Esterified estrogens

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Esterified estrogens
Estrone sulfate.svg
Estrone sulfate, the primary active component in esterified estrogens (constitutes about 75 to 85% of total content).
Equilin sulfate.svg
Equilin sulfate, the second most major active component in esterified estrogens (constitutes about 6 to 16% of total content).
Combination of
Sodium estrone sulfate Estrogen
Sodium equilin sulfate Estrogen
Clinical data
Trade names Estratab, Menest, others
Other namesEsterified oestrogens; EEs; Esterified equine estrogens; Esterified equine oestrogens; EEEs
Routes of
administration
By mouth [1]
Drug class Estrogen
ATC code
  • None
Legal status
Legal status
Identifiers
PubChem SID
DrugBank
UNII

Esterified estrogens (EEs), sold under the brand names Estratab and Menest among others, is an estrogen medication which is used hormone therapy for menopausal symptoms and low sex hormone levels in women, to treat breast cancer in both women and men, and to treat prostate cancer in men. [3] [4] [5] [6] [7] It is formulated alone or in combination with methyltestosterone. [3] [4] It is taken by mouth. [1]

Contents

Side effects of EEs include nausea, breast tension, edema, and breakthrough bleeding among others. [8] It is an estrogen, or an agonist of the estrogen receptors, the biological target of estrogens like estradiol. [5] [3] [4] EEs are a prodrug mainly of estradiol and to a lesser extent of equilin. [5]

EEs were introduced for medical use by 1970. [9] They are available in only a few countries, such as Chile and the United States. [3] They have also been marketed in Argentina and Switzerland in the past. [3]

Medical uses

EEs are used in hormone therapy for menopausal symptoms, female hypogonadism, ovariectomy, and primary ovarian failure and in the treatment of breast cancer and prostate cancer. [4] [10]

Estrogen dosages for menopausal hormone therapy
Route/formEstrogenLowStandardHigh
Oral Estradiol 0.5–1 mg/day1–2 mg/day2–4 mg/day
Estradiol valerate 0.5–1 mg/day1–2 mg/day2–4 mg/day
Estradiol acetate 0.45–0.9 mg/day0.9–1.8 mg/day1.8–3.6 mg/day
Conjugated estrogens 0.3–0.45 mg/day0.625 mg/day0.9–1.25 mg/day
Esterified estrogens0.3–0.45 mg/day0.625 mg/day0.9–1.25 mg/day
Estropipate 0.75 mg/day1.5 mg/day3 mg/day
Estriol 1–2 mg/day2–4 mg/day4–8 mg/day
Ethinylestradiol a2.5–10 μg/day5–20 μg/day
Nasal spray Estradiol 150 μg/day300 μg/day600 μg/day
Transdermal patch Estradiol 25 μg/dayb50 μg/dayb100 μg/dayb
Transdermal gel Estradiol 0.5 mg/day1–1.5 mg/day2–3 mg/day
Vaginal Estradiol 25 μg/day
Estriol 30 μg/day0.5 mg 2x/week0.5 mg/day
IM Tooltip Intramuscular or SC injection Estradiol valerate 4 mg 1x/4 weeks
Estradiol cypionate 1 mg 1x/3–4 weeks3 mg 1x/3–4 weeks5 mg 1x/3–4 weeks
Estradiol benzoate 0.5 mg 1x/week1 mg 1x/week1.5 mg 1x/week
SC implant Estradiol 25 mg 1x/6 months50 mg 1x/6 months100 mg 1x/6 months
Footnotes:a = No longer used or recommended, due to health concerns. b = As a single patch applied once or twice per week (worn for 3–4 days or 7 days), depending on the formulation. Note: Dosages are not necessarily equivalent. Sources: See template.

Available forms

EEs are available in the form of 0.3 mg, 0.625 mg, 1.25 mg, and 2.5 mg oral tablets. [11] Estratest is a combination formulation of 1.25 mg EEs with 2.5 mg methyltestosterone. [12]

Side effects

Pharmacology

EEs consist primarily of sodium estrone sulfate and sodium equilin sulfate, and are very similar to conjugated estrogens (CEEs, conjugated equine estrogens; brand name Premarin). [5] [7] [13] [14] However, EEs and CEEs differ in the sources of their contents and in the percentages of their constituents; CEEs consist of approximately 53% sodium estrone sulfate and 25% sodium equilin sulfate, while EEs contain about 75 to 85% sodium estrone sulfate and 6 to 11% sodium equilin sulfate. [5] [3] [13] [15] [10] EEs have been found to produce similar serum levels of estrone and estradiol relative to CEEs, although with higher levels of estrone and lower levels of equilin. [5] [16] One study found that the risk of venous thrombosis may be less with EEs relative to CEEs. [15] [7]

