Estetrol

Last updated
Estetrol
Estetrol.svg
Estetrol 3D ball.png
Names
IUPAC name
Estra-1,3,5(10)-triene-3,15α,16α,17β-tetrol
Systematic IUPAC name
(1R,2R,3R,3aS,3bR,9bS,11aS)-11a-Methyl-2,3,3a,3b,4,5,9b,10,11,11a-decahydro-1H-cyclopenta[a]phenanthrene-1,2,3,7-tetrol
Other names
Oestetrol; E4; 15α-Hydroxyestriol
Identifiers
3D model (JSmol)
ChEBI
ECHA InfoCard 100.276.707 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
UNII
  • C[C@]12CC[C@H]3[C@H]([C@@H]1[C@H]([C@H]([C@@H]2O)O)O)CCC4=C3C=CC(=C4)O
Properties
C18H24O4
Molar mass 304.386 g/mol
1.38 mg/mL
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Estetrol (E4), or oestetrol, is one of the four natural estrogenic steroid hormones found in humans, along with estrone (E1), estradiol (E2), and estriol (E3). Estetrol is a major estrogen in the body. [1] [2] In contrast to estrone and estradiol, estetrol is a native estrogen of fetal life. Estetrol is produced exclusively by the fetal liver [1] and is found in detectable levels only during pregnancy, with relatively high levels in the fetus and lower levels in the maternal circulation. [1] [2]

Contents

In addition to its physiological role as a native hormone, estetrol can be used as a medication, see estetrol (medication). Estetrol, in combination with drospirenone, has recently been approved as a new estrogenic component of a combined oral contraceptive (COC) and estetrol alone is in clinical development for the treatment of menopausal symptoms as well as breast and prostate cancer.

Biological function

So far, the physiological function of estetrol remains unknown. The potential role of estetrol as a marker for fetal well-being has been studied quite extensively, but no correlation was found [3] due to the large intra- and inter-individual variation in maternal estetrol plasma levels during pregnancy. [4] [5] [6] [7]

Biological activity

Estetrol has a moderate affinity for estrogen receptors alpha (ERα) and beta (ERβ), with Ki values of 4.9 nM and 19 nM, respectively. [8] [9] As such, estetrol has 4- to 5-fold preference for ERα over ERβ. [8] [9] In different animal models, the potency of estetrol regarding its estrogenic effect observed in vivo is generally 10 to 20 times lower than the potency of ethinyl estradiol (EE) and is also lower than the potency of estradiol. [1] [8] Estetrol displays a highly selective binding to its primary targets ERα and ERβ, [8] [9] which ensures that estetrol has a low risk of non-specific side effects.

Selected biological properties of endogenous estrogens in rats
Estrogen ER Tooltip Estrogen receptor RBA Tooltip relative binding affinity (%) Uterine weight (%) Uterotrophy LH Tooltip Luteinizing hormone levels (%) SHBG Tooltip Sex hormone-binding globulin RBA Tooltip relative binding affinity (%)
Control–100–100–
Estradiol (E2) 100506 ± 20+++12–19100
Estrone (E1) 11 ± 8490 ± 22+++ ?20
Estriol (E3) 10 ± 4468 ± 30+++8–183
Estetrol (E4) 0.5 ± 0.2 ?Inactive ?1
17α-Estradiol 4.2 ± 0.8 ? ? ? ?
2-Hydroxyestradiol 24 ± 7285 ± 8+b31–6128
2-Methoxyestradiol 0.05 ± 0.04101Inactive ?130
4-Hydroxyestradiol 45 ± 12 ? ? ? ?
4-Methoxyestradiol 1.3 ± 0.2260++ ?9
4-Fluoroestradiol a180 ± 43 ?+++ ? ?
2-Hydroxyestrone 1.9 ± 0.8130 ± 9Inactive110–1428
2-Methoxyestrone 0.01 ± 0.00103 ± 7Inactive95–100120
4-Hydroxyestrone 11 ± 4351++21–5035
4-Methoxyestrone 0.13 ± 0.04338++65–9212
16α-Hydroxyestrone 2.8 ± 1.0552 ± 42+++7–24<0.5
2-Hydroxyestriol 0.9 ± 0.3302+b ? ?
2-Methoxyestriol 0.01 ± 0.00 ?Inactive ?4
Notes: Values are mean ± SD or range. ERRBA = Relative binding affinity to estrogen receptors of rat uterine cytosol. Uterine weight = Percentage change in uterine wet weight of ovariectomized rats after 72 hours with continuous administration of 1 μg/hour via subcutaneously implanted osmotic pumps. LH levels = Luteinizing hormone levels relative to baseline of ovariectomized rats after 24 to 72 hours of continuous administration via subcutaneous implant. Footnotes:a = Synthetic (i.e., not endogenous). b = Atypical uterotrophic effect which plateaus within 48 hours (estradiol's uterotrophy continues linearly up to 72 hours). Sources: See template.

