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Estetrol
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Estetrol
Skeletal formula of estetrol
Ball-and-stick model of the estetrol molecule
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
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.276.707 Edit this at Wikidata
EC Number
  • 840-340-4
KEGG
UNII
  • InChI=1S/C18H24O4/c1-18-7-6-12-11-5-3-10(19)8-9(11)2-4-13(12)14(18)15(20)16(21)17(18)22/h3,5,8,12-17,19-22H,2,4,6-7H2,1H3/t12-,13-,14-,15-,16-,17+,18+/m1/s1
    Key: AJIPIJNNOJSSQC-NYLIRDPKSA-N
  • 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]

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

[edit]

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

[edit]

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 ERTooltip Estrogen receptor RBATooltip relative binding affinity (%) Uterine weight (%) Uterotrophy LHTooltip Luteinizing hormone levels (%) SHBGTooltip Sex hormone-binding globulin RBATooltip relative binding affinity (%)
Control – 100 – 100 –
Estradiol (E2) 100 506 ± 20 +++ 12–19 100
Estrone (E1) 11 ± 8 490 ± 22 +++ ? 20
Estriol (E3) 10 ± 4 468 ± 30 +++ 8–18 3
Estetrol (E4) 0.5 ± 0.2 ? Inactive ? 1
17α-Estradiol 4.2 ± 0.8 ? ? ? ?
2-Hydroxyestradiol 24 ± 7 285 ± 8 +b 31–61 28
2-Methoxyestradiol 0.05 ± 0.04 101 Inactive ? 130
4-Hydroxyestradiol 45 ± 12 ? ? ? ?
4-Methoxyestradiol 1.3 ± 0.2 260 ++ ? 9
4-Fluoroestradiola 180 ± 43 ? +++ ? ?
2-Hydroxyestrone 1.9 ± 0.8 130 ± 9 Inactive 110–142 8
2-Methoxyestrone 0.01 ± 0.00 103 ± 7 Inactive 95–100 120
4-Hydroxyestrone 11 ± 4 351 ++ 21–50 35
4-Methoxyestrone 0.13 ± 0.04 338 ++ 65–92 12
16α-Hydroxyestrone 2.8 ± 1.0 552 ± 42 +++ 7–24 <0.5
2-Hydroxyestriol 0.9 ± 0.3 302 +b ? ?
2-Methoxyestriol 0.01 ± 0.00 ? Inactive ? 4
Notes: Values are mean ± SD or range. ER RBA = 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: [10][11][12][13][14][15][16][17][18]

Mode of action

[edit]

Tissue-selective effect

[edit]

Estetrol shows selective estrogenic, neutral or anti-estrogenic activities in certain cell types and tissues.[9][19][20] In rodent models, estetrol has shown to elicit potent estrogenic activity on ovulation,[21] brain,[22] bone tissue,[23] cardiovascular system,[24] and uterus, associated with ovulation inhibition, prevention of bone demineralization, cardioprotective effects and maintenance of uterovaginal tissues, respectively.[24][25]

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.[20][26] This property of estetrol is associated with antagonistic effects on breast cell proliferation, migration and invasion in the presence of estradiol.[20][27]

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.[28]

Estetrol can therefore be described as the first Native Estrogen with Selective Tissue activity (NEST).[29][30]

Differences vs SERMs

[edit]

The selective tissue activity of estetrol is different from the effects of selective estrogen receptor modulators (SERMs), like tamoxifen and raloxifene.[31] 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.[31] Estetrol recruits the same co-regulators as other estrogens, while SERMs recruit other co-regulators.[30]

ERα activation

[edit]

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.[24]

Biochemistry

[edit]

Biosynthesis

[edit]

In the fetal liver, estetrol is synthesized from estradiol (E2) and estriol (E3) by two fetal liver enzymes, 15α- and 16α-hydroxylase, through hydroxylation.[32][33][34][35] Estetrol can be detected in maternal urine from the 9th week of gestation.[2][36][37] 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

[edit]

In terms of plasma protein binding, estetrol displays moderate binding to albumin, and shows no binding to SHBG.[38][39] The overall low plasma protein binding results in a ~50% free active fraction.[38] This compares to a 1% active form for EE and ~2% for estradiol.[40] Estetrol is equally distributed between red blood cells and plasma.[3]

