Identification

Name
Gestrinone
Accession Number
DB11619
Type
Small Molecule
Groups
Approved
Description

Gestrinone, also known as ethylnorgestrienone, is a synthetic steroid of the 19-nortestosterone group that is marketed in Europe, Australia, and Latin America, though not the United States or Canada, and is used primarily in the treatment of endometriosis.

Gestrinone was developed in the early 1970s and was tested clinically as a weekly oral contraceptive in Europe and North America. Without significant advantages over other oral contraceptives and with its high cost, gestrinone was no longer used after the Stage II clinical trials. However, from 1982 this drug attracted increased interest due to significant therapeutic effects in the treatment endometriosis. Under different endocrine conditions, gestrinone possesses estrogenic, progestational, androgenic, antiestrogenic and antiprogesterone actions [7].

Structure
Thumb
Synonyms
  • Ethylnorgestrienone
External IDs
A 46 745 / A-46745 / R 2323 / R-2323 / RU 2323
International/Other Brands
Dimetriose / Dimetrose / Nemestran
Categories
UNII
1421533RCM
CAS number
16320-04-0
Weight
Average: 308.4141
Monoisotopic: 308.177630012
Chemical Formula
C21H24O2
InChI Key
BJJXHLWLUDYTGC-ANULTFPQSA-N
InChI
InChI=1S/C21H24O2/c1-3-20-11-9-17-16-8-6-15(22)13-14(16)5-7-18(17)19(20)10-12-21(20,23)4-2/h2,9,11,13,18-19,23H,3,5-8,10,12H2,1H3/t18-,19+,20+,21+/m1/s1
IUPAC Name
(10S,11S,14R,15S)-15-ethyl-14-ethynyl-14-hydroxytetracyclo[8.7.0.0²,⁷.0¹¹,¹⁵]heptadeca-1,6,16-trien-5-one
SMILES
[H][C@@]12CC[C@@](O)(C#C)[C@@]1(CC)C=CC1=C3CCC(=O)C=C3CC[C@@]21[H]

Pharmacology

Indication

Endometriosis with or without accompanying sterility. Treatment is limited to a single course of 6 months duration per lifetime [10, 11].

Pharmacodynamics

Gestrinone is a synthetic steroidal hormone which has androgenic, anti-estrogenic and anti-progestogenic properties [10]. The findings of several studies suggest that gestrinone is as effective as danazol in the treatment of infertility associated with endometriosis and is better tolerated, in terms of adverse effects [1, 2].

Gestrinone has moderate anti-estrogen, and anti-gonadal properties, which can lead to increased concentrations of free testosterone, and decrease the level of sex hormone-binding globulin, suppress the FSH and LH hormone peak levels and decrease the LH mean to reduce estrogen levels. In addition, gestrinone has a direct effect on the endometrium and ectopic endometrial receptors, which have the roles of anti-progesterone and anti-estrogen effects lead to endometrial and ectopic endometrial atrophy to achieve therapeutic effects [8].

Gestrinone inhibits the release of pituitary gonadotropins. The effect on ovarian hormone secretion results in the atrophy of endometrial tissue, resulting in the regression of endometriosis. Gestrinone is structurally related to norgestrel and possesses some androgenic and progestogenic activity. However, the gestrinone has an antiprogesterone effect on endometrial tissue [8].

The effect of oral gestrinone, 2.5 mg biweekly for 6 months, was studied in a group of 11 women with mild or moderate endometriosis laparoscopically confirmed. Painful symptoms were alleviated in all patients within 8 weeks from the start of treatment. Gonadotropins, prolactin (PRL) 17 beta-estradiol (17 beta-E2), estrone (E1), progesterone (P), androstenedione (A), and dehydroepiandrosterone sulfate (DHEA-S) remained in the physiological follicular phase range [4].

Total testosterone (TT) and sex hormone-binding globulin (SHBG) decreased, and free testosterone (FT) slightly increased. Metabolic studies showed a decrease in total triglyceride level, very low-density lipoprotein (VLDL) triglycerides, and high-density lipoprotein (HDL) and VLDL cholesterol [4].

Low-density lipoprotein cholesterol and apoprotein B were found to be increased during gestrinone therapy. It can be extrapolated that gestrinone possesses antiestrogenic, androgenic, and progestogenic effects at therapeutic dosages both by acting on both central and peripheral steroid receptors [4].

