Estradiol

Estradiol (E2) is a natural estrogen and the primary female sex hormone. E2 and its esters, including estradiol cypionate and estradiol valerate, are used in combined oral contraceptives alongside progestins and as components of hormone replacement therapy.

Tags
Approvals
US FDA-Approved
Related Compounds
Estradiol Cypionate Estradiol Valerate
estradiol
MOL SDF CML

Identifiers

Abbreviation

E2

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References

Names

  • oestradiol
  • 17β-oestradiol
  • 17β-estradiol
  • estra-1,3,5(10)-triene-3,17β-diol

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References

CASRN

50-28-2

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References

PubChem CID

5757

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References

  1. PubChem: Estradiol (View all citations for this reference)

ECHA InfoCard

  • 100.000.022
  • EC / List #: 200-023-8

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References

  1. ECHA: Estradiol (View all citations for this reference)

IUPHAR/BPS

1013

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References

  1. IUPHAR/BPS: 17β-Estradiol (View all citations for this reference)

DrugBank Accession Number

DB00783

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References

  1. DrugBank: Estradiol
    Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2017 Nov 8. doi: 10.1093/nar/gkx1037     (View all citations for this reference)

UNII

4TI98Z838E

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References

  1. UNII: Estradiol (View all citations for this reference)

KEGG Entry Number

D00105

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References

  1. KEGG: Estradiol (View all citations for this reference)

Wikipedia Entry Name

Estradiol

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References

  1. Wikipedia: Estradiol (View all citations for this reference)

ChEBI ID

CHEBI:16469

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References

  1. ChEBI: Estradiol (View all citations for this reference)

ChemSpider ID

5554

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References

  1. ChemSpider: Estradiol (View all citations for this reference)

PDB

Estradiol

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References

  1. PDB: Estradiol (View all citations for this reference)

NIST

Estradiol

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References

  1. NIST Chemistry WebBook: Estradiol. (View all citations for this reference)

ATC Code(s)

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References

  1. DrugBank: Estradiol
    Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2017 Nov 8. doi: 10.1093/nar/gkx1037     (View all citations for this reference)

Physical & Chemical Properties

Molecular Formula

C18H24O2

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References

Molecular Weight

272.38 g/mol

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References

Melting Point

178.5° C (ChemIDPlus, Toxnet)
151-152° C (DrugBank)

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References

  1. ChemIDPlus: A Toxnet Database. Estradiol. (View all citations for this reference)
  2. DrugBank: Estradiol
    Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2017 Nov 8. doi: 10.1093/nar/gkx1037     (View all citations for this reference)
  3. Toxnet: Estradiol. (View all citations for this reference)

Solubility

3.9 mg/L water at 27° C. Freely soluble in alcohol,;soluble in acetone, dioxane, other organic solvents; sparingly soluble in vegetable oils.

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References

  1. ChemIDPlus: A Toxnet Database. Estradiol. (View all citations for this reference)
  2. Toxnet: Estradiol. (View all citations for this reference)

logP

4.01

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References

  1. ChemIDPlus: A Toxnet Database. Estradiol. (View all citations for this reference)
  2. DrugBank: Estradiol
    Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2017 Nov 8. doi: 10.1093/nar/gkx1037     (View all citations for this reference)
  3. Toxnet: Estradiol. (View all citations for this reference)

Specific Optical Rotation

+76 - +83° at 25 °C for D (sodium) line (dioxane)

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References

  1. Toxnet: Estradiol. (View all citations for this reference)

UV Max Absorption

225, 280 nm

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References

  1. Toxnet: Estradiol. (View all citations for this reference)

Storage Conditions

Store between 15 and 30 °C.