Metabolism

[edit]

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][19][41][42] The two main metabolites, estetrol-3-glucuronide and estetrol-16-glucuronide, have negligible estrogenic activity.[41][42] (see Drospirenone/estetrol)

Excretion

[edit]

Estetrol is mainly excreted in urine.[8][19] Estetrol is an end-stage product of metabolism, which is not converted back into active metabolites like estriol, estradiol or estrone.[9][38]

Chemistry

[edit]
See also: List of estrogens
Structures of major endogenous estrogens
Chemical structures of major endogenous estrogens
Estrone (E1)
Estriol (E3)
Estetrol (E4)
The image above contains clickable links
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][43] It is structurally different from the other estrogens because of the presence of four hydroxyl groups, which explains the abbreviation E4.[8][43]

Synthesis

[edit]

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%)[44] without contaminants.

History

[edit]

Estetrol was first described in 1965 by Egon Diczfalusy and coworkers at the Karolinska Institute in Stockholm, Sweden,[45][32][33][46] 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.

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Estetrol

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from Grokipedia
Estetrol (E4), also spelled oestetrol, is a naturally occurring produced almost exclusively by the human fetal liver during , where it circulates at concentrations up to 12 ng/mL in fetal plasma and 1.2 ng/mL in maternal plasma at term. Distinguished by its four hydroxyl groups, E4 is the shortest-acting endogenous estrogen and exhibits high oral of approximately 90%, with a plasma half-life of 28–32 hours, primarily due to phase II metabolism rather than conversion to other estrogens. As a (SERM), it binds to estrogen receptors α (ERα) and β (ERβ) with moderate affinity—about four- to five-fold preference for ERα—but displays tissue-specific and effects, acting as an on nuclear ERα in the and while functioning as an on membrane-bound ERα in endothelial and tissues. Discovered in through analysis of pregnant women's urine, E4 is unique to humans and not produced in other species, with its physiological role during remaining incompletely understood but suggesting inherent tolerability. Pharmacologically, E4 differs from other estrogens like (E2) and (EE) by its weaker overall estrogenic potency—25-fold lower affinity for ERα compared to E2—and minimal impact on liver proteins such as (SHBG), , and hemostatic factors, resulting in a lower risk of venous thromboembolism (VTE) than EE-based contraceptives. It exerts neuroprotective, vasoprotective, and anti-inflammatory effects through both genomic (nuclear receptor-mediated) and non-genomic (membrane receptor) pathways, with limited stimulation of breast tissue proliferation, potentially reducing risk. These properties position E4 as a "natural with selective tissue actions" (NEST), making it suitable for hormonal therapies where minimizing adverse effects on and coagulation is critical. Clinically, E4 is approved for use in combined oral contraceptives (COCs), notably as Nextstellis (14.2 mg estetrol monohydrate equivalent to 15 mg anhydrous estetrol with 3 mg ), which received U.S. FDA approval in April 2021 for preventing pregnancy in females of reproductive age. Phase III trials demonstrated high contraceptive efficacy, with a of 0.29–2.65 pregnancies per 100 woman-years, ovulation suppression in over 99% of cycles, and favorable bleeding patterns (82.9–94.4% incidence of scheduled withdrawal bleeding). It also shows promise in menopausal (HRT), with a 15 mg daily dose reducing symptoms by up to 30% in phase II/III studies, and has orphan drug designation for treating neonatal hypoxic-ischemic encephalopathy. Ongoing research explores its potential in and other estrogen-sensitive conditions, leveraging its selective profile to balance efficacy and safety.