Mechanism of action

Gestrinone has weak agonist activity on progesterone receptors in the rabbit endometrium and progesterone antagonist activity in various other pharmacological test systems. In addition, it has moderate agonist activity on prostatic androgen receptors in vitro. In several in vivo experiments, this activity was found to be low [11].

The primary action of gestrinone is on the hypothalamic-pituitary axis where it inhibits gonadotrophin release with a weak inhibitory effect on its synthesis. It also possesses anti-estrogen activity. The suppression of the ovular gonadotrophin peak is observed after the first month of treatment; the resulting decline in ovarian hormone secretion rapidly leads to endometrial atrophy. Aside from its central action, gestrinone also has anti-progesterone activity on cell receptors in both endometrium and extra-uterine ectopic implants. Gestrinone has no direct estrogen and/or uterotrophic effects [11].

A study was done to examine the efficacy of gestrinone in emergency contraception. The data from the study suggest that the mechanism of action of gestrinone used for the purposes of emergency contraception is likely the inhibition of implantation by acting on the endometrium as opposed to the inhibition of ovulation [5].

TargetActionsOrganism
USex hormone-binding globulin
antagonist
Human
UProgesterone receptor
antagonist
agonist
Human
UGlucocorticoid receptor
antagonist
Human
UAndrogen receptor
antagonist
Human
UGonadotropin-releasing hormone receptor
antagonist
Human
UEstrogen receptor alpha
antagonist
agonist
Human
Absorption

The oral absorption of gestrinone is 30% ±30 [11].

Volume of distribution

67 L [11]

Protein binding
Not Available
Metabolism

Gestrinone undergoes hydroxylation in the liver. Gestrinone is actively metabolized in the liver, mainly by hydroxylation, to conjugated metabolites 16b-hydroxy,13-ethyl (1-OH) and D-homo gestrinone. In vitro studies have shown that the metabolites are active but weaker than the unchanged drug [6, 9, 11].

Route of elimination

About 40-45% of a dose is excreted in the urine and 30-35% in the feces [11].

Half life

Plasma half-life is 24 hr [6].

Clearance

Renal Excretion accounts for < 1 % [6].

Toxicity

Many of gestrinone's adverse effects occur due to its androgenic activity. These effects include acne, seborrhea, hirsutism, weight gain and deepening of the voice. Most patients develop at least one adverse event while taking this drug. This is because the drug is embryotoxic in some animals and may also cause masculinization of a female fetus. Gestrinone significantly reduces HDL concentrations [8].

It is advisable to monitor liver transaminases and cholesterol levels in hyperlipidemic patients, as well as glucose in diabetic patients. Gestrinone has shown to decrease in the concentration of thyroid-binding globulin. Therefore, a decrease in serum total thyroxine levels is commonly observed. This is without clinical significance as free thyroxine levels and thyroid-stimulating hormone levels remain within the normal reference range [11].

Affected organisms
  • Humans
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinGestrinone may decrease the anticoagulant activities of (R)-warfarin.
(S)-WarfarinGestrinone may decrease the anticoagulant activities of (S)-Warfarin.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Gestrinone.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Gestrinone.
5-androstenedioneThe metabolism of Gestrinone can be decreased when combined with 5-androstenedione.
6-Deoxyerythronolide BThe metabolism of Gestrinone can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Gestrinone.
7-ethyl-10-hydroxycamptothecinThe metabolism of Gestrinone can be decreased when combined with 7-ethyl-10-hydroxycamptothecin.
9-aminocamptothecinThe metabolism of 9-aminocamptothecin can be decreased when combined with Gestrinone.
AbataceptThe metabolism of Gestrinone can be increased when combined with Abatacept.
Food Interactions
Not Available

