Estetrol and Estetrol (medication): Difference between pages

{{Short description|Estrogen medication}}

{{About|estetrol as a medication|its role as a hormone|Estetrol}}

{{Drugbox

| Verifiedfields =

| Watchedfields =

| verifiedrevid = 437385642

| drug_name = Estetrol

| image = Estetrol.svg

| alt = Skeletal formula of estetrol

| width = 235px

| image2 = Estetrol 3D ball.png

| alt2 = Ball-and-stick model of the estetrol molecule

| width2 = 225px

<!-- Clinical data -->

| pronounce =

| tradename = ''With [[drospirenone]]:'' Estelle, Nextstellis

| Drugs.com =

| MedlinePlus =

| licence_EU = <!-- EMA uses INN (or special INN_EMA) -->

| DailyMedID = <!-- DailyMed may use generic or brand name (generic name preferred) -->

| licence_US = <!-- FDA may use generic or brand name (generic name preferred) -->

| pregnancy_AU = B3

| pregnancy_AU_comment = <ref>{{cite web | title=Updates to the Prescribing Medicines in Pregnancy database | website=Therapeutic Goods Administration (TGA) | date=21 December 2022 | url=https://www.tga.gov.au/resources/resource/guidance/updates-prescribing-medicines-pregnancy-database | access-date=2 January 2023}}</ref>

| pregnancy_category=

| routes_of_administration = [[Oral administration|By mouth]]<ref name="pmid18464023" /><ref name="pmid19167495" />

| class = [[Estrogen (medication)|Estrogen]]

| ATC_prefix = None

| ATC_suffix =

| ATC_supplemental = {{ATC|G03|AA18}}

<!-- Legal status -->

| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled -->

| legal_AU_comment =

| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->

| legal_BR_comment =

| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->

| legal_CA_comment =

| legal_DE = <!-- Anlage I, II, III or Unscheduled -->

| legal_DE_comment =

| legal_NZ = <!-- Class A, B, C -->

| legal_NZ_comment =

| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->

| legal_UK_comment =

| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->

| legal_US_comment =

| legal_EU =

| legal_EU_comment =

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->

| legal_UN_comment =

| legal_status = <!-- For countries not listed above -->

<!-- Pharmacokinetic data -->

| bioavailability = High<ref name="pmid18464021">{{cite journal | vauthors = Visser M, Holinka CF, Coelingh Bennink HJ | title = First human exposure to exogenous single-dose oral estetrol in early postmenopausal women | journal = Climacteric | volume = 11 | issue = Suppl 1 | pages = 31–40 | date = 2008 | pmid = 18464021 | doi = 10.1080/13697130802056511 | s2cid = 23568599 }}</ref>

| protein_bound = Moderately to [[human serum albumin|albumin]], not to {{abbrlink|SHBG|sex hormone-binding globulin}}<ref name="pmid18464021" /><ref name="pmid18464022">{{cite journal | vauthors = Hammond GL, Hogeveen KN, Visser M, Coelingh Bennink HJ | title = Estetrol does not bind sex hormone binding globulin or increase its production by human HepG2 cells | journal = Climacteric | volume = 11 | issue = Suppl 1 | pages = 41–6 | date = 2008 | pmid = 18464022 | doi = 10.1080/13697130701851814 | s2cid = 22715507 }}</ref>

| metabolism = Minimal, [[conjugation (biochemistry)|conjugation]] ([[glucuronidation]], [[sulfation]])<ref name="pmid18464023" /><ref name="pmid26212489">{{cite journal | vauthors = Mawet M, Maillard C, Klipping C, Zimmerman Y, Foidart JM, Coelingh Bennink HJ | title = Unique effects on hepatic function, lipid metabolism, bone and growth endocrine parameters of estetrol in combined oral contraceptives | journal = Eur J Contracept Reprod Health Care | volume = 20 | issue = 6 | pages = 463–75 | date = 2015 | pmid = 26212489 | pmc = 4699469 | doi = 10.3109/13625187.2015.1068934 | doi-broken-date = 1 November 2024 }}</ref>

| metabolites = Estetrol glucuronide<ref name="pmid26212489" /><ref name="pmid18464023" /><br />Estetrol sulfate<ref name="pmid26212489" />

| elimination_half-life = Mean: 28 hours<ref name="pmid18464021" /><ref name="pmid26212489" /><br />Range: 18–60 hours<ref name="pmid18464021" />

| excretion = [[Urine]]: 79.7% (as [[conjugation (biochemistry)|conjugate]]s)<ref name="pmid18464023" /><ref name="pmid26212489" />

<!--Identifiers-->

| CAS_number_Ref = {{cascite|correct|CAS}}

| CAS_number = 15183-37-6

| CAS_supplemental =

| PubChem = 27125

| IUPHAR_ligand =

| DrugBank_Ref =

| DrugBank = DB12235

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = ENB39R14VF

| KEGG_Ref =

| KEGG = D11513

| ChEBI_Ref =

| ChEBI = 142773

| ChEMBL_Ref =

| ChEMBL = 1230314

| NIAID_ChemDB =

| PDB_ligand = 4OH

| synonyms = Oestetrol; E4; 15α-Hydroxyestriol; Estra-1,3,5(10)-triene-3,15α,16α,17β-tetrol

