Segesterone acetate
Identification
- Name
- Segesterone acetate
- Accession Number
- DB14583
- Description
Segesterone acetate is a steroidal progestin or synthetic progesterone and a 19-norprogesterone derivative with no CH3 group radical in position 6 1. In animal studies, segesterone acetate was shown to be one of the most potent progestins 3. It mediates progestational activity 100 times higher than that of progesterone 5. It is commonly sold under the brand names Nestorone and Elcometrine and serves as an active component in hormonal contraceptives. It is also used as a treatment for endometriosis in South American countries. Segesterone acetate binds selectively to progesterone receptors and not androgen receptors 2. Due to its rapid hepatic metabolism, segesterone acetate must be administered parenterally 3. Segesterone acetate is not an orally active compound, but it is proved to be a potent anti-ovulatory agent when given in implants, vaginal rings or percutaneous gel 3.
On August 10, 2018, Annovera™ containing segesterone acetate and ethinyl estradiol was granted approval by the U.S. Food and Drug Administration (FDA) as the first and only contraceptive that provides an entire year of protection against unintended pregnancy while entirely under a woman's control. According to the Center for Disease Control, more than 43 million women in the U.S. are at risk of unintended pregnancy, which may be associated with an elevated risk for improper prenatal care, premature and low-birth-weight infants, and physical and mental health risks 8. The introduction of this new contraceptive method offers an expansion of birth control options for women while maintaining high efficacy and acceptability similar to existing shorter-acting combined hormonal methods 2. In clinical trials, Annovera™ achieved a 97.3% success in pregnancy prevention 8. Annovera™ is administered as a vaginal ring that is in place for 21 days and removed for 7 days each cycle. As with other hormonal contraceptives, Annovera™ carries the risk for serious cardiovascular events.
- Type
- Small Molecule
- Groups
- Approved, Experimental, Investigational
- Structure
Structure for Segesterone acetate (DB14583)
- Weight
- Average: 370.489
Monoisotopic: 370.214409446 - Chemical Formula
- C23H30O4
- Synonyms
- 16-Methylene-17-alpha-acetoxy-19-nor-4-pregnene-3,20-dione
- 17-Hydroxy-16-methylene-19-norpregn-4-ene-3,20-dione acetate
- Elcometrine
- Nestorone
- Segesterone acetate
- External IDs
- ST-1435
Pharmacology
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Segesterone acetate in combination with ethinyl estradiol is indicated for use by females of reproductive potential to prevent pregnancy as a combination hormonal contraceptive (CHC). It induces contraception for thirteen 28-day cycles (1 year) following vaginal administration. The vaginal system must remain in place continuously for 3 weeks (21 days) followed by a 1-week (7-day) vaginal system-free interval. The use in females with a body mass index of >29 kg/m^2 has not been adequately evaluated Label.
- Associated Therapies
- Contraindications & Blackbox Warnings
Contraindications & Blackbox WarningsWith our commercial data, access important information on dangerous risks, contraindications, and adverse effects.Our Blackbox Warnings cover Risks, Contraindications, and Adverse Effects- Pharmacodynamics
Segesterone acetate suppresses ovulation. In a Phase I randomized, placebo-controlled, randomized crossover study involving healthy adult female subjects, there was no clinically significant QTc interval prolongation following a single intravenous bolus dose of segesterone acetate Label. Segesterone acetate shows no androgenic, anabolic, or estrogenic activity 3. It also did not show uterotropic activity in ovariectomized rats 3. In the endometrial transformation test to assess the progestational activity, dose-dependent increases in both uterine weight was observed following subcutaneous administration of segesterone acetate 5.
