Estetrol

Clinical data
Other names	Oestetrol; E4; 15α-Hydroxyestriol; Estra-1,3,5(10)-triene-3,15α,16α,17β-tetrol
Pregnancy category	AU: B3[1]
Routes of administration	By mouth[2][3]
Drug class	Estrogen
ATC code	None
Pharmacokinetic data
Bioavailability	High[4]
Protein binding	Moderately toalbumin, not toSHBGTooltip sex hormone-binding globulin[4][5]
Metabolism	Minimal,conjugation (glucuronidation,sulfation)[2][6]
Metabolites	Estetrol glucuronide[6][2] Estetrol sulfate[6]
Eliminationhalf-life	Mean: 28 hours[4][6] Range: 18–60 hours[4]
Excretion	Urine: 79.7% (asconjugates)[2][6]
Identifiers
IUPAC name (8R,9S,13S,14S,15R,16R,17R)-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,15,16,17-tetrol
CAS Number	15183-37-6 Y
PubChemCID	27125
DrugBank	DB12235
ChemSpider	25245 Y
UNII	ENB39R14VF
KEGG	D11513
ChEBI	CHEBI:142773
ChEMBL	ChEMBL1230314
PDB ligand	4OH (PDBe,RCSB PDB)
Chemical and physical data
Formula	C18H24O4
Molar mass	304.386 g·mol−1
3D model (JSmol)	Interactive image
Solubility in water	1.38
SMILES 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
InChI 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 Y Key:AJIPIJNNOJSSQC-NYLIRDPKSA-N Y

Estetrol (E4) is anestrogen medication andnaturally occurringsteroid hormone which is used in combination with aprogestin incombined birth control pills and is under development for various other indications. These investigational uses includemenopausal hormone therapy to treat symptoms such asvaginal atrophy,hot flashes, andbone loss and the treatment ofbreast cancer andprostate cancer.^[2][3][7][8] It is takenby mouth.^[2][3]

Estetrol is anaturally occurring andbioidentical estrogen, or anagonist of theestrogen receptor, thebiological target ofestrogens likeendogenousestradiol.^[2][3] Due to its estrogenic activity, estetrol hasantigonadotropic effects and can inhibitfertility and suppresssex hormoneproduction and levels in both women and men.^[2][4][9] Estetrol differs in various ways both from other natural estrogens likeestradiol andsynthetic estrogens likeethinylestradiol, with implications fortolerability andsafety.^[2][4] For instance, it appears to have minimal estrogenic effects in thebreasts andliver.^{[2][4][10][6]} Estetrol interacts with nuclear ERα in a manner identical to that of the other estrogens^[11] and distinct from that observed with Selective Estrogen Receptor Modulators (SERMs).^[12]

Estetrol was first discovered in 1965, and basic research continued up until 1984.^[2][13] It started to be studied again as well as investigated for potential medical use in 2001, and by 2008, was of major interest for possible medical use.^[2][3] As of 2021, estetrol is in mid- to late-stage clinical development for a variety of indications.^[7][8]

Estetrol is available in combination with drospirenone in the following formulations, brand names and indications:^{[citation needed]}

• Estetrol (as monohydrate) 15 mg and drospirenone 3 mg Nextstellis (CA, US and Australia) – combined oral contraception
• Estetrol (as monohydrate) 15 mg and drospirenone 3 mg Drovelis (EU) – combined oral contraception
• Estetrol (as monohydrate) 15 mg and drospirenone 3 mg Lydisilka (EU) – combined oral contraception

Minimalside effects have been observed with estetrol in women.^[4][14] In men, decreasedlibido (in 40%) andnipple tenderness (in 35%) have been observed with high-dose (20–40 mg/day) estetrol for four weeks.^[9] The medication poses a risk ofendometrial hyperplasia andendometrial cancer in women similarly to other estrogens.^[2][14] As such, it is necessary to combine estetrol with aprogestogen in women with intactuteruses to prevent such risks.^[15][14] The safety of estetrol alone in women with an intact uterus is currently being investigated.^[16][17]

