Synthetic Conjugated Estrogens, A

Identification

Name
Synthetic Conjugated Estrogens, A
Accession Number
DB09317
Type
Small Molecule
Groups
Approved
Description

Synthetic conjugated estrogens A are composed of a blend of the following nine synthetic estrogenic substances: estrone sulfate, sodium equilin sulfate, sodium 17α-dihydroequilin sulfate, sodium 17α-estradiol sulfate, sodium 17β­ dihydroequilin sulfate, sodium 17α-dihydroequilenin sulfate, sodium 17β-dihydroequilenin sulfate, sodium equilenin sulfate, and sodium 17β-estradiol sulfate. This blend of nine estrogen derivatives are plant-derived forms of endogenous estrogens and contain many of the same compounds as the Conjugated Equine Estrogens (CEEs), although they are not considered to be equivalent. Available as the product Enjuvia (FDA), this combination of plant-derived estrogenic compounds is indicated for the treatment of moderate to severe vasomotor symptoms and vulvovaginal atrophy associated with menopause.

All estrogen products mimic the effects of endogenous estrogens in the body which are responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Estrogens act by binding to estrogen receptors on a wide variety of tissues in the body and modulating the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism. Prior to menopause, the primary source of estrogen is the ovarian follicle, which secretes 70-500 micrograms of estradiol daily, depending on the phase of the menstrual cycle. However, once a woman stops ovulating there is a sharp decline in the production of progesterone and estradiol by the ovaries and a consequent fluctuation in LH and FSH due to a lack of feedback control. This shift in hormone production is largely responsible for many of the symptoms experienced during and after menopause and includes hot flashes and other vasomotor symptoms, painful intercourse, vaginal dryness, and vulvovaginal atrophy. These symptoms are able to be reduced by replacing many of the hormones lost during and following menopause with synthetic or naturally occurring forms, in a therapy known as Hormone Replacement Therapy (HRT).

Pharmacologic estrogen products are available in a variety of formats. Although many of them contain several compounds in common (such as the estrogen derivatives sodium estrone sulfate and sodium equilin sulfate), they vary by their original source (such as horse-, human-, or plant-derived), and the remaining mixture of estrogenic derivatives. Conjugated Equine Estrogens (CEEs) are derived from the urine of pregnant mares and contain a blend of at least 10 estrogen derivatives. Marketed under the brand name Premarin, CEEs are the most frequently used form of conjugated estrogens. There is currently no generic form of CEEs available as a detailed analytical characterization of the active ingredients or of their estrogenic activity is not available at this time. Conjugated estrogens are also available in a plant-derived synthetic form that replicates the naturally occurring, horse-derived forms. Available as either "Synthetic Conjugated Estrogens, A" containing 9 estrogen derivatives (available as Cenestin) or as "Synthetic Conjugated Estrogens, B" containing 10 estrogen derivatives (available as Enjuvia), these products are isolated as precursors from yam or soy plants and then chemically modified to mimic the products available in their naturally occurring form.

Synonyms
  • Estrogens, Conjugated Synthetic A
Product Images
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
CenestinTablet, film coated0.3 mg/1OralTeva Women's Health2002-08-052016-04-30Us51285 0441 02 nlmimage10 253592ec
CenestinTablet, film coated0.45 mg/1OralPhysicians Total Care, Inc.2005-09-13Not applicableUs51285 0446 02 nlmimage10 38359c1c
CenestinTablet, film coated0.625 mg/1OralTeva Women's Health1999-05-122016-04-30Us51285 0442 02 nlmimage10 fe35ff1f
CenestinTablet, film coated1.25 mg/1OralPhysicians Total Care, Inc.2008-03-17Not applicableUs54868 143220180907 15195 vtczsh
CenestinTablet, film coated1.25 mg/1OralTeva Women's Health2000-03-202016-04-30Us51285 0444 02 nlmimage10 34359a0c
CenestinTablet, film coated0.45 mg/1OralTeva Women's Health2004-04-012015-04-30Us
CenestinTablet, film coated0.625 mg/1OralPhysicians Total Care, Inc.2003-08-11Not applicableUs54868 487920180907 15195 x32rrr
CenestinTablet, film coated0.9 mg/1OralTeva Women's Health1999-05-122016-04-30Us51285 0443 02 nlmimage10 213590dc
Categories
UNII
JM2621P2LS
CAS number
Not Available
Weight
Not Available
Chemical Formula
Not Available
InChI Key
Not Available
InChI
Not Available
IUPAC Name
Not Available
SMILES
Not Available

Pharmacology

Indication

For the treatment of moderate to severe vasomotor symptoms due to menopause and for treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause.