- Mechanism of action
Segesterone acetate selectively binds to the progesterone receptor (PR), a transcription factor belonging to the nuclear receptor superfamily, where it acts as an agonist and transactivator 5. According to the findings from docking experiments, it adopts the same docking position within the PR ligand-binding domain (LBD) as progesterone but due to additional stabilizing contacts between 17α-acetoxy and 16-methylene groups and PR LBD, segesterone acetate display higher potency than progesterone 5. As with other progestins, segesterone acetate prevents ovulation by blocking the midcycle surge in luteinizing hormone (LH) secretion, thereby inhibiting the development of ovarian follicles 6. When used in combination with segesterone acetate, ethinyl estradiol potentiates the antigonadotropic of the progestin and prevents irregular shedding of the endometrium 6. Segesterone acetate lacks androgenic activity, and displayed binding affinity to androgen receptors that was 500- to 600-fold less than that of testosterone 4. It does not display binding affinity toward estrogen receptors 4. When the relative binding affinities of segesterone acetate to human steroid receptors were investigated in vitro, it was demonstrated that segesterone acetate binds to the glucocorticoid receptor 3. However, segesterone acetate did not exert any glucocorticoid activity in the in vivo assays showing no increase in liver glycogen and tyrosine transaminase TAT 3.
Target Actions Organism AProgesterone receptor agonistactivatorHumans NAndrogen receptor agonistHumans NGlucocorticoid receptor agonistHumans - Absorption
Contraceptive vaginal rings provided sustained release of contraceptive levels of segesterone acetate over 90 days in a pharmacokinetic study of healthy women 2. Following vaginal administration for up to 13 cycles, segesterone acetate was absorbed into systemic administration and reached the peak plasma concentration in 2 hours in Cycle 1, Cycle 3, and Cycle 13. Concentrations declined after time to reach plasma concentration (Tmax) and became more constant after 96 hours post-dose.Over subsequent cycles of use, the peak serum concentrations of segesterone acetate decreased. In Cycle 1, 3 and 13, the peak plasma concentrations were 1147, 363, and 294 pg/mL Label.
- Volume of distribution
The volume of distribution of segesterone acetate is 19.6 L/kg Label.
- Protein binding
Serum protein binding of segesterone acetate is approximately 95% and it displays negligible binding affinity for sex hormone-binding globulin (SHBG) Label.
- Metabolism
Segesterone acetate undergoes rapid metabolism and inactivation in the liver 5. Based on the findings in vitro, the major oxidative metabolites in the serum include 5α-dihydro- and 17α-hydroxy-5α-dihydro metabolites constitute about 50% of exposure relative to segesterone acetate. The metabolites are not pharmacologically active with EC50 to progesterone receptor 10-fold higher than that of the parent compound Label. It was shown that 3α, 5α-tetrahydrosegesterone acetate acts as an activator at the GABA-A receptors in the brain 5.
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- Route of elimination
In a pharmacokinetic study, approximately 81.4% and 7.62% of the subcutaneously-administered dose in rats was excreted via feces and urine, respectively Label.
- Half-life
The mean (SD) half life of segesterone acetate is 4.5 (3.4) hours Label.
- Clearance
No pharmacokinetic data available.
- Adverse Effects
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There have been no reports of serious ill effects from overdose of combination hormonal contraceptive use. Overdosage may cause withdrawal bleeding in females and nausea. In case of suspected overdose, all vaginal systems containing segesterone acetate should be removed and symptomatic treatment should be initiated Label.
In a 2-year carcinogenicity study in rats receiving segesterone acetate via subdermal implants, there was no drug-related increase in tumor incidence. In a 2-year intravaginal carcinogenicity study in mice, segesterone acetate gel produced an increased incidence of adenocarcinoma and lobular hyperplasia in the breast at a supratherapeutic dose of 30 mg/kg/day. Segesterone acetate was not shown to be mutagenic or clastogenic Label.
- Affected organisms
- Not Available
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of Segesterone acetate can be increased when it is combined with Abametapir. Acetaminophen The metabolism of Segesterone acetate can be increased when combined with Acetaminophen. Acetazolamide The metabolism of Segesterone acetate can be increased when combined with Acetazolamide. Acetohexamide The therapeutic efficacy of Acetohexamide can be decreased when used in combination with Segesterone acetate. Alpelisib The metabolism of Segesterone acetate can be increased when combined with Alpelisib. Aminoglutethimide The metabolism of Segesterone acetate can be increased when combined with Aminoglutethimide. Amobarbital The metabolism of Segesterone acetate can be increased when combined with Amobarbital. Amprenavir The metabolism of Segesterone acetate can be increased when combined with Amprenavir. Apalutamide The metabolism of Segesterone acetate can be increased when combined with Apalutamide. Aprepitant The serum concentration of Aprepitant can be decreased when it is combined with Segesterone acetate. 