Estetrol-containingbirth control pills, similarly toestradiol-containing birth control pills, may have a lower risk ofvenous thromboembolism (VTE) thanethinylestradiol-containing birth control pills based on studies ofcoagulation.^[18][19] However, it is likely that another decade will be required before post-marketing epidemiological studies of VTE incidence with these birth control pills are completed and able to confirm this.^[20]

Estetrol is anagonist of theestrogen receptors (ERs), and hence is anestrogen.^[2][3] It has moderateaffinity forERα andERβ, with K_i values of 4.9 nM and 19 nM, respectively.^[2][21] As such, estetrol has 4- to 5-fold preference for ERα over ERβ.^[2][21] For comparison, the potentnonsteroidal estrogendiethylstilbestrol showed higher affinities for ERs, with K_i values of 0.286 nM for ERα and 0.199 nM for ERβ.^[21] Similarly, estetrol has low affinity for ERs relative to estradiol, and thus both estetrol and the related estrogenestriol require substantially higher concentrations than estradiol to produce similar effects.^[2] The affinity of estetrol for ERs is about 0.3% (rat) to 6.25% (human) of that of estradiol, and itsin vivopotency in animals is about 2 to 3% of that of estradiol.^[2] In women, estetrol has been found to be approximately 10 to 20 times less potent orally thanethinylestradiol, the most potent oral estrogen available.^[2] The high oral potency of estetrol in women in spite of relatively low affinity for the ERs is related to its highmetabolic stability and favorablepharmacokinetics.^[2]

Estetrol shows highselectivity for the ERs.^[2][21] It showed only 11 to 15% occupation of theandrogen,progesterone, andglucocorticoid receptors at a very high concentration of 10 μM.^[2][21] In addition, estetrol showed no affinity (>10 μM) for a set of 124 receptors andenzymes, with the sole exception of very weak affinity for theα_1B-adrenergic receptor (23% inhibition ofprazosin binding at a concentration of 10 μM).^[2][21] Due to its high selectivity for the ERs, estetrol is anticipated to have a low risk of undesirableoff-target activity and associatedside effects.^[2][21] Furthermore, estetrol showed noinhibition of the majorcytochrome P450enzymesCYP1A2,CYP2C9,CYP2C19,CYP2D6, andCYP3A4 at a very high concentration of 10 μM, unlike estradiol and ethinylestradiol.^[2][21] Conversely, estetrol moderately stimulated CYP3A4 (by 23%), while estradiol strongly stimulated CYP3A4 (by 83%) and ethinylestradiol moderately inhibited the enzyme (by 45%).^[2][21] These findings suggest that estetrol has a low potential fordrug interactions, including a lower potential than estradiol and particularly ethinylestradiol.^[2][21]

Estetrol has potentestrogenic effects inbone,vagina,uterus (bothmyometrium andendometrium),arteries, and certain areas of thebrain like thepituitary gland andhypothalamus (in terms ofhot flash relief,antigonadotropic effects, andovulation inhibition).^[2][31] It has comparable efficacy to ethinylestradiol onbone turnover and hot flashes and toestradiol valerate onvaginal atrophy.^[2][6][14] In addition, estetrol has stimulatory effects on the endometrium and poses a risk ofendometrial hyperplasia andendometrial cancer similar to other estrogens.^[2][14] Conversely, the effects of estetrol in certain othertissues such asbreast/mammary gland,liver,vascular tissue, and various brain areas differ, with weakly estrogenic or evenantiestrogenic effects occurring in such tissues.^{[2][10][6][31]} Based on its mixed effects in different tissues, estetrol has been described as a unique, "natural" estrogen, demonstrating absence of specific membrane receptor effects, and an interaction with ERα different from SERMs.^[2][12][31]