Biology

Biosynthesis

Estetrol (E4) is biosynthesized exclusively in the fetal liver during human pregnancy through a collaborative process involving the feto-placental unit. The primary precursors originate from the fetal adrenal glands, which produce dehydroepiandrosterone sulfate (DHEA-S). This sulfate is transported to the placenta, where placental sulfatase (STS) hydrolyzes it to DHEA, enabling subsequent conversions; deficiency in this enzyme severely impairs estrogen production, including E4. The proceeds via two main pathways: the phenolic and neutral routes, both culminating in the fetal liver. In the phenolic pathway, placental (CYP19A1) converts (derived from DHEA) to estrone, which is further reduced to (E2); E2 then enters the , undergoes sulfation, and is hydroxylated by 15α- and 16α-hydroxylases in the fetal liver to form E4. The neutral pathway involves initial 15α- and 16α-hydroxylation of DHEA-S in the fetal liver to 15α,16α-dihydroxy-DHEA-S, followed by transport to the for desulfation by sulfatase and by CYP19A1 to yield E4. A parallel sequence for the neutral route incorporates 16α-hydroxylation earlier in the fetal adrenal to form 16α-hydroxy-DHEA-S, leading to (E3) in the , which is then 15α-hydroxylated in the fetal liver to E4. These hydroxylases are expressed specifically in the fetal liver and disappear postnatally, ensuring E4's pregnancy-exclusive production. E4 levels in rise progressively, peaking in late at approximately 10-20 ng/mL, which is 10-20 times higher than maternal levels (0.4-1.2 ng/mL). This elevation reflects the pathway's efficiency and the fetal liver's high hydroxylase activity during .

Biological function

(E4) is a produced exclusively during by the fetal liver, where it is synthesized from precursors, and is absent in non-pregnant adults, indicating a specialized adaptive role in . The physiological functions of estetrol remain incompletely understood, but emerging evidence suggests potential neuroprotective effects in the , including attenuation of hypoxic-ischemic in neonatal models. Animal studies have demonstrated estetrol's role in promoting development and reducing relative to other estrogens, with strong antioxidative properties attributed to its multiple phenolic hydroxy groups that scavenge . Additionally, estetrol may contribute to the regulation of uteroplacental blood flow by modulating endothelial synthesis in the feto-placental unit, supporting vascular relaxation and improved oxygenation during . Unlike , which serves as a marker for fetal well-being, estetrol levels exhibit large intra- and interindividual variations and do not correlate reliably with gestational complications, rendering it unsuitable for clinical monitoring of fetal .

Distribution and levels

Estetrol concentrations in the fetal plasma during the third trimester of are substantially higher than in maternal plasma, typically ranging from 10 to 20 ng/mL in the compared to 0.5 to 1.2 ng/mL in the mother. This disparity arises from the exclusive production of estetrol in the fetal liver and more rapid conjugation and in the maternal circulation. In circulation, estetrol exhibits low binding to and moderate overall of approximately 46-50%, resulting in a substantial free fraction that facilitates its distribution throughout the body, including efficient penetration of the blood-brain barrier. The fetal liver serves as the primary site of its biosynthesis, contributing to its selective accumulation in fetal compartments during . Following delivery, estetrol levels plummet rapidly in both neonates and mothers, dropping to undetectable concentrations within days as fetal production ceases and maternal clearance occurs. Estetrol levels are highly dependent on , remaining low or undetectable prior to 18 weeks before rising exponentially to reach peak concentrations at 36-40 weeks. In non-pregnant adults, estetrol is present at minimal or negligible levels, reflecting its pregnancy-specific physiology.

Pharmacology

Pharmacodynamics

Estetrol (E4) binds to the estrogen receptors ERα and ERβ with moderate affinity, exhibiting Ki values of 4.9 nM for ERα and 19 nM for ERβ, which confers a 4- to 5-fold preference for ERα over ERβ. This binding affinity is approximately 10- to 20-fold lower than that of for ERα. These interactions position E4 as a weaker compared to , with relative binding affinities of 1% to 4% for ERα and ERβ. The primary mode of action for E4 involves nuclear of ERα, where it functions as a ligand-dependent to regulate through estrogen response elements, albeit with 100- to 1000-fold lower potency than . E4 also participates in -initiated signaling (MISS) for rapid cellular responses, such as endothelial production; however, it uniquely uncouples nuclear ERα from these pathways, enabling tissue-specific effects without the broad genomic and non-genomic seen with other . This decoupling minimizes off-target signaling in certain tissues while preserving beneficial actions. As a natural estrogen with selective tissue actions (NEST), E4 displays full at ERα in and vasculature, promoting osteoprotection and vasorelaxation, while exerting partial in and uterine tissues, resulting in limited proliferation. In the liver, E4 causes minimal stimulation, evidenced by the absence of increased (SHBG) production, which contrasts with the hepatic effects of . Unlike selective estrogen receptor modulators (SERMs), E4 acts as a full across estrogen-responsive tissues without antagonistic properties against -induced transcription. At the molecular level, E4 binding to ERα induces conformational changes that reposition helix 12, facilitating coactivator recruitment—such as SRC3 with low nanomolar affinity—in a manner akin to but distinct from , thereby supporting selective transcriptional activation in target tissues like and . This profile contributes to E4's reduced potency overall but enhanced safety in breast and liver compared to other estrogens.