<!-- Chemical and physical data -->

| IUPAC_name = (8''R'',9''S'',13''S'',14''S'',15''R'',16''R'',17''R'')-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[''a'']phenanthrene-3,15,16,17-tetrol

| C=18 | H=24 | O=4

| 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

| StdInChI_comment =

| density =

| density_notes =

| melting_point =

| melting_high =

| melting_notes =

| boiling_point =

| boiling_notes =

| solubility = 1.38

| sol_units =

| specific_rotation =

<!-- Definition and medical uses -->

'''Estetrol''' ('''E4''') is an [[estrogen (medication)|estrogen]] medication and [[natural product|naturally occurring]] [[steroid hormone]] which is used in combination with a [[progestin]] in [[combined birth control pill]]s and is under development for various other indications. These investigational uses include [[menopausal hormone therapy]] to treat symptoms such as [[vaginal atrophy]], [[hot flash]]es, and [[osteoporosis|bone loss]] and the treatment of [[breast cancer]] and [[prostate cancer]].<ref name="pmid18464023">{{cite journal | vauthors = Coelingh Bennink HJ, Holinka CF, Diczfalusy E | title = Estetrol review: profile and potential clinical applications | journal = Climacteric | volume = 11 | issue = Suppl 1 | pages = 47–58 | date = 2008 | pmid = 18464023 | doi = 10.1080/13697130802073425 | s2cid = 24003341 }}</ref><ref name="pmid19167495">{{cite journal | vauthors = Visser M, Coelingh Bennink HJ | title = Clinical applications for estetrol | journal = J. Steroid Biochem. Mol. Biol. | volume = 114 | issue = 1–2 | pages = 85–9 | date = March 2009 | pmid = 19167495 | doi = 10.1016/j.jsbmb.2008.12.013 | s2cid = 32081001 | url = http://www.kup.at/kup/pdf/9090.pdf}}</ref><ref name="AdisInsight-E4">{{Cite web | url=http://adisinsight.springer.com/drugs/800044874 | title=Estetrol - Mithra Pharmaceuticals - AdisInsight}}</ref><ref name="AdisInsight-E4/DRSP">{{Cite web | url=https://adisinsight.springer.com/drugs/800034634 | title=Drospirenone/estetrol - Mithra Pharmaceuticals | work = AdisInsight | publisher = Springer Nature Switzerland AG }}</ref> It is taken [[oral administration|by mouth]].<ref name="pmid18464023" /><ref name="pmid19167495" />

<!-- Side effects and mechanism -->

Estetrol is a [[natural product|naturally occurring]] and [[bioidentical hormone therapy|bioidentical]] estrogen, or an [[agonist]] of the [[estrogen receptor]], the [[biological target]] of [[estrogen]]s like [[endogenous]] [[estradiol]].<ref name="pmid18464023" /><ref name="pmid19167495" /> Due to its estrogenic activity, estetrol has [[antigonadotropic]] effects and can inhibit [[fertility]] and suppress [[sex hormone]] [[biosynthesis|production]] and levels in both women and men.<ref name="pmid18464023" /><ref name="pmid18464021" /><ref name="DutmanZimmerman2017" /> Estetrol differs in various ways both from other natural estrogens like [[estradiol (medication)|estradiol]] and [[synthetic compound|synthetic]] estrogens like [[ethinylestradiol]], with implications for [[tolerability]] and [[drug safety|safety]].<ref name="pmid18464023" /><ref name="pmid18464021" /> For instance, it appears to have minimal estrogenic effects in the [[breast]]s and [[liver]].<ref name="pmid18464023" /><ref name="pmid18464021" /><ref name="pmid25359896" /><ref name="pmid26212489" /> Estetrol interacts with nuclear ERα in a manner identical to that of the other estrogens <ref>{{cite journal | vauthors = Abot A, Fontaine C, Buscato M, Solinhac R, Flouriot G, Fabre A, Drougard A, Rajan S, Laine M, Milon A, Muller I, Henrion D, Adlanmerini M, Valéra MC, Gompel A, Gerard C, Péqueux C, Mestdagt M, Raymond-Letron I, Knauf C, Ferriere F, Valet P, Gourdy P, Katzenellenbogen BS, Katzenellenbogen JA, Lenfant F, Greene GL, Foidart JM, Arnal JF | display-authors = 6 | title = The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor α modulation, uncoupling nuclear and membrane activation | journal = EMBO Molecular Medicine | volume = 6 | issue = 10 | pages = 1328–1346 | date = October 2014 | pmid = 25214462 | pmc = 4287935 | doi = 10.15252/emmm.201404112 }}</ref> and distinct from that observed with Selective Estrogen Receptor Modulators (SERMs).<ref name=":0">Foidart, JM; et al. (2019). "30th Annual Meeting of The North America Menopause Society September 25 – 28, 2019, Chicago, IL". Menopause. 26 (12): 1445–1481. doi:10.1097/GME.0000000000001456. ISSN 1530-0374 </ref>

<!-- History, society, and culture -->

Estetrol was first discovered in 1965, and basic research continued up until 1984.<ref name="pmid18464023" /><ref name="pmid14303250" /> 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.<ref name="pmid18464023" /><ref name="pmid19167495" /> As of 2021, estetrol is in mid- to late-stage clinical development for a variety of indications.<ref name="AdisInsight-E4" /><ref name="AdisInsight-E4/DRSP" />

{{TOC limit|3}}

{{Estrogen dosages for menopausal hormone therapy}}

== Available forms ==

Estetrol is available in combination with drospirenone in the following formulations, brand names and indications:

* 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

==Side effects==

Minimal [[side effect]]s have been observed with estetrol in women.<ref name="pmid18464021" /><ref name="pmid27451327" /> In men, decreased [[libido]] (in 40%) and [[nipple tenderness]] (in 35%) have been observed with high-dose (20–40&nbsp;mg/day) estetrol for four weeks.<ref name="DutmanZimmerman2017" /> The medication poses a risk of [[endometrial hyperplasia]] and [[endometrial cancer]] in women similarly to other estrogens.<ref name="pmid18464023" /><ref name="pmid27451327" /> As such, it is necessary to combine estetrol with a [[progestogen]] in women with intact [[uterus]]es to prevent such risks.<ref name="pmid19387883">{{cite journal|vauthors=Nath A, Sitruk-Ware R|date=June 2009|title=Pharmacology and clinical applications of selective estrogen receptor modulators|journal=Climacteric|volume=12|issue=3|pages=188–205|doi=10.1080/13697130802657896|pmid=19387883|s2cid=25111733}}</ref><ref name="pmid27451327" /> The safety of estetrol alone in women with an intact uterus is currently being investigated.<ref name="NCT04209543" /><ref name="NCT04090957" />

Estetrol-containing [[birth control pill]]s, similarly to [[estradiol-containing birth control pill]]s, may have a lower risk of [[venous thromboembolism]] (VTE) than [[ethinylestradiol]]-containing birth control pills based on studies of [[coagulation]].<ref name="pmid34956081">{{cite journal | vauthors = Morimont L, Haguet H, Dogné JM, Gaspard U, Douxfils J | title = Combined Oral Contraceptives and Venous Thromboembolism: Review and Perspective to Mitigate the Risk | journal = Front Endocrinol (Lausanne) | volume = 12 | issue = | pages = 769187 | date = 2021 | pmid = 34956081 | pmc = 8697849 | doi = 10.3389/fendo.2021.769187 | url = | doi-access = free }}</ref><ref name="pmid33080636">{{cite journal | vauthors = Douxfils J, Morimont L, Bouvy C | title = Oral Contraceptives and Venous Thromboembolism: Focus on Testing that May Enable Prediction and Assessment of the Risk | journal = Semin Thromb Hemost | volume = 46 | issue = 8 | pages = 872–886 | date = November 2020 | pmid = 33080636 | doi = 10.1055/s-0040-1714140 | s2cid = 224821517 | url = }}</ref> 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.<ref name="pmid35133236">{{cite journal | vauthors = Grandi G, Facchinetti F, Bitzer J | title = Confirmation of the safety of combined oral contraceptives containing oestradiol on the risk of venous thromboembolism | journal = Eur J Contracept Reprod Health Care | volume = 27| issue = 2| pages = 83–84 | date = February 2022 | pmid = 35133236 | doi = 10.1080/13625187.2022.2029397 | s2cid = 246651102 | url = | quote = Moreover, the introduction of other new natural oestrogenic components, such as estetrol (E4) [12], could have a similar lower VTE impact; however, we will likely need another decade to obtain results from post-marketing studies.| doi-access = free }}</ref>

==Pharmacology==

===Pharmacodynamics===

Estetrol is an [[agonist]] of the [[estrogen receptor]]s (ERs), and hence is an [[estrogen (medication)|estrogen]].<ref name="pmid18464023" /><ref name="pmid19167495" /> It has moderate [[affinity (pharmacology)|affinity]] for [[ERα]] and [[ERβ]], with K_i values of 4.9&nbsp;nM and 19&nbsp;nM, respectively.<ref name="pmid18464023" /><ref name="pmid18464025">{{cite journal | vauthors = Visser M, Foidart JM, Coelingh Bennink HJ | title = In vitro effects of estetrol on receptor binding, drug targets and human liver cell metabolism | journal = Climacteric | volume = 11 | issue = Suppl 1 | pages = 64–68 | date = 2008 | pmid = 18464025 | doi = 10.1080/13697130802050340 | s2cid = 11027782 }}</ref> As such, estetrol has 4- to 5-fold preference for ERα over ERβ.<ref name="pmid18464023" /><ref name="pmid18464025" /> For comparison, the potent [[nonsteroidal estrogen]] [[diethylstilbestrol]] showed higher affinities for ERs, with K_i values of 0.286&nbsp;nM for ERα and 0.199&nbsp;nM for ERβ.<ref name="pmid18464025" /> Similarly, estetrol has low affinity for ERs relative to estradiol, and thus both estetrol and the related estrogen [[estriol (medication)|estriol]] require substantially higher concentrations than estradiol to produce similar effects.<ref name="pmid18464023" /> The affinity of estetrol for ERs is about 0.3% (rat) to 6.25% (human) of that of estradiol, and its ''[[in vivo]]'' [[potency (pharmacology)|potency]] in animals is about 2 to 3% of that of estradiol.<ref name="pmid18464023" /> In women, estetrol has been found to be approximately 10 to 20&nbsp;times less potent orally than [[ethinylestradiol]], the most potent oral estrogen available.<ref name="pmid18464023" /> The high oral potency of estetrol in women in spite of relatively low affinity for the ERs is related to its high [[metabolic stability]] and favorable [[pharmacokinetics]].<ref name="pmid18464023" />

