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

3D

Download

MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Segesterone acetate (DB14583)

×

Close

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

External IDs

• ST-1435

Pharmacology

Indication

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

• Hormonal Contraception

Contraindications & Blackbox Warnings

Learn about our commercial Contraindications & Blackbox Warnings data.

Learn More

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	agonist activator	Humans
NAndrogen receptor	agonist	Humans
NGlucocorticoid receptor	agonist	Humans

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.

Hover over products below to view reaction partners

• Segesterone acetate
  • 5α-dihydrosegesterone acetate
  • 20α­-dihydrosegesterone acetate
  • 3α, 5α-tetrahydrosegesterone acetate
  • 3β, 5α-tetrahydrosegesterone acetate
  • 17α-deacetylsegesterone acetate
  • 4, 5-dihydro-17α-deacetylsegesterone acetate

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

Learn about our commercial Adverse Effects data.

Learn More

Toxicity

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
Unlock Additional Data
Abametapir	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.

Additional Data Available

Extended Description
Extended Description
Extended description of the mechanism of action and particular properties of each drug interaction.
Learn more
Severity
Severity
A severity rating for each drug interaction, from minor to major.
Learn more
Evidence Level
Evidence Level
A rating for the strength of the evidence supporting each drug interaction.
Learn more
Action
Action
An effect category for each drug interaction. Know how this interaction affects the subject drug.
Learn more

Food Interactions

• 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

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
Annovera	Segesterone acetate (103 mg/1) + Ethinylestradiol (17.4 mg/1)	Ring	Vaginal	QPharma AB	2019-08-08	Not applicable

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][[email protected]@]12CC(=C)[[email protected]](OC(C)=O)(C(C)=O)[[email protected]@]1(C)CC[[email protected]]1([H])[[email protected]@]3([H])CCC(=O)C=C3CC[[email protected]@]21[H]

References

General References

1. 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]
2. 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]
3. Sitruk-Ware R: Pharmacological profile of progestins. Maturitas. 2008 Sep-Oct;61(1-2):151-7. [PubMed:19434887]
4. 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]
5. 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]
6. 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]
7. 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]
8. FDA Approves Annovera (segesterone acetate and ethinyl estradiol) Vaginal Contraceptive System - Drugs.com [Link]

External Links

ChemSpider

97161

RxNav

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	Not Yet 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	Healthy Volunteers	1
1	Recruiting	Treatment	Contraception	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
Unlock Additional Data
US10632066	No	2019-02-01	2039-02-01

Additional Data Available

Filed On
Filed On
The date on which a patent was filed with the relevant government.
Learn more

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

×

Unlock Data

There is additional data available for commercial users including Adverse Effects, Contraindications, and Blackbox Warnings. Contact us to learn more about these and other features.

Learn more

Drug created on August 13, 2018 15:06 / Updated on June 12, 2020 10:53