Pharmacokinetics

Estetrol is rapidly absorbed from the following , with a time to maximum plasma concentration (T_max) of 0.5 to 2 hours. Peak plasma levels are achieved quickly, and the is high, approximately 90%, attributed to minimal first-pass . This high supports once-daily dosing in therapeutic regimens. Estetrol exhibits a high unbound fraction in plasma, with approximately 50-54% free (non-protein bound), primarily binding moderately to (58.6%) and minimally to alpha-1-acid (11.2%), with no binding to . The apparent (Vz/F) is approximately 5940 L following oral administration of therapeutic doses. Metabolism of estetrol occurs mainly via phase II conjugation, forming and conjugates with negligible estrogenic activity; the dominant pathway is at the 16-position catalyzed by UGT2B7, with sulfate conjugation playing a minor role and minimal involvement of enzymes such as CYP3A4. No active metabolites are produced. Excretion of estetrol is primarily renal, with approximately 69% of the dose recovered in (predominantly as conjugates, with 0% unchanged drug) and 22% in (100% as unchanged drug), with total recovery of about 91%. The elimination is approximately 27 hours (range: 19-40 hours). Pharmacokinetics are linear and dose-proportional at therapeutic doses of 15-20 mg. Steady-state concentrations are reached within about 4 days.

Chemistry

Structure and properties

Estetrol, abbreviated as E4, has the molecular formula C18H24O4 and a molecular weight of 304.38 g/mol. Its systematic IUPAC name is (8R,9S,13S,14S,15R,16R,17R)-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopentaphenanthrene-3,15,16,17-tetrol, while its common chemical name is estra-1,3,5(10)-triene-3,15α,16α,17β-tetrol. The molecular structure of estetrol features a backbone typical of estrogens, consisting of four fused rings (A, B, C, and D) with aromatic ring A and hydroxyl groups attached at the 3, 15α, 16α, and 17β positions. This configuration includes four hydroxyl groups, setting it apart from , which has two (at 3 and 17β), and , which has three (at 3, 16α, and 17β). Estetrol appears as a white crystalline powder. It exhibits low in (1.4 g/L) but is soluble in organic solvents such as (5 mg/mL) and (20 mg/mL). The compound has a melting point of 233–236 °C. Its is defined by the configuration at C15 and C16, corresponding to the α orientation of the hydroxyl groups at these positions.

Synthesis

Estetrol for pharmaceutical use is produced through a semi-synthetic route starting from estrone, which is derived from plant sterols such as those extracted from soybeans. The process begins with the protection of the phenolic hydroxyl group at position 3 using a suitable group like methyl or benzyl to prevent unwanted reactions. The 17-keto group of the protected estrone is then stereospecifically reduced to the 17β-hydroxy configuration, typically employing sodium borohydride in the presence of cerium(III) chloride hydrate to favor the desired epimer and minimize formation of the 17α-isomer. Subsequent protection of the 17β-hydroxyl group with an acetate ester is followed by selective cis- of the Δ15 using in combination with a co-oxidant like and N-oxide, introducing the critical 15α,16α-diol moiety. Deprotection steps then remove the 3- and 17-protecting groups through base and, if necessary, catalytic , yielding estetrol. Key challenges in this synthesis include ensuring high during the 17-keto reduction to avoid epimerization and achieving precise control over the dihydroxylation to prevent over-oxidation or formation of trans-diols, which require rigorous purification such as and recrystallization. The overall route involves approximately eight steps, including multiple protections and deprotections, and is optimized for scalability without attempting , which is deemed impractical due to the molecule's structural complexity. Mithra Pharmaceuticals employs this plant-based, semi-synthetic process for industrial production, attaining estetrol purity greater than 99% via monitoring.