Estetrol shows high [[binding selectivity|selectivity]] for the ERs.<ref name="pmid18464023" /><ref name="pmid18464025" /> It showed only 11 to 15% occupation of the [[androgen receptor|androgen]], [[progesterone receptor|progesterone]], and [[glucocorticoid receptor]]s at a very high concentration of 10&nbsp;μM.<ref name="pmid18464023" /><ref name="pmid18464025" /> In addition, estetrol showed no affinity (>10&nbsp;μM) for a set of 124&nbsp;[[receptor (biochemistry)|receptor]]s and [[enzyme]]s, with the sole exception of very weak affinity for the [[α1B-adrenergic receptor|α_1B-adrenergic receptor]] (23% inhibition of [[prazosin]] binding at a concentration of 10&nbsp;μM).<ref name="pmid18464023" /><ref name="pmid18464025" /> Due to its high selectivity for the ERs, estetrol is anticipated to have a low risk of undesirable [[off-target activity]] and associated [[side effect]]s.<ref name="pmid18464023" /><ref name="pmid18464025" /> Furthermore, estetrol showed no [[enzyme inhibition|inhibition]] of the major [[cytochrome P450]] [[enzyme]]s [[CYP1A2]], [[CYP2C9]], [[CYP2C19]], [[CYP2D6]], and [[CYP3A4]] at a very high concentration of 10&nbsp;μM, unlike estradiol and ethinylestradiol.<ref name="pmid18464023" /><ref name="pmid18464025" /> Conversely, estetrol moderately stimulated CYP3A4 (by 23%), while estradiol strongly stimulated CYP3A4 (by 83%) and ethinylestradiol moderately inhibited the enzyme (by 45%).<ref name="pmid18464023" /><ref name="pmid18464025" /> These findings suggest that estetrol has a low potential for [[drug interaction]]s, including a lower potential than estradiol and particularly ethinylestradiol.<ref name="pmid18464023" /><ref name="pmid18464025" />

{{Affinities of estrogen receptor ligands for the ERα and ERβ}}

{{Relative affinities of estrogens for steroid hormone receptors and blood proteins}}

{{Selected biological properties of endogenous estrogens in rats}}

====Differences from other estrogens====

Estetrol has potent [[estrogen (medication)|estrogenic]] effects in [[bone]], [[vagina]], [[uterus]] (both [[myometrium]] and [[endometrium]]), [[artery|arteries]], and certain areas of the [[brain]] like the [[pituitary gland]] and [[hypothalamus]] (in terms of [[hot flash]] relief, [[antigonadotropic]] effects, and [[ovulation]] inhibition).<ref name="pmid18464023" /><ref name="pmid26056044" /> It has comparable efficacy to ethinylestradiol on [[bone turnover]] and hot flashes and to [[estradiol valerate]] on [[vaginal atrophy]].<ref name="pmid18464023" /><ref name="pmid26212489" /><ref name="pmid27451327" /> In addition, estetrol has stimulatory effects on the endometrium and poses a risk of [[endometrial hyperplasia]] and [[endometrial cancer]] similar to other estrogens.<ref name="pmid18464023" /><ref name="pmid27451327" /> Conversely, the effects of estetrol in certain other [[tissue (biology)|tissue]]s such as [[breast]]/[[mammary gland]], [[liver]], [[vascular system|vascular]] tissue, and various brain areas differ, with weakly estrogenic or even [[antiestrogen]]ic effects occurring in such tissues.<ref name="pmid18464023" /><ref name="pmid25359896" /><ref name="pmid26212489" /><ref name="pmid26056044" /> 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. <ref name="pmid18464023" /><ref name=":0" /><ref name="pmid26056044" />

Estetrol has a low estrogenic effect in breast/mammary gland, and when administered in combination with estradiol, [[receptor antagonist|antagonize]]s the effects of estradiol.<ref name="pmid18464023" /><ref name="pmid26056044">{{cite journal | vauthors = Gérard C, Mestdagt M, Tskitishvili E, Communal L, Gompel A, Silva E, Arnal JF, Lenfant F, Noel A, Foidart JM, Péqueux C | title = Combined estrogenic and anti-estrogenic properties of estetrol on breast cancer may provide a safe therapeutic window for the treatment of menopausal symptoms | journal = Oncotarget | volume = 6 | issue = 19 | pages = 17621–36 | date = July 2015 | pmid = 26056044 | pmc = 4627333 | doi = 10.18632/oncotarget.4184 }}</ref> Relative to estradiol, estetrol shows 100-fold lower potency in stimulating the [[cell proliferation|proliferation]] of human breast [[epithelial cell]]s ''[[in vitro]]'' and of mouse mammary gland cells ''[[in vivo]]''.<ref name="pmid25359896">{{cite journal | vauthors = Gérard C, Blacher S, Communal L, Courtin A, Tskitishvili E, Mestdagt M, Munaut C, Noel A, Gompel A, Péqueux C, Foidart JM | title = Estetrol is a weak estrogen antagonizing estradiol-dependent mammary gland proliferation | journal = J. Endocrinol. | volume = 224 | issue = 1 | pages = 85–95 | date = January 2015 | pmid = 25359896 | doi = 10.1530/JOE-14-0549 | doi-access = free }}</ref> In [[animal model]]s, estetrol shows antiestrogenic effects, antagonizing the stimulatory effects of estradiol and preventing [[tumor]] development in a [[7,12-dimethylbenz(a)anthracene]] (DMBA) mammary tumor model.<ref name="pmid18464023" /><ref name="pmid26056044" /><ref name="pmid25961355">{{cite journal | vauthors = Visser M, Kloosterboer HJ, Bennink HJ | title = Estetrol prevents and suppresses mammary tumors induced by DMBA in a rat model | journal = Horm Mol Biol Clin Investig | volume = 9 | issue = 1 | pages = 95–103 | date = April 2012 | pmid = 25961355 | doi = 10.1515/hmbci-2012-0015 | s2cid = 35660932 }}</ref> As such, it is anticipated that estetrol may cause minimal proliferation of breast tissue and that it may be useful in the treatment of [[breast cancer]].<ref name="pmid18464023" /><ref name="pmid25359896" />