References

General References
  1. Fedele L, Bianchi S, Viezzoli T, Arcaini L, Candiani GB: Gestrinone versus danazol in the treatment of endometriosis. Fertil Steril. 1989 May;51(5):781-5. [PubMed:2523321]
  2. Presl J, Laitl J, Pilka L, Ventruba P: [Gestrinone in the therapy of sterility due to endometriosis]. Cesk Gynekol. 1992 Oct;57(8):401-7. [PubMed:1473163]
  3. Wang Q, Wu Z, Wang Y, Luo G, Wu E, Gao X: Determination of gestrinone in human serum by liquid chromatography--electrospray tandem mass spectrometry. J Chromatogr B Biomed Sci Appl. 2000 Sep 15;746(2):151-9. [PubMed:11076067]
  4. Venturini PL, Bertolini S, Brunenghi MC, Daga A, Fasce V, Marcenaro A, Cimato M, De Cecco L: Endocrine, metabolic, and clinical effects of gestrinone in women with endometriosis. Fertil Steril. 1989 Oct;52(4):589-95. [PubMed:2806598]
  5. Gao X, Wu E, Chen G: Mechanism of emergency contraception with gestrinone: a preliminary investigation. Contraception. 2007 Sep;76(3):221-7. doi: 10.1016/j.contraception.2007.05.089. Epub 2007 Jul 26. [PubMed:17707720]
  6. Gestrinone [Link]
  7. Gestrinone Pub Chef [Link]
  8. Therapeutic effects of mifepristone combined with Gestrinone on patients with endometriosis [Link]
  9. Australian Gestrinone Prescriber Article [Link]
  10. Gestrinone MIMS label [Link]
  11. Approved Product Information, Dimetriose [Link]
  12. Evolution of medical treatment for endometriosis: back to the roots? [Link]
  13. Gestrinone [Link]
External Links
Human Metabolome Database
HMDB0002720
KEGG Drug
D04317
PubChem Compound
27812
PubChem Substance
347828012
ChemSpider
25877
BindingDB
50423515
ChEBI
89642
ChEMBL
CHEMBL1868702
Wikipedia
Gestrinone
ATC Codes
G03XA02 — Gestrinone

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)150-152http://www.lookchem.com/Gestrinone/
boiling point (°C)507.638http://www.lookchem.com/Gestrinone/
Predicted Properties
PropertyValueSource
Water Solubility0.00969 mg/mLALOGPS
logP3.39ALOGPS
logP2.85ChemAxon
logS-4.5ALOGPS
pKa (Strongest Acidic)17.88ChemAxon
pKa (Strongest Basic)-1.5ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area37.3 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity93.73 m3·mol-1ChemAxon
Polarizability35.65 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
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

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-oxosteroids / 17-hydroxysteroids / Cyclohexenones / Ynones / Tertiary alcohols / Cyclic alcohols and derivatives / Acetylides / Organic oxides / Hydrocarbon derivatives
Substituents
Estrogen-skeleton / 3-oxosteroid / Hydroxysteroid / Oxosteroid / 17-hydroxysteroid / Cyclohexenone / Ynone / Cyclic alcohol / Tertiary alcohol / Ketone
Molecular Framework
Aliphatic homopolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Antagonist
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. Gestrinone [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Antagonist
Agonist
General Function
Zinc ion binding
Specific Function
The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Progesterone receptor ...
Gene Name
PGR
Uniprot ID
P06401
Uniprot Name
Progesterone receptor
Molecular Weight
98979.96 Da
References
  1. Gestrinone [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Antagonist
General Function
Zinc ion binding
Specific Function
Receptor for glucocorticoids (GC). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modula...
Gene Name
NR3C1
Uniprot ID
P04150
Uniprot Name
Glucocorticoid receptor
Molecular Weight
85658.57 Da
References
  1. Gestrinone [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Antagonist
General Function
Zinc ion binding
Specific Function
Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Transcription ...
Gene Name
AR
Uniprot ID
P10275
Uniprot Name
Androgen receptor
Molecular Weight
98987.9 Da
References
  1. Gestrinone [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Antagonist
General Function
Peptide binding
Specific Function
Receptor for gonadotropin releasing hormone (GnRH) that mediates the action of GnRH to stimulate the secretion of the gonadotropic hormones luteinizing hormone (LH) and follicle-stimulating hormone...
Gene Name
GNRHR
Uniprot ID
P30968
Uniprot Name
Gonadotropin-releasing hormone receptor
Molecular Weight
37730.355 Da
References
  1. Gestrinone [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Antagonist
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

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Karalliedde L., Clarke S., Collignon U. and Karalliedde J. (2010). Adverse drug interactions: a handbook for prescribers. Taylor and Francis group.

Drug created on August 26, 2016 09:51 / Updated on November 02, 2018 07:13