Medical use

Contraception

Estetrol is used in combination with drospirenone as a combined oral contraceptive (COC) for pregnancy prevention in women of reproductive age. The approved formulation, marketed as Nextstellis in the United States and Drovelis in the European Union, consists of 14.2 mg estetrol (equivalent to 15 mg estetrol monohydrate) and 3 mg drospirenone per active tablet. It is administered in a 24/4 regimen, comprising 24 days of active tablets followed by 4 days of placebo tablets, taken once daily at the same time. The U.S. Food and Drug Administration (FDA) approved this combination in April 2021 for females of reproductive potential aged 16 years and older, while the European Medicines Agency (EMA) approved it in May 2021 for women aged 18 years and older. The contraceptive efficacy of estetrol/drospirenone was demonstrated in two phase 3, multicenter trials (NCT02817828 and NCT02817841) involving over 3,700 women aged 16–50 years. The Pearl Index, a measure of contraceptive failure rate per 100 woman-years of use, was 0.47 (95% CI: 0.12–1.87) in the European/Russian trial and 2.65 (95% CI: 1.73–3.88) in the North American trial for women under 35 years, indicating high effectiveness with typical use. This efficacy is primarily achieved through suppression of ovulation, mediated by estetrol's selective activation of estrogen receptor alpha (ERα), which inhibits follicle-stimulating hormone (FSH) and luteinizing hormone (LH) secretion from the pituitary gland. Estetrol/drospirenone offers advantages in bleeding control and hemostatic effects compared to ethinylestradiol (EE)-based COCs. In the phase 3 trials, unscheduled bleeding or spotting occurred in 26.9% of cycles overall, decreasing from 30.3% in cycle 1 to 17.4% by cycle 12, with most users (87.2–90.4%) maintaining predictable scheduled bleeding patterns. Regarding hemostasis, the combination induces a smaller increase in activated protein C resistance (APCr; +30.0%) than EE/drospirenone (+164.5%) or EE/levonorgestrel (+218.5%), suggesting a potentially lower risk of venous thromboembolism.

Menopausal hormone therapy

Estetrol (E4) is under investigation as a monotherapy for (MHT), particularly for the treatment of moderate to severe symptoms (VMS) in postmenopausal women. In the phase 3 E4COMFORT clinical program, which included two pivotal randomized, double-blind, placebo-controlled trials (NCT04090957 and NCT04209543) involving over 2,300 women aged 40 to 65 years, oral estetrol at doses of 15 mg or 20 mg daily demonstrated significant efficacy in reducing VMS. The primary endpoints focused on the change in frequency and severity of moderate to severe hot flushes, with both doses showing statistically significant improvements compared to by week 12 (p < 0.01). Specifically, the frequency of hot flushes was reduced by up to 80% from baseline at week 12, while severity decreased by up to 56%. These results position estetrol as a promising option for VMS management, with the 15 mg dose identified as the minimum effective regimen for monotherapy. Beyond VMS relief, estetrol exhibits benefits on other menopausal symptoms and risk factors. In secondary analyses from the E4COMFORT trials and related studies, estetrol 15 mg daily improved vaginal health by promoting estrogenic effects on and reducing signs of , as evidenced by increased maturation index and decreased pH. It also showed positive effects on bone health, with significant reductions in bone turnover markers such as (CTX) and procollagen type 1 N-terminal propeptide (P1NP) observed at 3 months and 1 year compared to , suggesting potential preservation of density. Notably, the E4COMFORT II trial (NCT04209543) reported no significant impact on after 52 weeks of treatment, even among women at high cardiovascular risk (e.g., elevated HbA1c, , or triglycerides), indicating a favorable cardiovascular profile relative to some traditional MHT options. Estetrol's tissue-selective agonism, characterized by strong activation of estrogen receptors in the , , and while exhibiting minimal effects on breast and liver tissues, contributes to its balanced benefit-risk profile in MHT. This selectivity may enhance safety for long-term use in postmenopausal women. As of November 2025, regulatory submissions for estetrol (branded as Donesta) for VMS treatment have been filed or are pending with the FDA and EMA, with marketing authorization expected in the and by 2026, contingent on ongoing review processes.