Relative oral potencies of estrogens
Estrogen HF Tooltip Hot flashes VE Tooltip Vaginal epithelium UCa Tooltip Urinary calcium FSH Tooltip Follicle-stimulating hormone LH Tooltip Luteinizing hormone HDL Tooltip High-density lipoprotein-C Tooltip Cholesterol SHBG Tooltip Sex hormone-binding globulin CBG Tooltip Corticosteroid-binding globulin AGT Tooltip AngiotensinogenLiver
Estradiol 1.01.01.01.01.01.01.01.01.01.0
Estrone  ? ? ?0.30.3 ? ? ? ? ?
Estriol 0.30.30.10.30.30.2 ? ? ?0.67
Estrone sulfate  ?0.90.90.8–0.90.90.50.90.5–0.71.4–1.50.56–1.7
Conjugated estrogens 1.21.52.01.1–1.31.01.53.0–3.21.3–1.55.01.3–4.5
Equilin sulfate  ? ?1.0 ? ?6.07.56.07.5 ?
Ethinylestradiol 12015040060–150100400500–600500–6003502.9–5.0
Diethylstilbestrol  ? ? ?2.9–3.4 ? ?26–2825–37205.7–7.5
Sources and footnotes
Notes: Values are ratios, with estradiol as standard (i.e., 1.0). Abbreviations:HF = Clinical relief of hot flashes. VE = Increased proliferation of vaginal epithelium. UCa = Decrease in UCa Tooltip urinary calcium. FSH = Suppression of FSH Tooltip follicle-stimulating hormone levels. LH = Suppression of LH Tooltip luteinizing hormone levels. HDL-C, SHBG, CBG, and AGT = Increase in the serum levels of these liver proteins. Liver = Ratio of liver estrogenic effects to general/systemic estrogenic effects (hot flashes/gonadotropins). Sources: See template.
Protein binding and metabolic clearance rates of estrogens
Compound RBA Tooltip Relative binding affinity to
SHBG Tooltip sex hormone-binding globulin (%)
Bound to
SHBG (%)
Bound to
albumin (%)
Total
bound
(%)
MCR Tooltip Metabolic clearance rate
(L/day/m2)
17β-Estradiol 50376198580
Estrone 121680961050
Estriol 0.3191921110
Estrone sulfate 00999980
17β-Dihydroequilin 30 ? ? ?1250
Equilin 82613 ?2640
17β-Dihydroequilin sulfate 0 ? ? ?375
Equilin sulfate 0 ? ? ?175
Δ8-Estrone  ? ? ? ?1710
Notes:RBA for SHBG (%) is compared to 100% for testosterone. Sources: See template.

Chemistry

EEs contain synthetic, plant-derived estrogens and are manufactured from soybeans and yams. [6] [7]

History

EEs were introduced for medical use by 1970. [9]

Society and culture

Generic names

Estrogens, esterified is the generic name of the drug and its USP Tooltip United States Pharmacopeia. [17] It is also known as esterified estrogens. [4]

Brand names

EEs are marketed under a variety of brand names including Amnestrogen, Estragyn, Estratab, Evex, Femibel, Femogen, Menest, Neo Estrone Tab, and Oestro-Feminal alone, and, in combination with methyltestosterone, under the brand names Covaryx, Delitan, Eemt, Essian, Estratest, Feminova-T, Menogen, and Syntest. [3] [6] [4]

Availability

EEs are or have been marketed in Argentina, Chile, Switzerland, and the United States. [3] Both EEs and the combination of EEs and methyltestosterone are listed as being marketed only in Chile and the United States as of present. [3]

See also

Related Research Articles

<span class="mw-page-title-main">Estrone</span> Chemical compound

Estrone (E1), also spelled oestrone, is a steroid, a weak estrogen, and a minor female sex hormone. It is one of three major endogenous estrogens, the others being estradiol and estriol. Estrone, as well as the other estrogens, are synthesized from cholesterol and secreted mainly from the gonads, though they can also be formed from adrenal androgens in adipose tissue. Relative to estradiol, both estrone and estriol have far weaker activity as estrogens. Estrone can be converted into estradiol, and serves mainly as a precursor or metabolic intermediate of estradiol. It is both a precursor and metabolite of estradiol.

