Identification

Name
Estriol
Accession Number
DB04573  (EXPT01361, DB05375)
Type
Small Molecule
Groups
Approved, Investigational, Vet approved
Description

A hydroxylated metabolite of estradiol or estrone that has a hydroxyl group at C3-beta, 16-alpha, and 17-beta position. Estriol is a major urinary estrogen. During pregnancy, large amount of estriol is produced by the placenta. Isomers with inversion of the hydroxyl group or groups are called epiestriol. Though estriol is used as part of the primarily North American phenomenon of bioidentical hormone replacement therapy, it is not approved for use by the FDA or Health Canada. It is however available in the United States by prescription filled only by compounding pharmacies. It has also been approved and marketed throughout Europe and Asia for approximately 40 years for the treatment of post-menopausal hot flashes.

Structure
Thumb
Synonyms
  • (16alpha,17beta)-Estra-1,3,5(10)-triene-3,16,17-triol
  • (16α,17β)-estra-1,3,5(10)-triene-3,16,17-triol
  • 1,3,5(10)-Estratriene-3,16-alpha,17beta-triol
  • 16-alpha-Hydroxyestradiol
  • 16alpha-hydroxyestradiol
  • 16α-hydroxyestradiol
  • 3,16alpha,17beta-Trihydroxy-delta(1,3,5)-estratriene
  • Deuslon-a
  • Estriel
  • Estriol
  • Oestriol
  • Trihydroxyestrin
External IDs
16.ALPHA.-HYDROXYESTRADIOL
International/Other Brands
Aacifemine (Organon) / Colpoestriol (Temis-Lostalo) / Ovestin (Merck Sharp & Dohme) / Synapause E (Organon)
Categories
UNII
FB33469R8E
CAS number
50-27-1
Weight
Average: 288.3814
Monoisotopic: 288.172544634
Chemical Formula
C18H24O3
InChI Key
PROQIPRRNZUXQM-ZXXIGWHRSA-N
InChI
InChI=1S/C18H24O3/c1-18-7-6-13-12-5-3-11(19)8-10(12)2-4-14(13)15(18)9-16(20)17(18)21/h3,5,8,13-17,19-21H,2,4,6-7,9H2,1H3/t13-,14-,15+,16-,17+,18+/m1/s1
IUPAC Name
(1S,10R,11S,13R,14R,15S)-15-methyltetracyclo[8.7.0.0²,⁷.0¹¹,¹⁵]heptadeca-2(7),3,5-triene-5,13,14-triol
SMILES
[H][C@@]12C[C@@H](O)[C@H](O)[C@@]1(C)CC[C@]1([H])C3=C(CC[C@@]21[H])C=C(O)C=C3

Pharmacology

Indication

Used as a test to determine the general health of an unborn fetus.

Pharmacodynamics

Estriol (also oestriol) is one of the three main estrogens produced by the human body. It is only produced in significant amounts during pregnancy as it is made by the placenta. In pregnant women with multiple sclerosis (MS), estriol reduces the disease's symptoms noticeably, according to researchers at UCLA's Geffen Medical School.

Mechanism of action

Estriol levels can be measured to give an indication of the general health of the fetus. DHEA-S is produced by the adrenal cortex of the fetus. This is converted to estriol by the placenta. If levels of "unconjugated estriol" are abnormally low in a pregnant woman, this may indicate a problem with the development of the child. The drug interacts with a target cell receptor. When the estrogen receptor has bound its ligand it can enter the nucleus of the target cell, and regulate gene transcription which leads to formation of messenger RNA. The mRNA interacts with ribosomes to produce specific proteins that express the effect of estriol upon the target cell. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins and suppress follicle-stimulating hormone (FSH) from the anterior pituitary.

TargetActionsOrganism
AEstrogen receptor alpha
agonist
Human
UEstrogen receptor beta
agonist
Human
USex hormone-binding globulinNot AvailableHuman
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity

ORAL (LD50): Acute: >2000 mg/kg [Rat].

Affected organisms
  • Humans and other mammals
Pathways
PathwayCategory
Estrone MetabolismMetabolic
Estrone MetabolismMetabolic
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinEstriol may decrease the anticoagulant activities of (R)-warfarin.
(S)-WarfarinEstriol may decrease the anticoagulant activities of (S)-Warfarin.
3,5-diiodothyropropionic acidThe therapeutic efficacy of 3,5-diiodothyropropionic acid can be decreased when used in combination with Estriol.
4-hydroxycoumarinEstriol may decrease the anticoagulant activities of 4-hydroxycoumarin.
AbaloparatideThe therapeutic efficacy of Abaloparatide can be decreased when used in combination with Estriol.
AbciximabEstriol may decrease the anticoagulant activities of Abciximab.
AbemaciclibThe serum concentration of Estriol can be increased when it is combined with Abemaciclib.
AbituzumabEstriol may increase the thrombogenic activities of Abituzumab.
AcebutololThe serum concentration of Acebutolol can be decreased when it is combined with Estriol.
AceclofenacAceclofenac may increase the thrombogenic activities of Estriol.
Food Interactions
Not Available

References

Synthesis Reference

James V. Freeman, Gary M. Johnson, "Synthesis of 6.alpha.-functionalized estriol haptens and protein conjugates thereof." U.S. Patent US5902888, issued June, 1973.