Other indications

Estetrol, in combination with , is under investigation for the treatment of endometriosis-associated pain and reduction of size. A multicenter, placebo-controlled phase 3 trial (NCT05837624) conducted in 2024 demonstrated that cyclic administration of estetrol 15 mg/ 3 mg significantly reduced endometriosis-associated , improved objective gynecological findings such as size, and enhanced measures compared to , with a favorable safety profile including potentially lower risk of thromboembolic events relative to traditional estrogens. In (PCOS), estetrol/ has shown metabolic advantages over / in a randomized crossover from January 2024 to January 2025. The study, involving women diagnosed with PCOS per Rotterdam criteria, found that estetrol/ improved glucose tolerance and other parameters without inferior effects, suggesting a beneficial profile for managing metabolic disturbances in this population. Estetrol holds potential as an adjunct in estrogen receptor-positive (ER+) , particularly for advanced or anti-estrogen-resistant cases. A phase 2 dose-escalation trial in postmenopausal women with ER+/HER2- locally advanced or reported anti-tumor effects, including tumor suppression, at high doses (up to 120 mg daily) over 12 weeks, with good tolerability and no dose-limiting toxicity; improvements were also noted, supporting further exploration for symptom management in survivors. Preclinical further indicates neuroprotective actions of estetrol, such as antioxidative, neurogenic, and angiogenic effects that attenuate hypoxic-ischemic in animal models. Estetrol has received designation from the FDA in 2019 and the EMA in 2017 for the treatment of neonatal hypoxic-ischemic , based on its neuroprotective potential, though development remains at the preclinical stage with no ongoing trials reported as of November 2025. Additionally, a trial (NCT06396221) is assessing inhibition with quick-start initiation of estetrol/ combined oral contraceptives, comparing efficacy and safety to /gestodene regimens.

Safety and adverse effects

Common side effects

The most frequently reported adverse effects of estetrol-containing therapies, particularly in combined oral contraceptives with , include irregularities, mood disturbances, , and symptoms. In pooled data from two phase 3 trials involving 3,632 women, irregularities occurred in 10.8% of participants, mood disturbances in 9.1%, in 6.3%, and symptoms (such as tenderness or pain) in 5.4%. These effects were generally mild to moderate and led to discontinuation in a small proportion of users, with irregularities accounting for 2.8% of discontinuations. Bleeding irregularities, often manifesting as unscheduled spotting or breakthrough bleeding, are most common during the initial treatment cycles and tend to resolve with continued use. In the phase 3 trials, the incidence of unscheduled bleeding or spotting decreased from 30.3% in cycle 1 to 17.4% by cycle 12, with predictable scheduled bleeding occurring in 87.2% to 90.4% of cycles after the first few months. By cycle 3, the pattern stabilizes for most users, similar to other combined oral contraceptives but with a more favorable profile compared to ethinylestradiol-based formulations. Other common effects include minimal and limited alterations in (SHBG) or lipid profiles. was reported in 3.0% of phase 3 trial participants, typically less than 1 kg on average. Estetrol/ treatment resulted in a modest 63.1% increase in SHBG levels after 12 weeks, substantially lower than the 205.9% increase seen with /, with no clinically significant adverse shifts in such as HDL-cholesterol or triglycerides. Overall, the incidence of these adverse effects in phase 3 studies was lower than with -containing combined oral contraceptives, contributing to good tolerability.

Serious risks

Estetrol, when used in combined oral contraceptives or menopausal , carries risks of , though clinical trials indicate a lower incidence compared to ethinyl estradiol-based formulations, based on hemostatic marker changes and low event rates. In phase III trials involving over 3,600 women, only one venous thromboembolism (VTE) case was reported (0.03% incidence), attributed in part to estetrol's minimal impact on liver-derived proteins such as fibrinogen and prothrombin, unlike synthetic estrogens that elevate these factors. Cardiovascular risks with estetrol include potential for and , particularly in women over 35 who smoke, those with , , or ; however, the 2025 E4COMFORT II phase III trial demonstrated neutral effects on after one year of treatment in postmenopausal women, including those with elevated cardiovascular risk factors like high HbA1c and . Caution is advised for smokers aged 35 or older, as combined hormonal contraceptives increase arterial thrombotic risks in this group. Regarding , short-term use of estetrol-containing products shows no increased risk, consistent with general combined oral contraceptive data where any elevation is small and limited to current or recent users; long-term data remain pending due to the relative novelty of estetrol formulations. Estetrol is contraindicated in women with current or history of . Key contraindications for estetrol include history of VTE or conditions predisposing to arterial/ (e.g., over age 35, , ), current or past , undiagnosed , severe (e.g., hepatic or ), and renal impairment or . For contraception, estetrol is X, as hormonal contraceptives can cause fetal harm and are not indicated during ; discontinuation is required if occurs. Estetrol's tissue-selective modulation may underlie its relatively favorable risk profile by limiting effects on prothrombotic pathways.