Associated Conditions
Pharmacodynamics
Not Available
Mechanism of action

All estrogen products mimic the effects of endogenous estrogens in the body which are responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Estrogens act by binding to estrogen receptors on a wide variety of tissues in the body and modulating the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism. Prior to menopause, the primary source of estrogen is the ovarian follicle, which secretes 70-500 micrograms of estradiol daily, depending on the phase of the menstrual cycle. However, once a woman stops ovulating there is a sharp decline in the production of progesterone and estradiol by the ovaries and a consequent fluctuation in LH and FSH due to a lack of feedback control. This shift in hormone production is largely responsible for many of the symptoms experienced during and after menopause and includes hot flashes and other vasomotor symptoms, painful intercourse, vaginal dryness, and vulvovaginal atrophy. These symptoms are able to be reduced by replacing many of the hormones lost during and following menopause with synthetic or naturally occurring forms, in a therapy known as Hormone Replacement Therapy (HRT).

TargetActionsOrganism
AEstrogen receptor alpha
ligand
Human
Absorption

Synthetic conjugated estrogens, A are soluble in water and are well absorbed from the gastrointestinal tract after release from the drug formulation. The Cenestin tablet releases the synthetic conjugated estrogens, A slowly over a period of several hours

Volume of distribution

The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs.

Protein binding

Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin.

Metabolism

Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women a significant portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4).

Route of elimination

Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.

Half life

The half life of baseline-corrected estrone and equilin was found to be 10.6 hr and 9.7 hr, respectively.

Clearance
Not Available
Toxicity
Not Available
Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
16-BromoepiandrosteroneThe serum concentration of 16-Bromoepiandrosterone can be increased when it is combined with Synthetic Conjugated Estrogens, A.
19-norandrostenedioneThe serum concentration of 19-norandrostenedione can be increased when it is combined with Synthetic Conjugated Estrogens, A.
5-androstenedioneThe serum concentration of 5-androstenedione can be increased when it is combined with Synthetic Conjugated Estrogens, A.
AceclofenacAceclofenac may increase the thrombogenic activities of Synthetic Conjugated Estrogens, A.
AcetaminophenAcetaminophen may decrease the excretion rate of Synthetic Conjugated Estrogens, A which could result in a higher serum level.
AcetazolamideThe metabolism of Synthetic Conjugated Estrogens, A can be decreased when combined with Acetazolamide.
Acetyl sulfisoxazoleThe metabolism of Synthetic Conjugated Estrogens, A can be decreased when combined with Acetyl sulfisoxazole.
AcyclovirAcyclovir may decrease the excretion rate of Synthetic Conjugated Estrogens, A which could result in a higher serum level.
Adefovir DipivoxilAdefovir Dipivoxil may decrease the excretion rate of Synthetic Conjugated Estrogens, A which could result in a higher serum level.
AlbendazoleThe metabolism of Synthetic Conjugated Estrogens, A can be decreased when combined with Albendazole.
Food Interactions
Not Available

References

General References
  1. Stevens RE, Roy R, Phelps KV: Evaluation of single- and multiple-dose pharmacokinetics of synthetic conjugated estrogens, A (Cenestin) tablets: a slow-release estrogen replacement product. J Clin Pharmacol. 2002 Mar;42(3):332-41. [PubMed:11865971]
  2. 14. (2015). In Pharmacology for Women’s Health. Jones & Bartlett Publishers.
External Links
PubChem Substance
347910437
ChEMBL
CHEMBL1201649
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Conjugated_estrogen
FDA label
Download (6.85 MB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentMenopausal Hot Flushes1
3CompletedTreatmentMenopause1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Tablet, film coatedOral0.3 mg/1
Tablet, film coatedOral0.45 mg/1
Tablet, film coatedOral0.625 mg/1
Tablet, film coatedOral0.9 mg/1
Tablet, film coatedOral1.25 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5908638No1995-07-262015-07-26Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
Not Available
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Classification
Not classified

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Ligand
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

Drug created on November 17, 2015 10:08 / Updated on October 01, 2018 14:49