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- Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of segesterone acetate. If coadministration is necessary, back up contraception should be used.
Products
Comprehensive & structured drug product infoFrom application numbers to product codes, connect different identifiers through our commercial datasets.Easily connect various identifiers back to our datasets- Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Annovera Segesterone acetate (103 mg/1) + Ethinylestradiol (17.4 mg/1) Ring Vaginal TherapeuticsMD, Inc. 2019-08-12 Not applicable US 
Annovera Segesterone acetate (103 mg/1) + Ethinylestradiol (17.4 mg/1) Ring Vaginal QPharma AB 2019-08-08 Not applicable US
Categories
- Drug Categories
- Adrenal Cortex Hormones
- Contraceptive Agents, Female
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Substrates
- Drug Implants
- Fused-Ring Compounds
- Hormonal Contraceptives for Systemic Use
- Intravaginal Contraceptives
- Norpregnanes
- Norpregnenes
- Norsteroids
- Reproductive Control Agents
- Steroids
- Classification
- Not classified
Chemical Identifiers
- UNII
- 9AMX4Q13CC
- CAS number
- 7759-35-5
- InChI Key
- CKFBRGLGTWAVLG-GOMYTPFNSA-N
- InChI
- InChI=1S/C23H30O4/c1-13-11-21-20-7-5-16-12-17(26)6-8-18(16)19(20)9-10-22(21,4)23(13,14(2)24)27-15(3)25/h12,18-21H,1,5-11H2,2-4H3/t18-,19+,20+,21-,22-,23-/m0/s1
- IUPAC Name
- (1R,3aS,3bR,9aR,9bS,11aS)-1-acetyl-11a-methyl-2-methylidene-7-oxo-1H,2H,3H,3aH,3bH,4H,5H,7H,8H,9H,9aH,9bH,10H,11H,11aH-cyclopenta[a]phenanthren-1-yl acetate
- SMILES
- [H][C@@]12CC(=C)[C@](OC(C)=O)(C(C)=O)[C@@]1(C)CC[C@]1([H])[C@@]3([H])CCC(=O)C=C3CC[C@@]21[H]
References
- General References
- Simmons KB, Kumar N, Plagianos M, Roberts K, Hoskin E, Han L, Alami M, Creasy G, Variano B, Merkatz R: Effects of concurrent vaginal miconazole treatment on the absorption and exposure of Nestorone(R) (segesterone acetate) and ethinyl estradiol delivered from a contraceptive vaginal ring: a randomized, crossover drug-drug interaction study. Contraception. 2018 Mar;97(3):270-276. doi: 10.1016/j.contraception.2017.10.010. Epub 2017 Oct 31. [PubMed:29097225]
- Jensen JT, Edelman AB, Chen BA, Archer DF, Barnhart KT, Thomas MA, Burke AE, Westhoff CL, Wan LS, Sitruk-Ware R, Kumar N, Variano B, Blithe DL: Continuous dosing of a novel contraceptive vaginal ring releasing Nestorone(R) and estradiol: pharmacokinetics from a dose-finding study. Contraception. 2018 May;97(5):422-427. doi: 10.1016/j.contraception.2018.01.012. Epub 2018 Feb 2. [PubMed:29409834]
- Sitruk-Ware R: Pharmacological profile of progestins. Maturitas. 2008 Sep-Oct;61(1-2):151-7. [PubMed:19434887]
- Kumar N, Koide SS, Tsong Y, Sundaram K: Nestorone: a progestin with a unique pharmacological profile. Steroids. 2000 Oct-Nov;65(10-11):629-36. [PubMed:11108869]
- Kumar N, Fagart J, Liere P, Mitchell SJ, Knibb AR, Petit-Topin I, Rame M, El-Etr M, Schumacher M, Lambert JJ, Rafestin-Oblin ME, Sitruk-Ware R: Nestorone(R) as a Novel Progestin for Nonoral Contraception: Structure-Activity Relationships and Brain Metabolism Studies. Endocrinology. 2017 Jan 1;158(1):170-182. doi: 10.1210/en.2016-1426. [PubMed:27824503]
- Rivera R, Yacobson I, Grimes D: The mechanism of action of hormonal contraceptives and intrauterine contraceptive devices. Am J Obstet Gynecol. 1999 Nov;181(5 Pt 1):1263-9. [PubMed:10561657]