Mode of action

Tissue-selective effect

Estetrol shows selective estrogenic, neutral or anti-estrogenic activities in certain cell types and tissues. [9] [10] [11] In rodent models, estetrol has shown to elicit potent estrogenic activity on ovulation, [12] brain, [13] bone tissue, [14] cardiovascular system, [15] and uterus, associated with ovulation inhibition, prevention of bone demineralization, cardioprotective effects and maintenance of uterovaginal tissues, respectively. [15] [16]

Data from preclinical studies also suggest that estetrol has anti-estrogenic like effects on the breast and a limited impact on normal or malignant breast tissue when used at therapeutic concentration. [11] [17] This property of estetrol is associated with antagonistic effects on breast cell proliferation, migration and invasion in the presence of estradiol. [11] [18]

The molecular mechanisms of action driving its tissue-selective actions rely on a specific profile of ERα activation, uncoupling nuclear and membrane activation.

In the liver, Estetrol has a neutral activity, which is reflected by a minimal impact on synthesis of hepatic coagulation factors, minimal impact on sex hormone-binding globulin (SHBG) synthesis and limited impact on lipid parameters, including triglycerides. [19]

Estetrol can therefore be described as the first Native Estrogen with Selective Tissue activity (NEST). [20] [21]

Differences vs SERMs

The selective tissue activity of estetrol is different from the effects of selective estrogen receptor modulators (SERMs), like tamoxifen and raloxifene. [22] Estetrol, like SERMs, has selective tissue activity. However, SERMs interact with the ligand binding domain of ERα in a manner that is distinct from that of estrogens, including estetrol. [22] Estetrol recruits the same co-regulators as other estrogens, while SERMs recruit other co-regulators. [21]

ERα activation

Estrogens can elicit their effects via nuclear ERα and/or membrane ERα signaling pathways. Estetrol presents a distinctive mode of action in terms of ERα activation. Like other estrogens, estetrol binds to, and activates the nuclear ERα to induce gene transcription. However, estetrol induces very limited activity via membrane ERα in several tissues (e.g. in the breast) and antagonizes this pathway in the presence of estradiol, thereby uniquely uncoupling nuclear and membrane activation. [15]

Biochemistry

Biosynthesis

In the fetal liver, estetrol is synthesized from estradiol (E2) and estriol (E3) by two fetal liver enzymes, 15α- and 16α-hydroxylase, through hydroxylation. [23] [24] [25] [26] Estetrol can be detected in maternal urine from the 9th week of gestation. [2] [27] [28] After birth, the neonatal liver rapidly loses its capacity to synthesize estetrol. During the second trimester of pregnancy, high levels of estetrol can be found in maternal plasma, with steadily rising concentrations of unconjugated estetrol to about 1 ng/mL (>3 nM) towards the end of pregnancy. Fetal plasma levels have been reported to be over 10 times higher than maternal plasma levels at parturition. [1]

Distribution

In terms of plasma protein binding, estetrol displays moderate binding to albumin, and shows no binding to SHBG. [29] [30] The overall low plasma protein binding results in a ~50% free active fraction. [29] This compares to a 1% active form for EE and ~2% for estradiol. [31] Estetrol is equally distributed between red blood cells and plasma. [3]

Metabolism

Cytochrome P450 (CYP) enzymes do not play a major role in the metabolism of estetrol. [8] Instead, estetrol undergoes extensive phase 2 metabolism in the liver to form glucuronide and sulphate conjugates. [8] [10] [32] [33] The two main metabolites, estetrol-3-glucuronide and estetrol-16-glucuronide, have negligible estrogenic activity. [32] [33] (see Drospirenone/estetrol)

Excretion

Estetrol is mainly excreted in urine. [8] [10] Estetrol is an end-stage product of metabolism, which is not converted back into active metabolites like estriol, estradiol or estrone. [9] [29]

Chemistry

Structures of major endogenous estrogens
Chemical structures of major endogenous estrogens no labels.png
Estrone (E1)
Estradiol (E2)
Estriol (E3)
Estetrol (E4)
Interactive icon.svg
Note the hydroxyl (–OH) groups: estrone (E1) has one, estradiol (E2) has two, estriol (E3) has three, and estetrol (E4) has four.