References

Toxicology

GHS Hazard Code(s)

Class Category Code Description
Carcinogenicity 2 H351 Suspected of causing cancer if inhaled
Reproductive Toxicity 1A H360 May damage fertility or the unborn child
Reproductive Toxicity, Effects On or Via Lactation H362 May cause harm to breast-fed children
Reproductive Toxicity 1B H360 May damage fertility or the unborn child
Specific Target Organ Toxicity, Repeated Exposure 1 H372 Causes damage to organs through prolonged or repeated exposure
Specific Target Organ Toxicity, Repeated Exposure 2 H373 Causes damage to organs through prolonged or repeated exposure

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References

  1. ECHA: Estradiol (View all citations for this reference)

Side Effects

Respiratory tract infection, localized exfoliation, headache, endometrial disorder, vulvovaginal mucotic infection, vulvovaginal pruritus, application site reaction, breast tenderness

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References

  1. Side Effect Resource 4.1: Estradiol (View all citations for this reference)

Carcinogenicity

"There is sufficient evidence in humans for the carcinogenicity of post-menopausal estrogen therapy. There is sufficient evidence in experimental animals for the carcinogenicity of estradiol and estrone."

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References

  1. Toxnet: Estradiol. (View all citations for this reference)
  2. WHO International Agency for Research on Cancer: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Volume 91: Combined Estrogen-Progestogen Contraceptives and Combined Estrogen-Progestogen Menopausal Therapy. 2007, Lyon, France. (View all citations for this reference)

Mutagenicity

Not found to be mutagenic in the Ames Salmonella/microsome direct plate incorporation protocol.

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References

  1. Lang, R.; Reimann, R. Studies for a Genotoxic Potential of Some Endogenous and Exogenous Sex Steroids. I. Communication: Examination for the Induction of Gene Mutations Using the Ames Salmonella/microsome Test and the HGPRT Test in V79 Cells. Environ. Mol. Mutagen. 1993, 21 (3), 272–304. (View all citations for this reference)

LD50

LD, rat subcutaneous: > 300 mg/kg

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References

  1. ChemIDPlus: A Toxnet Database. Estradiol. (View all citations for this reference)

MRTD

0.5 mg/kg/day

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References

  1. DSSTox (FDAMDD) FDA Maximum (Recommended) Daily Dose Database. National Center for Biotechnology Information. PubChem BioAssay Database; AID=1195. (View all citations for this reference)

Biochemistry & Pharmacology

Estrogen Receptor Activity

Agonist

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References

  1. Alam, S. M.; Pal, R.; Nagar, S.; Islam, M. A.; Saha, A., Pharmacophore search for anti-fertility and estrogenic potencies of estrogen analogs. J. Mol. Model. 2008, 14 (11), 1071-1082.
    2. (View all citations for this reference)
  2. KEGG: Estradiol (View all citations for this reference)

Target Pathways

Endocrine and other factor-regulated calcium reabsorption

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References

  1. KEGG: Estradiol (View all citations for this reference)

Bioavailability

< 5%

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References

  1. Stanczyk, F. Z.; Archer, D. F.; Bhavnani, B. R., Ethinyl estradiol and 17 beta-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment. Contraception 2013, 87 (6), 706-727.
    2. (View all citations for this reference)

Elimination Half-Life (t1/2)

Oral: 13-30 h (Stanczyk)
36 h (DrugBank)
20.1 h from oral administration (Toxnet)

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References

  1. Stanczyk, F. Z.; Archer, D. F.; Bhavnani, B. R., Ethinyl estradiol and 17 beta-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment. Contraception 2013, 87 (6), 706-727.
    2. (View all citations for this reference)
  2. DrugBank: Estradiol
    Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2017 Nov 8. doi: 10.1093/nar/gkx1037     (View all citations for this reference)
  3. Toxnet: Estradiol. (View all citations for this reference)

Serum Protein Binding

60% to albumin, 38% to SHBG.

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References

  1. Stanczyk, F. Z.; Archer, D. F.; Bhavnani, B. R., Ethinyl estradiol and 17 beta-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment. Contraception 2013, 87 (6), 706-727.
    2. (View all citations for this reference)
  2. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 12e, 2011 > Estrogens and Progestins. Laurence L. Brunton, Bruce A. Chabner, Björn C. Knollmann.
    3. (View all citations for this reference)
  3. Toxnet: Estradiol. (View all citations for this reference)

Metabolism

Hepatic, if oral administration.

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References

  1. Toxnet: Estradiol. (View all citations for this reference)

Excretion

54% in urine, 6% in feces.

