Synthetic Conjugated Estrogens, A

Identification

Summary

Synthetic Conjugated Estrogens, A is a mixture of estrogens used to treat a variety of postmenopausal symptoms, including vaginal atrophy and dyspareunia.

Brand Names

Cenestin

Generic Name

Synthetic Conjugated Estrogens, A

DrugBank Accession Number

DB09317

Background

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.

Type

Small Molecule

Groups

Approved

Synonyms

• Estrogens, Conjugated Synthetic A

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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.

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Management of	Moderate vulvovaginal atrophy		••••••••••••
Management of	Moderate vasomotor symptoms		••••••••••••
Management of	Severe vulvovaginal atrophy		••••••••••••
Management of	Severe vasomotor symptoms		••••••••••••

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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).

Target	Actions	Organism
AEstrogen receptor alpha	ligand	Humans

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

Adverse Effects

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Toxicity

Not Available

Pathways

Not Available

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Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">

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
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Abacavir	Abacavir may decrease the excretion rate of Synthetic Conjugated Estrogens, A which could result in a higher serum level.
Abametapir	The serum concentration of Synthetic Conjugated Estrogens, A can be increased when it is combined with Abametapir.
Abciximab	Synthetic Conjugated Estrogens, A may decrease the anticoagulant activities of Abciximab.
Aceclofenac	Aceclofenac may increase the thrombogenic activities of Synthetic Conjugated Estrogens, A.
Acemetacin	Acemetacin may decrease the excretion rate of Synthetic Conjugated Estrogens, A which could result in a higher serum level.

Food Interactions

• Avoid grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum concentration of synthetic conjugated estrogens, A.
• Avoid St. John's Wort. This herb induces CYP3A4 metabolism and may reduce serum levels of synthetic conjugated estrogens, A.

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Product Images

PreviousNext

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Cenestin	Tablet, film coated	1.25 mg/1	Oral	Teva Women's Health	2000-03-20	2016-04-30
Cenestin	Tablet, film coated	0.45 mg/1	Oral	Teva Women's Health	2004-04-01	2015-04-30
Cenestin	Tablet, film coated	0.625 mg/1	Oral	Physicians Total Care, Inc.	2003-08-11	Not applicable
Cenestin	Tablet, film coated	0.9 mg/1	Oral	Teva Women's Health	1999-05-12	2016-04-30
Cenestin	Tablet, film coated	0.3 mg/1	Oral	Teva Women's Health	2002-08-05	2016-04-30

Categories

Drug Categories

• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 Substrates
• Drugs that are Mainly Renally Excreted
• Estrogens
• Gonadal Hormones
• Gonadal Steroid Hormones
• Hormones
• Hormones, Hormone Substitutes, and Hormone Antagonists
• Thyroxine-binding globulin inducers

Classification

Not classified

Affected organisms

Not Available

Chemical Identifiers

UNII

JM2621P2LS

CAS number

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. [Article]
2. 14. (2015). In Pharmacology for Women’s Health. Jones & Bartlett Publishers.

External Links

PubChem Substance

347910437

RxNav

253166

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 Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
3	Completed	Treatment	Hot Flashes	1
3	Completed	Treatment	Menopause	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet, film coated	Oral	0.3 mg/1
Tablet, film coated	Oral	0.45 mg/1
Tablet, film coated	Oral	0.625 mg/1
Tablet, film coated	Oral	0.9 mg/1
Tablet, film coated	Oral	1.25 mg/1

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US5908638	No	1999-06-01	2015-07-26

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

Chromatographic Properties

Collision Cross Sections (CCS)

Not Available

Targets

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Details1. Estrogen receptor alpha

Kind

Protein

Organism

Humans

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

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Drug created at November 17, 2015 17:08 / Updated at June 12, 2020 16:52