Estetrol has relatively minimal effects on liver function.<ref name="pmid25359896" /><ref name="pmid26212489" /> In contrast to estradiol and ethinylestradiol, estetrol does not stimulate the hepatic production of SHBG ''in vitro''.<ref name="pmid18464022" /> In addition, it has been found to produce minimal changes in [[liver protein synthesis]] in women relative to ethinylestradiol, including production of [[sex hormone-binding globulin]] (SHBG), [[corticosteroid-binding globulin]] (CBG), [[angiotensinogen]] (AGT), [[ceruloplasmin]], [[cholesterol]], [[triglyceride]]s, estrogen-sensitive [[coagulation protein]]s, [[insulin-like growth factor 1]] (IGF-1), and [[insulin-like growth factor-binding protein]]s (IGFBPs).<ref name="pmid25359896" /><ref name="pmid18464023" /><ref name="pmid26212489" /> In a clinical study, 10&nbsp;mg/day estetrol showed only 15 to 20% of the increase of 20&nbsp;μg/day ethinylestradiol on SHBG and AGT levels (both dosages being oral contraceptive dosages).<ref name="pmid28712325">{{cite journal | vauthors = Farris M, Bastianelli C, Rosato E, Brosens I, Benagiano G | title = Pharmacodynamics of combined estrogen-progestin oral contraceptives: 2. effects on hemostasis | journal = Expert Review of Clinical Pharmacology | volume = 10 | issue = 10 | pages = 1129–1144 | date = October 2017 | pmid = 28712325 | doi = 10.1080/17512433.2017.1356718 | s2cid = 205931204 }}</ref><ref name="pmid27593335">{{cite journal | vauthors = Kluft C, Zimmerman Y, Mawet M, Klipping C, Duijkers IJ, Neuteboom J, Foidart JM, Bennink HC | display-authors = 6 | title = Reduced hemostatic effects with drospirenone-based oral contraceptives containing estetrol vs. ethinyl estradiol | journal = Contraception | volume = 95 | issue = 2 | pages = 140–147 | date = February 2017 | pmid = 27593335 | doi = 10.1016/j.contraception.2016.08.018 | hdl = 2268/247756 | hdl-access = free }}</ref> For comparison, it has been reported that a dosage of estradiol that is of similar potency to ethinylestradiol in terms of {{abbrlink|FSH|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.<ref name="pmid16112947" /> Estetrol has shown only minor effects on [[hemostatic]] [[biomarker]]s, including both on [[coagulation]] and [[fibrinolysis]].<ref name="pmid26212489" /><ref>{{cite journal | vauthors = Douxfils J, Klipping C, Duijkers I, Kinet V, Mawet M, Maillard C, Jost M, Rosing J, Foidart JM | display-authors = 6 | title = Evaluation of the effect of a new oral contraceptive containing estetrol and drospirenone on hemostasis parameters | journal = Contraception | volume = 102 | issue = 6 | pages = 396–402 | date = December 2020 | pmid = 32956694 | doi = 10.1016/j.contraception.2020.08.015 | s2cid = 221843478 }}</ref> Due to its minimal influence on liver function, estetrol is expected to have a lower risk of [[venous thromboembolism]] (VTE), a serious but rare adverse effect of all known estrogens, and other undesirable side effects.<ref name="pmid18464023" /> Also, oral estrogens like ethinylestradiol are associated with a reduction in [[lean body mass]] due to suppression of hepatic IGF-1 production, and this may not be expected with estetrol.<ref name="pmid16112947">{{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 | issue = Suppl 1 | pages = 3–63 | date = August 2005 | pmid = 16112947 | doi = 10.1080/13697130500148875 | s2cid = 24616324 }}</ref><ref name="pmid26212489" />