Estetrol has a low estrogenic effect in breast/mammary gland, and when administered in combination with estradiol,antagonizes the effects of estradiol.^[2][31] Relative to estradiol, estetrol shows 100-fold lower potency in stimulating theproliferation of human breastepithelial cellsin vitro and of mouse mammary gland cellsin vivo.^[10] Inanimal models, estetrol shows antiestrogenic effects, antagonizing the stimulatory effects of estradiol and preventingtumor development in a7,12-dimethylbenz(a)anthracene (DMBA) mammary tumor model.^[2][31][32] As such, it is anticipated that estetrol may cause minimal proliferation of breast tissue and that it may be useful in the treatment ofbreast cancer.^[2][10]

Estetrol has relatively minimal effects on liver function.^[10][6] In contrast to estradiol and ethinylestradiol, estetrol does not stimulate the hepatic production of SHBGin vitro.^[5] In addition, it has been found to produce minimal changes inliver protein synthesis in women relative to ethinylestradiol, including production ofsex hormone-binding globulin (SHBG),corticosteroid-binding globulin (CBG),angiotensinogen (AGT),ceruloplasmin,cholesterol,triglycerides, estrogen-sensitivecoagulation proteins,insulin-like growth factor 1 (IGF-1), andinsulin-like growth factor-binding proteins (IGFBPs).^[10][2][6] In a clinical study, 10 mg/day estetrol showed only 15 to 20% of the increase of 20 μg/day ethinylestradiol on SHBG and AGT levels (both dosages being oral contraceptive dosages).^[33][34] For comparison, it has been reported that a dosage of estradiol that is of similar potency to ethinylestradiol in terms ofFSHTooltip follicle-stimulating hormone suppression and hot flash relief possesses about 25% of the potency of ethinylestradiol on SHBG increase and about 35% of the potency of ethinylestradiol on AGT increase.^[35] Estetrol has shown only minor effects onhemostaticbiomarkers, including both oncoagulation andfibrinolysis.^[6][36] Due to its minimal influence on liver function, estetrol is expected to have a lower risk ofvenous thromboembolism (VTE), a serious but rare adverse effect of all known estrogens, and other undesirable side effects.^[2] Also, oral estrogens like ethinylestradiol are associated with a reduction inlean body mass due to suppression of hepatic IGF-1 production, and this may not be expected with estetrol.^[35][6]

Estetrol has potent estrogenic effects in the brain in terms of relief of hot flashes,antigonadotropic effects, andovulation inhibition.^[2] However, animal studies investigating the effects of estetrol on levels ofallopregnanolone andβ-endorphin in various brain areas have shown weak estrogenic effects when given alone and antiestrogenic effects in the presence of estradiol, suggesting that estetrol may have SERM-like effects in some regions of the brain by mediating weak estrogenic effects on the levels of allopregnanolone and β-endorphin when administered alone, or by causing antiestrogenic effects in the presence of estradiol in-vivo.^[31][37][38] Estetrol has mixed effects in the vascular system similarly.^[31][39] It has been found to have estrogenic effects onatheroma prevention in arteries (and hence might be expected to have beneficial effects onatherosclerosis), but has antiestrogenic effects against estradiol-inducedendothelialnitric oxide synthase activation and acceleration of endothelial healing.^[31][39]

Administration of single doses of estetrol to postmenopausal women strongly suppressedsecretion ofluteinizing hormone (LH) andfollicle-stimulating hormone (FSH), demonstrating potentantigonadotropic effects.^[2][4] Levels of LH were not suppressed by a dose of 0.1 or 1 mg, were slightly suppressed by a dose of 10 mg, and were profoundly suppressed by a dose of 100 mg (by a maximum of 48% 4-hours post-dose).^[2][4] A profound and sustained inhibition of FSH levels (by a maximum of 41% 48-hours post-dose), lasting up to a week, was found with a 100 mg dose of estetrol (other doses were not assessed).^[2][4] The antigonadotropic effects of estetrol result in inhibition ofovulation and hence are involved in itshormonal contraceptive effects in women.^[2][40][4] In addition, the antigonadotropic effects of estetrol cause suppression ofgonadalsex hormoneproduction.^[9] In healthy men, 40 mg/day estetrol suppressed totaltestosterone levels by 60% andestradiol levels by 62% when measured at day 28 of administration.^[9] In another study of healthy men, testosterone levels were suppressed with estetrol therapy by 28% at 20 mg/day, by 60% at 40 mg/day, and by 76% at 60 mg/day after 4 weeks.^[41] Suppression of testosterone levels is the primary basis for the use of estetrol in the treatment ofprostate cancer.^[9][41]