Estetrol, also known as 15α-hydroxyestriol or as estra-1,3,5(10)-triene-3,15α,16α,17β-tetrol, is an estrane steroid and derivative of estrin (estratriene). [8] [34] It is structurally different from the other estrogens because of the presence of four hydroxyl groups, which explains the abbreviation E4. [8] [34]

Synthesis

Estetrol itself is a naturally-produced estrogen by the human fetal liver. However, for human use, estetrol is synthesized from estrone, which is obtained from phytosterols extracted from soybeans. The synthesis of estetrol results in very pure estetrol (>99.9%) [35] without contaminants.

History

Estetrol was first described in 1965 by Egon Diczfalusy and coworkers at the Karolinska Institute in Stockholm, Sweden, [36] [23] [24] [37] who identified and isolated this novel, native estrogen from late pregnancy urine and from the urine of newborn infants. Basic research on estetrol was conducted from 1965 to 1984. [1] [2] It was established that estetrol is exclusively synthesized in the human fetal liver. Since 1984, further research was virtually abandoned because estetrol was regarded as a weak and unimportant pregnancy estrogen. [1] [2] In 2001 Herjan Coelingh Bennink at Pantarhei Bioscience in the Netherlands re-started the investigation of estetrol as a potentially useful natural estrogen for human use, [1] resulting in the introduction of E4 as the estrogenic component of a combined oral contraceptive in 2021.

Related Research Articles

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

Estradiol (E2), also called oestrogen, oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of female reproductive cycles such as estrous and menstrual cycles. Estradiol is responsible for the development of female secondary sexual characteristics such as the breasts, widening of the hips and a female pattern of fat distribution. It is also important in the development and maintenance of female reproductive tissues such as the mammary glands, uterus and vagina during puberty, adulthood and pregnancy. It also has important effects in many other tissues including bone, fat, skin, liver, and the brain.

<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">Estriol</span> Chemical compound

Estriol (E3), also spelled oestriol, 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 estrone. Levels of estriol in women who are not pregnant are almost undetectable. However, during pregnancy, estriol is synthesized in very high quantities by the placenta and is the most produced estrogen in the body by far, although circulating levels of estriol are similar to those of other estrogens due to a relatively high rate of metabolism and excretion. Relative to estradiol, both estriol and estrone have far weaker activity as estrogens.

<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 combination drug preparations known as conjugated estrogens and esterified estrogens. CEEs is the most commonly used form of estrogen medications 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">Drospirenone</span> Medication drug

Drospirenone is a progestin and antiandrogen medication which is used in birth control pills to prevent pregnancy and in menopausal hormone therapy, among other uses. It is available both alone under the brand name Slynd and in combination with an estrogen under the brand name Yasmin among others. The medication is an analog of the drug spironolactone. Drospirenone is taken by mouth.

<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.

An estrogen ester is an ester of an estrogen, most typically of estradiol but also of other estrogens such as estrone, estriol, and even nonsteroidal estrogens like diethylstilbestrol. Esterification renders estradiol into a prodrug of estradiol with increased resistance to first-pass metabolism, slightly improving its oral bioavailability. In addition, estrogen esters have increased lipophilicity, which results in a longer duration when given by intramuscular or subcutaneous injection due to the formation of a long-lasting local depot in muscle and fat. Conversely, this is not the case with intravenous injection or oral administration. Estrogen esters are rapidly hydrolyzed into their parent estrogen by esterases once they have been released from the depot. Because estradiol esters are prodrugs of estradiol, they are considered to be natural and bioidentical forms of estrogen.

<span class="mw-page-title-main">16α-Hydroxyestrone</span> Chemical compound

16α-Hydroxyestrone (16α-OH-E1), or hydroxyestrone, also known as estra-1,3,5(10)-triene-3,16α-diol-17-one, is an endogenous steroidal estrogen and a major metabolite of estrone, as well as an intermediate in the biosynthesis of estriol. It is a potent estrogen similarly to estrone, and it has been suggested that the ratio of 16α-hydroxyestrone to 2-hydroxyestrone, the latter being much less estrogenic in comparison and even antiestrogenic in the presence of more potent estrogens like estradiol, may be involved in the pathophysiology of breast cancer. Conversely, 16α-hydroxyestrone may help to protect against osteoporosis.