US5902888
General References
  1. Soldan SS, Alvarez Retuerto AI, Sicotte NL, Voskuhl RR: Immune modulation in multiple sclerosis patients treated with the pregnancy hormone estriol. J Immunol. 2003 Dec 1;171(11):6267-74. [PubMed:14634144]
  2. Trimesta [Link]
External Links
Human Metabolome Database
HMDB0000153
KEGG Drug
D00185
KEGG Compound
C05141
PubChem Compound
5756
PubChem Substance
46505881
ChemSpider
5553
BindingDB
50410506
ChEBI
27974
ChEMBL
CHEMBL193482
Therapeutic Targets Database
DAP001019
PharmGKB
PA164769104
HET
ESL
Wikipedia
Estriol
ATC Codes
G03CC06 — EstriolG03CA04 — Estriol
PDB Entries
1x8v / 3q95
MSDS
Download (75.9 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedPreventionVaginal Health1
1CompletedTreatmentMenopause1
1RecruitingPreventionPregnancy1
1RecruitingTreatmentAtrophic Vaginitis1
1RecruitingTreatmentMenopause / Painful Intercourse / Sexual Dysfunctions1
2CompletedTreatmentHereditary Haemorrhagic Telangiectasia (HHT) / Nasal Bleeding1
2CompletedTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)1
2CompletedTreatmentVulvovaginal Atrophy2
2RecruitingTreatmentMultiple Sclerosis, Primary Progressive / Relapsing Remitting Multiple Sclerosis (RRMS) / Secondary Progressive Multiple Sclerosis (SPMS)1
2TerminatedTreatmentMenopause1
2Unknown StatusDiagnosticPremenstrual Syndrome1
2Unknown StatusTreatmentPremenstrual Syndrome1
3CompletedTreatmentVulvovaginal Atrophy1
3TerminatedTreatmentAtrophic Vaginitis1
4CompletedSupportive CareAtrophic Vaginitis / Endometrial Hyperplasia / Pelvic Organ Prolapse (POP)1
4CompletedTreatmentVulvovaginal Atrophy1
4Not Yet RecruitingTreatmentGenital Prolapse1
Not AvailableRecruitingNot AvailableLocalized Provoked Vulvodynia1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Jiangxi Yuneng Pharmchem Co. Ltd.
  • NutriScience Innovations LLC
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)82-86Organon Laboratories Limited, England; British Patent 879,014; October 4, 1961.
logP2.45HANSCH,C ET AL. (1995)
Predicted Properties
PropertyValueSource
Water Solubility0.119 mg/mLALOGPS
logP2.54ALOGPS
logP2.67ChemAxon
logS-3.4ALOGPS
pKa (Strongest Acidic)10.33ChemAxon
pKa (Strongest Basic)-3.2ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area60.69 Å2ChemAxon
Rotatable Bond Count0ChemAxon
Refractivity81.27 m3·mol-1ChemAxon
Polarizability33.07 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9966
Blood Brain Barrier+0.7057
Caco-2 permeable+0.7591
P-glycoprotein substrateSubstrate0.7862
P-glycoprotein inhibitor INon-inhibitor0.9208
P-glycoprotein inhibitor IINon-inhibitor0.9805
Renal organic cation transporterNon-inhibitor0.8619
CYP450 2C9 substrateNon-substrate0.7536
CYP450 2D6 substrateNon-substrate0.7993
CYP450 3A4 substrateSubstrate0.6892
CYP450 1A2 substrateNon-inhibitor0.6618
CYP450 2C9 inhibitorNon-inhibitor0.9399
CYP450 2D6 inhibitorNon-inhibitor0.9619
CYP450 2C19 inhibitorNon-inhibitor0.7086
CYP450 3A4 inhibitorNon-inhibitor0.8932
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9152
Ames testNon AMES toxic0.9133
CarcinogenicityNon-carcinogens0.9147
BiodegradationNot ready biodegradable0.9811
Rat acute toxicity1.9758 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.948
hERG inhibition (predictor II)Inhibitor0.7684
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Download (2.96 KB)
Spectra
SpectrumSpectrum TypeSplash Key
GC-MS Spectrum - GC-MS (3 TMS)GC-MSsplash10-005a-1983000000-2f46d0d29b48132f7670
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
GC-MS Spectrum - EI-BGC-MSsplash10-000i-4970000000-1aa2bbf3f32fd687c37d
GC-MS Spectrum - GC-MSGC-MSsplash10-005a-1983000000-2f46d0d29b48132f7670
Mass Spectrum (Electron Ionization)MSsplash10-000i-3950000000-c2f0781bc5056d66aaf5
MS/MS Spectrum - Quattro_QQQ 10V, PositiveLC-MS/MSsplash10-0a4i-5900000000-2102cb581ac98fea87b0
MS/MS Spectrum - Quattro_QQQ 25V, PositiveLC-MS/MSsplash10-0a4i-1900000000-1fab12be883127f80c67
MS/MS Spectrum - Quattro_QQQ 40V, PositiveLC-MS/MSsplash10-0a4i-5900000000-2102cb581ac98fea87b0
MS/MS Spectrum - EI-B (JEOL JMS-01-SG-2) , PositiveLC-MS/MSsplash10-000i-4970000000-1aa2bbf3f32fd687c37d
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
MS/MS Spectrum - Linear Ion Trap , negativeLC-MS/MSsplash10-000i-0390000000-891430228022fb330b42
1H NMR Spectrum1D NMRNot Applicable
[1H,13C] 2D NMR Spectrum2D NMRNot Applicable