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References

  1. Stanczyk, F. Z.; Archer, D. F.; Bhavnani, B. R., Ethinyl estradiol and 17 beta-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment. Contraception 2013, 87 (6), 706-727.
    2. (View all citations for this reference)
  2. Toxnet: Estradiol. (View all citations for this reference)

Caco-2 Permeability

-4.77

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References

  1. DrugBank: Estradiol
    Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2017 Nov 8. doi: 10.1093/nar/gkx1037     (View all citations for this reference)

Indications

For the treatment of urogenital symptoms associated with post-menopausal atrophy of the vagina (such as dryness, burning, pruritus and dyspareunia) and/or the lower urinary tract (urinary urgency and dysuria).

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References

  1. DrugBank: Estradiol
    Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2017 Nov 8. doi: 10.1093/nar/gkx1037     (View all citations for this reference)

Metabolites

Name
Structure
Notes
4-Hydroxyestradiol
structure

Formed by CYP1B1 in the liver. Minor pathway in liver but is formed in larger amount in extrahepatic tissues. Thought to be the most carcinogenic of all estradiol metabolites. Can bind to estrogen receptors.

2-Hydroxyestradiol
structure

Formed in liver by CYP1A2, CYP3A4, and CYP2C9. Major metabolic pathway of estradiol in liver. Has about 7% and 11% the affinity of estradiol to ERα and ERβ, respectively. Weakly estrogenic, with some antagonistic effects. Can be further metabolized to 2-methoxyestradiol by catechol O-methyltransferase (COMT) in the liver. Can also be metabolized to free radicals that cause DNA damage.

Other Estradiol Metabolites

A number of other hydroxylated metabolites are also formed (6α-, 6β-, 7α-, 12β-, 15α-, 15β-, 16α, and 16β-hydroxyestradiol). Estradiol may also be metabolized to hydroxyestrones, such as 2-, 4-, and 16α-hydroxyestrone.

Estriol
structure

Major urinary metabolite. Formed from the estradiol metabolite estrone. 80 times less potent estrogen agonist than estradiol.

Estrone
structure

Formed in the liver by CYP2C9, CYP2C19, and CYP2C8. Undergoes further conversion to estriol, the major urinary metabolite. 10 times less potent estrogen agonist that estradiol.

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Impurities

Name
Structure
CASRN
Other Names & Identifiers
Estra-1,3,5(10),9(11)-tetraene-3,17β-diol
structure

791-69-5

  • BP Estradiol Hemihydrate Impurity D

4-Methylestra-1,3,5(10)-triene-3,17β-diol
structure

  • BP Estradiol Hemihydrate Impurity C

6-Dehydroestradiol
structure

7291-41-0

  • BP Estradiol Vaginal Tablets Impurity 3
  • Δ6-Estradiol

6-Ketoestradiol
structure

571-92-6

  • BP Estradiol Vaginal Tablets Impurity 2
  • 3,17β-dihydroxyestra-1,3,5(10)-trien-6-one

6β-Hydroxyestradiol
structure

547-81-9

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US FDA-Approved Products

Name
Formulation
Status
ANDA #
Menostar, #020376
ESTRADIOL: 0.05, 0.1, 0.075, 0.025, 0.0375, 0.06, 0.014 mg/day
Extended Release Film

Prescription

020375

Estradiol, #206388
ESTRADIOL: 10 μg
Vaginal Tablet

Prescription

206388

Vivelle-Dot
ESTRADIOL: 0.0375 mg/day, 0.075 mg/day, 0.05 mg/day, 0.1 mg/day Film, extended release; transdermal Discontinued ESTRADIOL: 0.0375 mg/day, 0.075 mg/day, 0.05 mg/day, 0.1 mg/day, 0.025 mg/day Film, extended release; transdermal Prescription

Prescription

020538

Vivelle, #021167
ESTRADIOL: 0.0375 mg/day, 0.075 mg/day, 0.025 mg/day Film, extended release; transdermal Discontinued ESTRADIOL: 0.05 mg/day, 0.1 mg/day Film, extended release; transdermal Prescription

Discontinued; Prescription

021167

Vivelle, #020323
ESTRADIOL: 0.0375 mg/day, 0.075 mg/day, 0.025 mg/day Film, extended release; transdermal Discontinued ESTRADIOL: 0.05 mg/day, 0.1 mg/day Film, extended release; transdermal Prescription

Discontinued

020323

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