<span class="mw-page-title-main">Methyltestosterone</span> Chemical compound

Methyltestosterone, sold under the brand names Android, Metandren, and Testred among others, is an androgen and anabolic steroid (AAS) medication which is used in the treatment of low testosterone levels in men, delayed puberty in boys, at low doses as a component of menopausal hormone therapy for menopausal symptoms like hot flashes, osteoporosis, and low sexual desire in women, and to treat breast cancer in women. It is taken by mouth or held in the cheek or under the tongue.

<span class="mw-page-title-main">Equilin</span> Chemical compound

Equilin is a naturally occurring estrogen sex hormone found in horses as well as a medication. It is one of the estrogens present in the estrogen mixtures known as conjugated estrogens and esterified estrogens. CEEs is the most commonly used form of estrogen in hormone replacement therapy (HRT) for menopausal symptoms in the United States. Estrone sulfate is the major estrogen in CEEs while equilin sulfate is the second major estrogen in the formulation, present as about 25% of the total.

<span class="mw-page-title-main">Ethinylestradiol</span> Estrogen medication

Ethinylestradiol (EE) is an estrogen medication which is used widely in birth control pills in combination with progestins. In the past, EE was widely used for various indications such as the treatment of menopausal symptoms, gynecological disorders, and certain hormone-sensitive cancers. It is usually taken by mouth but is also used as a patch and vaginal ring.

<span class="mw-page-title-main">Esterified estrogens/methyltestosterone</span> Pharmaceutical combination

Esterified estrogens/methyltestosterone (EEs/MT), sold under brand names such as Covaryx, Eemt, Essian, Estratest, Menogen, and Syntest, is a hormonal preparation that combines esterified estrogens (EEs) with methyltestosterone (MT) in one tablet and is used in menopausal hormone therapy.

<span class="mw-page-title-main">Estrone sulfate</span> Chemical compound

Estrone sulfate, also known as E1S, E1SO4 and estrone 3-sulfate, is a natural, endogenous steroid and an estrogen ester and conjugate.

<span class="mw-page-title-main">Estriol succinate</span> Chemical compound

Estriol succinate, sold under the brand name Synapause among others, is an estrogen medication which is used in the treatment of menopausal symptoms. It is taken by mouth, in through the vagina, and by injection.

<span class="mw-page-title-main">Conjugated estrogens</span> Estrogen medication

Conjugated estrogens (CEs), or conjugated equine estrogens (CEEs), sold under the brand name Premarin among others, is an estrogen medication which is used in menopausal hormone therapy and for various other indications. It is a mixture of the sodium salts of estrogen conjugates found in horses, such as estrone sulfate and equilin sulfate. CEEs are available in the form of both natural preparations manufactured from the urine of pregnant mares and fully synthetic replications of the natural preparations. They are formulated both alone and in combination with progestins such as medroxyprogesterone acetate. CEEs are usually taken by mouth, but can also be given by application to the skin or vagina as a cream or by injection into a blood vessel or muscle.

<span class="mw-page-title-main">Estradiol sulfate</span> Chemical compound

Estradiol sulfate (E2S), or 17β-estradiol 3-sulfate, is a natural, endogenous steroid and an estrogen ester. E2S itself is biologically inactive, but it can be converted by steroid sulfatase into estradiol, which is a potent estrogen. Simultaneously, estrogen sulfotransferases convert estradiol to E2S, resulting in an equilibrium between the two steroids in various tissues. Estrone and E2S are the two immediate metabolic sources of estradiol. E2S can also be metabolized into estrone sulfate (E1S), which in turn can be converted into estrone and estradiol. Circulating concentrations of E2S are much lower than those of E1S. High concentrations of E2S are present in breast tissue, and E2S has been implicated in the biology of breast cancer via serving as an active reservoir of estradiol.

<span class="mw-page-title-main">17β-Dihydroequilin</span> Chemical compound

17β-Dihydroequilin is a naturally occurring estrogen sex hormone found in horses as well as a medication. As the C3 sulfate ester sodium salt, it is a minor constituent (1.7%) of conjugated estrogens. However, as equilin, with equilin sulfate being a major component of CEEs, is transformed into 17β-dihydroequilin in the body, analogously to the conversion of estrone into estradiol, 17β-dihydroequilin is, along with estradiol, the most important estrogen responsible for the effects of CEEs.