The oral bioavailability of estetrol in rats was 70% relative tosubcutaneous injection.^[2] The high oral bioavailability of estetrol^[42] is in contrast toestradiol,estrone, andestriol (all very low, in the range of 5% and below), but is more similar toethinylestradiol (38–48%).^[4][35] Estetrol shows a high and lineardose–response relationship across oral doses of 0.1 to 100 mg in humans, and shows lowinterindividual variability.^[2][4] Upon oral administration, estetrol is very rapidlyabsorbed, withmaximal levels in blood occurring within 15 to 80 minutes.^[4][6] At a dosage of 20 mg/day estetrol, peak levels of estetrol of 3,490 pg/mL and trough levels of 2,005 pg/mL have been reported.^[6] The highwater solubility of estetrol makes it optimal for passage of theblood–brain barrier, and the drug may be expected to have effects in thecentral nervous system.^[2] In accordance, estetrol shows clear central effects such as alleviation ofhot flashes andantigonadotropic effects in humans.^[14][40][9] In terms ofplasma protein binding, estetrol is bound moderately toalbumin, and is not bound to SHBG.^[4][5] This is in contrast to estradiol, which binds to SHBG with highaffinity, but is similar to estriol and ethinylestradiol, which have only very low affinity for SHBG.^[4][2] Due to its lack of affinity for SHBG, theplasmadistribution or availability for target tissues of estetrol is not limited or otherwise influenced by SHBG.^[3]

Estetrol ismetabolized slowly and minimally, and is nottransformed into other estrogens such as estradiol, estrone, or estriol.^[2][21][4] This is related to the fact that estetrol is already an end-stage product ofphase I estrogen metabolism in humans.^[4] The medication isconjugated viaglucuronidation and to a lesser extent viasulfation.^[2][6] Thebiological half-life of estetrol is about 28 hours, with a range of 18 to 60 hours.^[4][6] The blood half-lives of estradiol and estriol, at about 1 to 2 hours and 20 minutes, respectively, are far shorter than that of estetrol, whereas the biological half-life of ethinylestradiol, at approximately 20 hours, is more similar to that of estetrol.^[4]Enterohepatic recirculation may occur with estetrol, similarly to other steroidal estrogens, although it has also been reported that estetrol does not seem to enter the enterohepatic circulation.^[4][43] Estetrol isexcreted mostly or completely inurine, virtually entirely in the form ofconjugates (unconjugated accounting for 0.2–0.7%).^[6][2] In one study, a median of 79.7% (range 61.1–99.0%) was recovered from urine; this was primarily as estetrol glucuronide (median 60.7%, range 47.6–77.2%), and, to a lesser extent, as estetrol sulfate (median 17.6%, range 13.2–22.1%).^[6]

v t e Structures of major endogenous estrogens Estrone (E1) Estradiol (E2) Estriol (E3) Estetrol (E4) Note thehydroxyl (–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 anaturally occurringestranesteroid and aderivative ofestrin (estra-1,3,5(10)-triene).^[2][3] It has fourhydroxyl groups, which is the basis for its abbreviation ofE4.^[2][3] For comparison,estriol (E3) has three hydroxyl groups,estradiol (E2) has two hydroxyl groups, andestrone (E1) has one hydroxyl group and oneketone.^[2]

Chemical syntheses of estetrol have been published.^[44]