Taxonomy

Description
This compound belongs to the class of organic compounds known as estrogens and derivatives. These are steroids with a structure containing a 3-hydroxylated estrane.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Steroids and steroid derivatives
Sub Class
Estrane steroids
Direct Parent
Estrogens and derivatives
Alternative Parents
3-hydroxysteroids / 17-hydroxysteroids / 16-alpha-hydroxysteroids / Phenanthrenes and derivatives / Tetralins / 1-hydroxy-2-unsubstituted benzenoids / Secondary alcohols / Cyclic alcohols and derivatives / 1,2-diols / Hydrocarbon derivatives
Substituents
Estrogen-skeleton / 3-hydroxysteroid / 17-hydroxysteroid / 16-hydroxysteroid / 16-alpha-hydroxysteroid / Hydroxysteroid / Phenanthrene / Tetralin / 1-hydroxy-2-unsubstituted benzenoid / Benzenoid
Molecular Framework
Aromatic homopolycyclic compounds
External Descriptors
17beta-hydroxy steroid, 3-hydroxy steroid, 16alpha-hydroxy steroid (CHEBI:27974) / C18 steroids (estrogens) and derivatives, Estrane and derivatives, Estrogens (C05141) / C18 steroids (estrogens) and derivatives (LMST02010003)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Zinc ion binding
Specific Function
Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissu...
Gene Name
ESR1
Uniprot ID
P03372
Uniprot Name
Estrogen receptor
Molecular Weight
66215.45 Da
References
  1. Sasson S: Equilibrium binding analysis of estrogen agonists and antagonists: relation to the activation of the estrogen receptor. Pathol Biol (Paris). 1991 Jan;39(1):59-69. [PubMed:2011412]
  2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Agonist
General Function
Zinc ion binding
Specific Function
Nuclear hormone receptor. Binds estrogens with an affinity similar to that of ESR1, and activates expression of reporter genes containing estrogen response elements (ERE) in an estrogen-dependent m...
Gene Name
ESR2
Uniprot ID
Q92731
Uniprot Name
Estrogen receptor beta
Molecular Weight
59215.765 Da
References
  1. Mishra RG, Stanczyk FZ, Burry KA, Oparil S, Katzenellenbogen BS, Nealen ML, Katzenellenbogen JA, Hermsmeyer RK: Metabolite ligands of estrogen receptor-beta reduce primate coronary hyperreactivity. Am J Physiol Heart Circ Physiol. 2006 Jan;290(1):H295-303. Epub 2005 Sep 30. [PubMed:16199482]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Androgen binding
Specific Function
Functions as an androgen transport protein, but may also be involved in receptor mediated processes. Each dimer binds one molecule of steroid. Specific for 5-alpha-dihydrotestosterone, testosterone...
Gene Name
SHBG
Uniprot ID
P04278
Uniprot Name
Sex hormone-binding globulin
Molecular Weight
43778.755 Da
References
  1. Hong H, Branham WS, Ng HW, Moland CL, Dial SL, Fang H, Perkins R, Sheehan D, Tong W: Human sex hormone-binding globulin binding affinities of 125 structurally diverse chemicals and comparison with their binding to androgen receptor, estrogen receptor, and alpha-fetoprotein. Toxicol Sci. 2015 Feb;143(2):333-48. doi: 10.1093/toxsci/kfu231. Epub 2014 Oct 27. [PubMed:25349334]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent transport of organic anions such as sulfobromophthalein (BSP) and conjugated (taurocholate) and unconjugated (cholate) bile acids (By similarity). Selectively inhibit...
Gene Name
SLCO1A2
Uniprot ID
P46721
Uniprot Name
Solute carrier organic anion transporter family member 1A2
Molecular Weight
74144.105 Da
References
  1. Kanai N, Lu R, Bao Y, Wolkoff AW, Vore M, Schuster VL: Estradiol 17 beta-D-glucuronide is a high-affinity substrate for oatp organic anion transporter. Am J Physiol. 1996 Feb;270(2 Pt 2):F326-31. [PubMed:8779894]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inducer
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Kim WY, Benet LZ: P-glycoprotein (P-gp/MDR1)-mediated efflux of sex-steroid hormones and modulation of P-gp expression in vitro. Pharm Res. 2004 Jul;21(7):1284-93. [PubMed:15290871]

Drug created on September 07, 2007 15:04 / Updated on November 02, 2018 06:01