History

Discovery

Estetrol was first identified in 1965 by researchers at the , including A. A. Hagen, M. Barr, and E. Diczfalusy, through metabolic studies of 17β-estradiol in early infancy; it was detected as a in the of newborn infants using chromatographic separation techniques. In 1967, G. Zucconi and colleagues, also affiliated with the Diczfalusy group, successfully isolated estetrol from human and newborn , providing definitive characterization of the compound via further chromatographic and spectroscopic methods. This work established estetrol as a natural uniquely associated with . The name "estetrol" (abbreviated E4) was coined by Elio Gurpide in 1966, denoting its four hydroxyl groups at positions 3, 15α, 16α, and 17β—distinguishing it from estrone (E1, one OH group), (E2, two OH groups), and (E3, three OH groups). Early structural analyses highlighted its derivation from through additional 15α-hydroxylation, underscoring its chemical uniqueness among estrogens. Research in the and confirmed estetrol's fetal origin, demonstrating its exclusive synthesis in the human fetal liver during the second and third trimesters, followed by conjugation and placental transfer to the maternal circulation. Levels in maternal and plasma rise progressively from around the ninth week of , peaking near term, which led to investigations into its potential physiological role in fetal protection and development. However, despite these findings, scientific interest in estetrol waned by the late and into the , primarily due to its relatively weak estrogenic potency compared to and significant challenges in , which limited the availability of pure material for extensive biological studies. The seminal 1965 publication in Acta Endocrinologica marked the initial key report on its identification.

Development and approvals

Interest in estetrol as a pharmaceutical agent was revived in 2001 by Herjan J.T. Coelingh Bennink at Pantarhei Bioscience in , the , following its initial discovery in the 1960s, with early preclinical and phase 1 studies highlighting its favorable safety profile, particularly for contraception due to minimal impact on clotting factors and liver proteins compared to synthetic estrogens. Development advanced through partnerships, with Pantarhei out-licensing estetrol to Pharmaceuticals in 2015 for non-oncological uses, leading to the formulation of estetrol 15 mg/ 3 mg (E4/DRSP) as a combined oral contraceptive. Phase 3 trials, including the multicenter E4 FREEDOM study (NCT02817828) conducted from 2016 to 2019 in and , and a parallel trial in the and , demonstrated high contraceptive efficacy, predictable bleeding patterns, and good tolerability over 13 cycles. These trials supported regulatory submissions, resulting in approvals for E4/DRSP in 2021: by in March as Nextstellis, by the FDA in April, and by the EMA in May as Drovelis, marking estetrol's first commercial availability as the first estrogen derived from pregnancy-specific fetal production. Mithra Pharmaceuticals led global development and commercialization outside the , while Mayne Pharma secured exclusive rights for the market through a 20-year license and supply agreement in 2019, launching Nextstellis shortly after FDA approval. Patents covering estetrol formulations, including the monohydrate form and E4/DRSP combinations, provide protection extending into the , with a key patent lasting until 2036. Ongoing research includes phase 2/3 trials in 2024-2025 evaluating E4/DRSP for endometriosis-associated pain, showing reductions in endometrioma size and symptom relief, and for polycystic ovary syndrome (PCOS), assessing effects on glucose tolerance compared to ethinylestradiol/drospirenone. Estetrol-only formulations for menopausal hormone therapy are in late-stage development, with approvals anticipated in 2026 based on phase 3 data demonstrating no significant blood pressure changes even in women at cardiovascular risk.

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