenous natural estrogen in human: Updated estrogen metabolism pathways and its environmental risk analysis". The Science of the Total Environment. 829: 154693. Bibcode:2022ScTEn.829o4693T. doi:10.1016/j.scitotenv.2022.154693. PMID 35318059. S2CID 247579981.
  7. ↑ Perusquía M, Navarrete E (21 July 2005). "Evidence that 17alpha-estradiol is biologically active in the uterine tissue: antiuterotonic and antiuterotrophic action". Reproductive Biology and Endocrinology. 3: 30. doi:10.1186/1477-7827-3-30. PMC 1201169. PMID 16042770.
  8. ↑ Strong R, Miller RA, Antebi A, Astle CM, Bogue M, Denzel MS, Fernandez E, Flurkey K, Hamilton KL, Lamming DW, Javors MA, Magalhães JP, Martinez PA, McCord JM, Miller BF (October 2016). "Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α-glucosidase inhibitor or a Nrf2-inducer". Aging Cell. 15 (5): 872–884. doi:10.1111/acel.12496. ISSN 1474-9718. PMC 5013015. PMID 27312235.
  9. ↑ Stout MB, Steyn FJ, Jurczak MJ, Camporez JG, Zhu Y, Hawse JR, Jurk D, Palmer AK, Xu M, Pirtskhalava T, Evans GL, de Souza Santos R, Frank AP, White TA, Monroe DG (2016-01-24). "17α-Estradiol Alleviates Age-related Metabolic and Inflammatory Dysfunction in Male Mice Without Inducing Feminization". The Journals of Gerontology Series A: Biological Sciences and Medical Sciences. 72 (1): 3–15. doi:10.1093/gerona/glv309. ISSN 1079-5006. PMC 5155656. PMID 26809497.
  10. ↑ Garratt M, Bower B, Garcia GG, Miller RA (December 2017). "Sex differences in lifespan extension with acarbose and 17-α estradiol: gonadal hormones underlie male-specific improvements in glucose tolerance and mTORC 2 signaling". Aging Cell. 16 (6): 1256–1266. doi:10.1111/acel.12656. ISSN 1474-9718. PMC 5676051. PMID 28834262.
  11. ↑ Garratt M, Lagerborg KA, Tsai Y, Galecki A, Jain M, Miller RA (August 2018). "Male lifespan extension with 17-α estradiol is linked to a sex-specific metabolomic response modulated by gonadal hormones in mice". Aging Cell. 17 (4): e12786. doi:10.1111/acel.12786. PMC 6052402. PMID 29806096.
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