<span class="mw-page-title-main">Catechol estrogen</span>

A catechol estrogen is a steroidal estrogen that contains catechol (1,2-dihydroxybenzene) within its structure. The catechol estrogens are endogenous metabolites of estradiol and estrone and include the following compounds:

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

Estriol glucuronide (E3G), or oestriol glucuronide, also known as estriol monoglucuronide, as well as estriol 16α-β-D-glucosiduronic acid, is a natural, steroidal estrogen and the glucuronic acid conjugate of estriol. It occurs in high concentrations in the urine of pregnant women as a reversibly formed metabolite of estriol. Estriol glucuronide is a prodrug of estriol, and was the major component of Progynon and Emmenin, estrogenic products manufactured from the urine of pregnant women that were introduced in the 1920s and 1930s and were the first orally active estrogens. Emmenin was succeeded by Premarin, which is sourced from the urine of pregnant mares and was introduced in 1941. Premarin replaced Emmenin due to the fact that it was easier and less expensive to produce.

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

Estradiol glucuronide, or estradiol 17β-D-glucuronide, is a conjugated metabolite of estradiol. It is formed from estradiol in the liver by UDP-glucuronyltransferase via attachment of glucuronic acid and is eventually excreted in the urine by the kidneys. It has much higher water solubility than does estradiol. Glucuronides are the most abundant estrogen conjugates.

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

The hydroxylation of estradiol is one of the major routes of metabolism of the estrogen steroid hormone estradiol. It is hydroxylated into the catechol estrogens 2-hydroxyestradiol and 4-hydroxyestradiol and into estriol (16α-hydroxyestradiol), reactions which are catalyzed by cytochrome P450 enzymes predominantly in the liver, but also in various other tissues.

<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">Estriol (medication)</span> Chemical compound

Estriol (E3), sold under the brand name Ovestin among others, is an estrogen medication and naturally occurring steroid hormone which is used in menopausal hormone therapy. It is also used in veterinary medicine as Incurin to treat urinary incontinence due to estrogen deficiency in dogs. The medication is taken by mouth in the form of tablets, as a cream that is applied to the skin, as a cream or pessary that is applied in the vagina, and by injection into muscle.

<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">Estetrol (medication)</span> Estrogen medication

Estetrol (E4) is an estrogen medication and naturally occurring steroid hormone which is used in combination with a progestin in combined birth control pills and is under development for various other indications. These investigational uses include menopausal hormone therapy to treat symptoms such as vaginal atrophy, hot flashes, and bone loss and the treatment of breast cancer and prostate cancer. It is taken by mouth.

<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.

Ethinylestradiol/drospirenone/prasterone (EE/DRSP/DHEA), known under developmental code names like Androgen Restored Contraceptive (ARC), Female Balance Pill, Pill-Plus, and Triple Oral Contraceptive, is a combination of ethinylestradiol (EE), an estrogen, drospirenone (DRSP), a progestin, antimineralocorticoid, and antiandrogen, and prasterone, an androgen prohormone and neurosteroid, which is under development for use as a birth control pill to prevent pregnancy in women. Clinical studies of this formulation have been conducted and published. Estrogens and progestogens suppress testosterone levels in women, and the addition of 50 mg prasterone, an oral prohormone of testosterone, has been found to restore total testosterone levels to normal levels. However, free testosterone levels, although higher with the addition of prasterone, remain significantly lower than usual despite prasterone inclusion.

<span class="mw-page-title-main">2-Methoxyestriol</span> Chemical compound

2-Methoxyestriol (2-MeO-E3) is an endogenous estrogen metabolite. It is specifically a metabolite of estriol and 2-hydroxyestriol. It has negligible affinity for the estrogen receptors and no estrogenic activity. However, 2-methoxyestriol does have some non-estrogen receptor-mediated cholesterol-lowering effects.

<span class="mw-page-title-main">15α-Hydroxyestradiol</span> Chemical compound

15α-Hydroxyestradiol (15α-OH-E2) is an endogenous estrogen which occurs during pregnancy. It is structurally related to estriol (16α-hydroxyestradiol) and estetrol.

References

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  26. ↑ Strauss JF, Barbieri RL (2009). Yen and Jaffe's Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management. Elsevier Health Sciences. p. 262. ISBN   978-1-4160-4907-4.
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  32. 1 2 "Nexstellis Label" (PDF). FDA. Retrieved 2022-04-12.
  33. 1 2 "Drovelis Label" (PDF). EMA. Retrieved 2022-04-12.
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