Estetrol has potent estrogenic effects in the brain in terms of relief of hot flashes, [[antigonadotropic]] effects, and [[ovulation]] inhibition.<ref name="pmid18464023" /> However, animal studies investigating the effects of estetrol on levels of [[allopregnanolone]] and [[β-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.<ref name="pmid26056044" /><ref name="pmid24787659">{{cite journal | vauthors = Pluchino N, Santoro AN, Casarosa E, Giannini A, Genazzani A, Russo M, Russo N, Petignat P, Genazzani AR | title = Effect of estetrol administration on brain and serum allopregnanolone in intact and ovariectomized rats | journal = J. Steroid Biochem. Mol. Biol. | volume = 143 | pages = 285–90 | date = September 2014 | pmid = 24787659 | doi = 10.1016/j.jsbmb.2014.04.011 | s2cid = 21359519 }}</ref><ref name="pmid25595451">{{cite journal | vauthors = Pluchino N, Drakopoulos P, Casarosa E, Freschi L, Petignat P, Yaron M, Genazzani AR | title = Effect of estetrol on Beta-Endorphin level in female rats | journal = Steroids | volume = 95 | pages = 104–10 | date = March 2015 | pmid = 25595451 | doi = 10.1016/j.steroids.2015.01.003 | s2cid = 32178988 }}</ref> Estetrol has mixed effects in the vascular system similarly.<ref name="pmid26056044" /><ref name="pmid25214462">{{cite journal | vauthors = Abot A, Fontaine C, Buscato M, Solinhac R, Flouriot G, Fabre A, Drougard A, Rajan S, Laine M, Milon A, Muller I, Henrion D, Adlanmerini M, Valéra MC, Gompel A, Gerard C, Péqueux C, Mestdagt M, Raymond-Letron I, Knauf C, Ferriere F, Valet P, Gourdy P, Katzenellenbogen BS, Katzenellenbogen JA, Lenfant F, Greene GL, Foidart JM, Arnal JF | title = The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor α modulation, uncoupling nuclear and membrane activation | journal = EMBO Mol Med | volume = 6 | issue = 10 | pages = 1328–46 | date = October 2014 | pmid = 25214462 | pmc = 4287935 | doi = 10.15252/emmm.201404112 }}</ref> It has been found to have estrogenic effects on [[atheroma]] prevention in arteries (and hence might be expected to have beneficial effects on [[atherosclerosis]]), but has antiestrogenic effects against estradiol-induced [[endothelium|endothelial]] [[nitric oxide synthase]] activation and acceleration of endothelial healing.<ref name="pmid26056044" /><ref name="pmid25214462" />

{{Relative oral potencies of estrogens}}

====Antigonadotropic effects====

Administration of single doses of estetrol to postmenopausal women strongly suppressed [[secretion]] of [[luteinizing hormone]] (LH) and [[follicle-stimulating hormone]] (FSH), demonstrating potent [[antigonadotropic]] effects.<ref name="pmid18464023" /><ref name="pmid18464021" /> Levels of LH were not suppressed by a dose of 0.1 or 1&nbsp;mg, were slightly suppressed by a dose of 10&nbsp;mg, and were profoundly suppressed by a dose of 100&nbsp;mg (by a maximum of 48% 4-hours post-dose).<ref name="pmid18464023" /><ref name="pmid18464021" /> 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&nbsp;mg dose of estetrol (other doses were not assessed).<ref name="pmid18464023" /><ref name="pmid18464021" /> The antigonadotropic effects of estetrol result in inhibition of [[ovulation]] and hence are involved in its [[hormonal contraceptive]] effects in women.<ref name="pmid18464023" /><ref name="pmid26394847" /><ref name="pmid18464021" /> In addition, the antigonadotropic effects of estetrol cause suppression of [[gonad]]al [[sex hormone]] [[biosynthesis|production]].<ref name="DutmanZimmerman2017" /> In healthy men, 40&nbsp;mg/day estetrol suppressed total [[testosterone]] levels by 60% and [[estradiol]] levels by 62% when measured at day 28 of administration.<ref name="DutmanZimmerman2017" /> In another study of healthy men, testosterone levels were suppressed with estetrol therapy by 28% at 20&nbsp;mg/day, by 60% at 40&nbsp;mg/day, and by 76% at 60&nbsp;mg/day after 4&nbsp;weeks.<ref name="pmid29931320">{{cite journal |vauthors=Coelingh Bennink HJ, Zimmerman Y, Verhoeven C, Dutman AE, Mensinga T, Kluft C, Reisman Y, Debruyne FM |title=A Dose Escalating Study with the Fetal Estrogen Estetrol in Healthy Males |journal=J. Clin. Endocrinol. Metab. |volume=103 |issue=9 |pages=3239–3249 |date=June 2018 |pmid=29931320 |doi=10.1210/jc.2018-00147|doi-access=free }}</ref> Suppression of testosterone levels is the primary basis for the use of estetrol in the treatment of [[prostate cancer]].<ref name="DutmanZimmerman2017" /><ref name="pmid29931320" />

===Pharmacokinetics===

[[File:Levels of estetrol after a single dose of different doses of oral estetrol in postmenopausal women.png|thumb|Estetrol levels following a single dose of different doses of oral estetrol (E4) in postmenopausal women<ref name="pmid18464023" />]]