<span class="mw-page-title-main">8,9-Dehydroestrone</span> Chemical compound

8,9-Dehydroestrone, or Δ8-estrone, also known as estra-1,3,5(10),8-tetraen-3-ol-17-one, is a naturally occurring estrogen found in horses which is closely related to equilin, equilenin, and estrone, and, as the 3-sulfate ester sodium salt, is a minor constituent (3.5%) of conjugated estrogens (Premarin). It produces 8,9-dehydro-17β-estradiol as an important active metabolite, analogously to conversion of estrone or estrone sulfate into estradiol. The compound was first described in 1997. In addition to 8,9-dehydroestrone and 8,9-dehydro-17β-estradiol, 8,9-dehydro-17α-estradiol is likely also to be present in conjugated estrogens, but has not been identified at this time.

<span class="mw-page-title-main">8,9-Dehydroestradiol</span> Chemical compound

8,9-Dehydroestradiol, or Δ8-17β-estradiol, also known as estra-1,3,5(10),8-tetraen-17β-ol-3-one, is a naturally occurring steroidal estrogen found in horses which is closely related to equilin, equilenin, and estradiol, and, as the 3-sulfate ester sodium salt, is a minor constituent of conjugated estrogens (Premarin). It is also an important active metabolite of 8,9-dehydroestrone, analogously to conversion of estrone or estrone sulfate into estradiol.

<span class="mw-page-title-main">Estradiol (medication)</span> Steroidal hormone medication

Estradiol (E2) is a medication and naturally occurring steroid hormone. It is an estrogen and is used mainly in menopausal hormone therapy and to treat low sex hormone levels in women. It is also used in hormonal birth control for women, in feminizing hormone therapy for transgender women, and in the treatment of hormone-sensitive cancers like prostate cancer in men and breast cancer in women, among other uses. Estradiol can be taken by mouth, held and dissolved under the tongue, as a gel or patch that is applied to the skin, in through the vagina, by injection into muscle or fat, or through the use of an implant that is placed into fat, among other routes.

<span class="mw-page-title-main">Estrogen (medication)</span> Type of medication

An estrogen (E) is a type of medication which is used most commonly in hormonal birth control and menopausal hormone therapy, and as part of feminizing hormone therapy for transgender women. They can also be used in the treatment of hormone-sensitive cancers like breast cancer and prostate cancer and for various other indications. Estrogens are used alone or in combination with progestogens. They are available in a wide variety of formulations and for use by many different routes of administration. Examples of estrogens include bioidentical estradiol, natural conjugated estrogens, synthetic steroidal estrogens like ethinylestradiol, and synthetic nonsteroidal estrogens like diethylstilbestrol. Estrogens are one of three types of sex hormone agonists, the others being androgens/anabolic steroids like testosterone and progestogens like progesterone.

<span class="mw-page-title-main">Estrone (medication)</span> Estrogen medication

Estrone (E1), sold under the brand names Estragyn, Kestrin, and Theelin among many others, is an estrogen medication and naturally occurring steroid hormone which has been used in menopausal hormone therapy and for other indications. It has been provided as an aqueous suspension or oil solution given by injection into muscle and as a vaginal cream applied inside of the vagina. It can also be taken by mouth as estradiol/estrone/estriol and in the form of prodrugs like estropipate and conjugated estrogens.

<span class="mw-page-title-main">Estrone sulfate (medication)</span> Chemical compound

Estrone sulfate (E1S) is an estrogen medication and naturally occurring steroid hormone. It is used in menopausal hormone therapy among other indications. As the sodium salt, it is the major estrogen component of conjugated estrogens (Premarin) and esterified estrogens. In addition, E1S is used on its own as the piperazine salt estropipate. The compound also occurs as a major and important metabolite of estradiol and estrone. E1S is most commonly taken by mouth, but in the form of Premarin can also be taken by parenteral routes such as transdermal, vaginal, and injection.

Equine estrogens, or horse estrogens, are estrogens found in horses. They include the following:

<span class="mw-page-title-main">Pharmacokinetics of estradiol</span>

The pharmacology of estradiol, an estrogen medication and naturally occurring steroid hormone, concerns its pharmacodynamics, pharmacokinetics, and various routes of administration.

<span class="mw-page-title-main">Conjugated estriol</span> Pharmaceutical drug

Conjugated estriol, sold under the brand names Progynon and Emmenin, is an estrogen medication which was previously used for estrogen-type indications such as the treatment of menopausal symptoms in women. The term specifically refers to formulations of estriol conjugates which were manufactured from the estrogen-rich urine of pregnant women and were used as medications in the 1920s and 1930s. Conjugated estriol is analogous to and was superseded by conjugated estrogens, which is manufactured from the urine of pregnant mares. Conjugated estriol was among the first forms of pharmaceutical estrogen to be used in medicine. It was taken by mouth.

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