- Prasad PV, Bashir M, Sitruk-Ware R, Kumar N: Single-dose pharmacokinetics of Nestorone, a potential female-contraceptive. Steroids. 2010 Mar;75(3):252-64. doi: 10.1016/j.steroids.2009.12.011. Epub 2010 Jan 11. [PubMed:20064539]
- FDA Approves Annovera (segesterone acetate and ethinyl estradiol) Vaginal Contraceptive System - Drugs.com [Link]
- External Links
- ChemSpider
- 97161
- 2055977
- ChEBI
- 135563
- ChEMBL
- CHEMBL3707377
- ZINC
- ZINC000005167230
- Wikipedia
- Segesterone_acetate
- FDA label
- Download (2.18 MB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Completed Prevention Contraception 2 2 Completed Prevention Contraception 1 2 Recruiting Other Healthy Volunteers / Male Contraception / Men 1 1 Completed Diagnostic Contraception 1 1 Completed Other Healthy Men / Healthy Women / Male Contraception / Product Transference 1 1 Completed Other Healthy Volunteers 1 1 Completed Prevention Contraception 1 1 Completed Treatment Antifungal Drug Adverse Reaction 1 1 Completed Treatment Contraception / Women 1 1 Completed Treatment Healthy Volunteers 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Ring Vaginal - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US10632066 No 2019-02-01 2039-02-01 US US10780047 No 2019-02-01 2039-02-01 US US10765628 No 2019-02-01 2039-02-01 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 173-177 FDA Label water solubility Insoluble FDA Label - Predicted Properties
Property Value Source Water Solubility 0.00231 mg/mL ALOGPS logP 2.52 ALOGPS logP 3.64 ChemAxon logS -5.2 ALOGPS pKa (Strongest Acidic) 17.46 ChemAxon pKa (Strongest Basic) -4.7 ChemAxon Physiological Charge 0 ChemAxon Hydrogen Acceptor Count 3 ChemAxon Hydrogen Donor Count 0 ChemAxon Polar Surface Area 60.44 Å2 ChemAxon Rotatable Bond Count 3 ChemAxon Refractivity 102.95 m3·mol-1 ChemAxon Polarizability 41.79 Å3 ChemAxon Number of Rings 4 ChemAxon Bioavailability 1 ChemAxon Rule of Five Yes ChemAxon Ghose Filter Yes ChemAxon Veber's Rule No ChemAxon MDDR-like Rule No ChemAxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- AgonistActivator
- 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
- Kumar N, Fagart J, Liere P, Mitchell SJ, Knibb AR, Petit-Topin I, Rame M, El-Etr M, Schumacher M, Lambert JJ, Rafestin-Oblin ME, Sitruk-Ware R: Nestorone(R) as a Novel Progestin for Nonoral Contraception: Structure-Activity Relationships and Brain Metabolism Studies. Endocrinology. 2017 Jan 1;158(1):170-182. doi: 10.1210/en.2016-1426. [PubMed:27824503]
- Sitruk-Ware R: Pharmacological profile of progestins. Maturitas. 2008 Sep-Oct;61(1-2):151-7. [PubMed:19434887]
- Kumar N, Koide SS, Tsong Y, Sundaram K: Nestorone: a progestin with a unique pharmacological profile. Steroids. 2000 Oct-Nov;65(10-11):629-36. [PubMed:11108869]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Agonist
- 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
- Kumar N, Koide SS, Tsong Y, Sundaram K: Nestorone: a progestin with a unique pharmacological profile. Steroids. 2000 Oct-Nov;65(10-11):629-36. [PubMed:11108869]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Agonist
- 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
- Sitruk-Ware R: Pharmacological profile of progestins. Maturitas. 2008 Sep-Oct;61(1-2):151-7. [PubMed:19434887]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- 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
Drug created on August 13, 2018 21:06 / Updated on February 21, 2021 18:54