The oral bioavailability of estetrol in rats was 70% relative to [[subcutaneous injection]].<ref name="pmid18464023" /> The high oral bioavailability of estetrol <ref>{{cite journal | vauthors = Visser M, Holinka CF, Coelingh Bennink HJ | title = First human exposure to exogenous single-dose oral estetrol in early postmenopausal women | journal = Climacteric | volume = 11 1| issue = sup1 | pages = 31–40 | date = 2008 | pmid = 18464021 | doi = 10.1080/13697130802056511 | s2cid = 23568599 }}</ref> is in contrast to [[estradiol (medication)|estradiol]], [[estrone (medication)|estrone]], and [[estriol (medication)|estriol]] (all very low, in the range of 5% and below), but is more similar to [[ethinylestradiol]] (38–48%).<ref name="pmid18464021" /><ref name="pmid16112947" /> Estetrol shows a high and linear [[dose–response relationship]] across oral doses of 0.1 to 100&nbsp;mg in humans, and shows low [[interindividual variability]].<ref name="pmid18464023" /><ref name="pmid18464021" /> Upon oral administration, estetrol is very rapidly [[absorption (pharmacokinetics)|absorbed]], with [[Cmax (pharmacology)|maximal levels]] in blood occurring within 15 to 80&nbsp;minutes.<ref name="pmid18464021" /><ref name="pmid26212489" /> At a dosage of 20&nbsp;mg/day estetrol, peak levels of estetrol of 3,490&nbsp;pg/mL and trough levels of 2,005&nbsp;pg/mL have been reported.<ref name="pmid26212489" /> The high [[water solubility]] of estetrol makes it optimal for passage of the [[blood–brain barrier]], and the drug may be expected to have effects in the [[central nervous system]].<ref name="pmid18464023" /> In accordance, estetrol shows clear central effects such as alleviation of [[hot flash]]es and [[antigonadotropic]] effects in humans.<ref name="pmid27451327">{{cite journal | vauthors = Coelingh Bennink HJ, Verhoeven C, Zimmerman Y, Visser M, Foidart JM, Gemzell-Danielsson K | title = Clinical effects of the fetal estrogen estetrol in a multiple-rising-dose study in postmenopausal women | journal = Maturitas | volume = 91 | pages = 93–100 | date = September 2016 | pmid = 27451327 | doi = 10.1016/j.maturitas.2016.06.017 | doi-access = free }}</ref><ref name="pmid26394847">{{cite journal | vauthors = Duijkers IJ, Klipping C, Zimmerman Y, Appels N, Jost M, Maillard C, Mawet M, Foidart JM, Coelingh Bennink HJ | display-authors = 6 | title = Inhibition of ovulation by administration of estetrol in combination with drospirenone or levonorgestrel: Results of a phase II dose-finding pilot study | journal = The European Journal of Contraception & Reproductive Health Care | volume = 20 | issue = 6 | pages = 476–489 | date = 2015 | pmid = 26394847 | pmc = 4673580 | doi = 10.3109/13625187.2015.1074675 | doi-broken-date = 1 November 2024 }}</ref><ref name="DutmanZimmerman2017">{{cite journal| vauthors = Dutman E, Zimmerman Y, Coelingh-Bennink H|title=The effects of the human fetal estrogen estetrol (E4) in healthy men to estimate its potential use for the treatment of prostate cancer|journal=European Urology Supplements|volume=16|issue=3|year=2017|pages=e362–e364|issn=1569-9056|doi=10.1016/S1569-9056(17)30276-2}}</ref> In terms of [[plasma protein binding]], estetrol is bound moderately to [[human serum albumin|albumin]], and is not bound to SHBG.<ref name="pmid18464021" /><ref name="pmid18464022" /> This is in contrast to estradiol, which binds to SHBG with high [[affinity (pharmacology)|affinity]], but is similar to estriol and ethinylestradiol, which have only very low affinity for SHBG.<ref name="pmid18464021" /><ref name="pmid18464023" /> Due to its lack of affinity for SHBG, the [[blood plasma|plasma]] [[distribution (pharmacology)|distribution]] or availability for target tissues of estetrol is not limited or otherwise influenced by SHBG.<ref name="pmid19167495" />

Estetrol is [[metabolism|metabolized]] slowly and minimally, and is not [[biotransformation|transformed]] into other estrogens such as estradiol, estrone, or estriol.<ref name="pmid18464023" /><ref name="pmid18464025" /><ref name="pmid18464021" /> This is related to the fact that estetrol is already an end-stage product of [[Drug metabolism#Phase I – modification|phase I]] estrogen metabolism in humans.<ref name="pmid18464021" /> The medication is [[conjugation (biochemistry)|conjugated]] via [[glucuronidation]] and to a lesser extent via [[sulfation]].<ref name="pmid18464023" /><ref name="pmid26212489">{{cite journal | vauthors = Mawet M, Maillard C, Klipping C, Zimmerman Y, Foidart JM, Coelingh Bennink HJ | title = Unique effects on hepatic function, lipid metabolism, bone and growth endocrine parameters of estetrol in combined oral contraceptives | journal = Eur J Contracept Reprod Health Care | volume = 20 | issue = 6 | pages = 463–75 | date = 2015 | pmid = 26212489 | pmc = 4699469 | doi = 10.3109/13625187.2015.1068934 | doi-broken-date = 1 November 2024 }}</ref> The [[biological half-life]] of estetrol is about 28&nbsp;hours, with a range of 18 to 60&nbsp;hours.<ref name="pmid18464021" /><ref name="pmid26212489" /> The blood half-lives of estradiol and estriol, at about 1 to 2&nbsp;hours and 20&nbsp;minutes, respectively, are far shorter than that of estetrol, whereas the biological half-life of ethinylestradiol, at approximately 20&nbsp;hours, is more similar to that of estetrol.<ref name="pmid18464021" /> [[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.<ref name="pmid18464021" /><ref name="pmid18462934" /> Estetrol is [[excretion|excreted]] mostly or completely in [[urine]], virtually entirely in the form of [[conjugation (biochemistry)|conjugate]]s (unconjugated accounting for 0.2–0.7%).<ref name="pmid26212489" /><ref name="pmid18464023" /> 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%).<ref name="pmid26212489" />