Estetrol was discovered in 1965 by Egon Diczfalusy and coworkers at the Karolinska Institute in Stockholm, Sweden, via isolation from theurine of pregnant women.^[2][13] Basic research on estetrol was conducted from 1965 to 1984.^[2][3] It was established that estetrol is exclusively synthesized in the human fetal liver. In 1984, estetrol was regarded as a weak estrogen, which hampered its interest, and further research was virtually abandoned.^[2][3] Subsequently, in 2001 Pantarhei Bioscience re-started to investigate estetrol using state-of-the-art technologies, with the sole reasoning that estetrol must have some biological role or function of importance as it would not be produced in such high quantities in the fetus otherwise.^[2] By 2008, estetrol was of major interest for potential clinical use, and development was in-progress.^[2][3] As of 2020, the phase III clinical development (in combination with drospirenone) for hormonal contraception has been completed^[45][46] and it is in mid- to late-stage clinical development for a variety of other indications.^[8] including menopausal hormone therapy (MHT) by Mithra Pharmaceuticals and advanced breast and prostate cancer by Pantarhei Oncology.

Estetrol 15 mg in combination with drospirenone 3 mg has been approved for the use of hormonal contraception in Europe,^[47][48] the US,^[49] Canada^[50] and Australia^[51] and is pending approval in other countries.

Estetrol is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name.^[52]

Estetrol is under development for use alone for a variety of indications. Applications includemenopausal hormone therapy among others.^[2][3] The phase III clinical development of estetrol forvasomotor symptoms and genitourinary symptoms of menopause has been initiated in October 2019.^[53] As of June 2018, it is inphase IIclinical trials forbreast cancer andprostate cancer.^{[citation needed]}

In addition to a single-drug formulation, estetrol is being developed in combination with theprogestindrospirenone for hormonal contraception (use as abirth control pill) to prevent pregnancy. Drospirenone is a potentantimineralocorticoid andantiandrogen in addition toprogestogen, and in relation to this, is said to have aprogesterone-like medication profile.^[54][55][8] The clinical development program forhormonal contraception of theestetrol/drospirenone combination has been completed, and as of 2020, the dossier is under review by both theEuropean Medicines Agency (EMA) and the U.S.Food and Drug Administration (FDA).^[16][17]

Estetrol has been studied in humans atoral doses of 0.1 to 1000mg.^[2][4][14] Dosages of between 2 and 40 mg/day estetrol have been studied in postmenopausal women and found to be effective in the alleviation ofmenopausal symptoms.^[14]

High single doses of estetrol of 1000 mg have been studied in women and were found to be well-tolerated.^[4] Estetrol is 10 to 20 times less potent orally than the highly potent estrogenethinylestradiol.^[4] Duringpregnancy, estetrol levels increase to high concentrations of about 723 pg/mL on average in the mother and about 9,034 pg/mL on average in thefetus (measured viaumbilical cord blood) by term.^[56] Estetrol levels are 10 to 20 times higher in the fetal circulation than in the maternal circulation (which is a consequence of the fact that estetrol is produced exclusively in the fetalliver).^[4][56] The production of high amounts of estetrol during pregnancy suggests that it may be a reasonably safe compound at such concentrations.^[43]

Estetrol shows minimal to noinhibition orinduction ofcytochrome P450enzymes.^[2][21] In addition, estetrol undergoes minimal phase Imetabolism by CYP450 enzymes, but is conjugated viaglucuronidation and to a lesser extentsulfation and thenexcreted.^[2][21] As such, estetrol is expected to harbor a low risk fordrug interactions.^[2][21]

• Birth control pill formulations
• Estrogens and progestogens
• Drospirenone/estetrol

• "Estetrol".Drug Information Portal. U.S. National Library of Medicine. Archived fromthe original on 16 April 2021.

• Drugs not assigned an ATC code
• Antigonadotropins
• Estranes
• Estrogens
• Hormonal antineoplastic drugs
• Hormonal contraception
• Immunomodulating drugs
• Hydroxyarenes
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• Selective estrogen receptor modulators

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