==Chemistry==

{{See also|List of estrogens#Estriol derivatives}}

{{Chemical structures of major endogenous estrogens medication version|align=right|caption=Note the [[hydroxyl group|hydroxyl]] (–OH) [[functional group|group]]s: 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 a [[natural compound|naturally occurring]] [[estrane]] [[steroid]] and a [[chemical derivative|derivative]] of [[estrin (compound)|estrin]] (estra-1,3,5(10)-triene).<ref name="pmid18464023" /><ref name="pmid19167495" /> It has four [[hydroxyl group]]s, which is the basis for its abbreviation of ''E4''.<ref name="pmid18464023" /><ref name="pmid19167495" /> For comparison, [[estriol (medication)|estriol]] (E3) has three hydroxyl groups, [[estradiol (medication)|estradiol]] (E2) has two hydroxyl groups, and [[estrone (medication)|estrone]] (E1) has one hydroxyl group and one [[ketone]].<ref name="pmid18464023" />

===Synthesis===

[[Chemical synthesis|Chemical syntheses]] of estetrol have been published.<ref name="pmid18464024">{{cite journal | vauthors = Warmerdam EG, Visser M, Coelingh Bennink HJ, Groen M | title = A new route of synthesis of estetrol | journal = Climacteric | volume = 11 | issue = Suppl 1 | pages = 59–63 | date = 2008 | pmid = 18464024 | doi = 10.1080/13697130802054078 | s2cid = 42017011 }}</ref>

==History==

Estetrol was discovered in 1965 by Egon Diczfalusy and coworkers at the Karolinska Institute in Stockholm, Sweden, via isolation from the [[urine]] of pregnant women.<ref name="pmid18464023" /><ref name="pmid14303250">{{cite journal | vauthors = Hagen AA, Barr M, Diczfalusy E | title = Metabolism of 17-beta-oestradiol-4-14-C in early infancy | journal = Acta Endocrinol. | volume = 49 | issue = 2| pages = 207–20 | date = June 1965 | pmid = 14303250 | doi = 10.1530/acta.0.0490207 }}</ref> Basic research on estetrol was conducted from 1965 to 1984.<ref name="pmid18464023" /><ref name="pmid19167495"/> 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.<ref name="pmid18464023" /><ref name="pmid19167495" /> 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.<ref name="pmid18464023" /> By 2008, estetrol was of major interest for potential clinical use, and development was in-progress.<ref name="pmid18464023" /><ref name="pmid19167495" /> As of 2020, the phase III clinical development (in combination with drospirenone) for hormonal contraception has been completed<ref>{{ClinicalTrialsGov|NCT02817841|E4 FREEDOM (Female Response Concerning Efficacy and Safety of Estetrol/Drospirenone as Oral Contraceptive in a Multicentric Study) - United States/Canada Study}}</ref><ref>{{ClinicalTrialsGov| NCT02817828 |Estetra. (2019) E4 FREEDOM (Female Response Concerning Efficacy and Safety of Estetrol/Drospirenone as Oral Contraceptive in a Multicentric Study) - EU/Russia Study.}}</ref> and it is in mid- to late-stage clinical development for a variety of other indications.<ref name="AdisInsight-E4/DRSP" /> including menopausal hormone therapy (MHT) by Mithra Pharmaceuticals and advanced breast and prostate cancer by Pantarhei Oncology.

==Society and culture==

=== Legal status ===

Estetrol 15 mg in combination with drospirenone 3 mg has been approved for the use of hormonal contraception in Europe,<ref>{{Cite web|title=Drovelis EMEA authorisation|url=https://www.ema.europa.eu/en/medicines/human/EPAR/drovelis#authorisation-details-section|access-date=4 November 2021|website=European Medicines Agency (EMA)|date=2 June 2021 }}</ref><ref>{{Cite web|title=Lydisilka EMEA authorisation|url=https://www.ema.europa.eu/en/medicines/human/EPAR/lydisilka#authorisation-details-section|access-date=4 November 2021|website=European Medicines Agency (EMA)|date=2 June 2021 }}</ref> the US,<ref>{{Cite web|title=Nextstellis Approval FDA|url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=214154|access-date=4 November 2021|website=U.S. Food & Drug Administration (FDA)}}</ref> Canada<ref>{{Cite web|title=Nextstellis Approval Health Canada|url=https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=100241|access-date=4 November 2021|website=Health Canada, Government of Canada| date=25 April 2012 }}</ref> and Australia<ref>{{Cite web |title=Nexstellis Approval ARTG |url=https://www.ebs.tga.gov.au/servlet/xmlmillr6?dbid=ebs/PublicHTML/pdfStore.nsf&docid=ACA7090741588318CA25880D003CF2B9&agid=(PrintDetailsPublic)&actionid=1 |access-date=6 June 2022 |website=Australian Government, Department of Health. }}{{Dead link|date=March 2024 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> and is pending approval in other countries.

===Generic names===

Estetrol is the [[generic term|generic name]] of the drug and its {{abbrlink|INN|International Nonproprietary Name}}.<ref name="WHO2016">{{Cite web|url=http://apps.who.int/medicinedocs/documents/s23133en/s23133en.pdf|title = Essential Medicines and Health Products Information Portal}}{{dead link|date=December 2021|bot=medic}}{{cbignore|bot=medic}}</ref>

==Research==

Estetrol is under development for use alone for a variety of indications. Applications include [[menopausal hormone therapy]] among others.<ref name="pmid18464023" /><ref name="pmid19167495" /> The phase III clinical development of estetrol for [[vasomotor symptom]]s and genitourinary symptoms of menopause has been initiated in October 2019.<ref name=":1">{{Cite web|title=News|url=https://www.mithra.com/en/news|archive-url=https://web.archive.org/web/20151001010907/http://www.mithra.com/en/news/|url-status=dead|archive-date=October 1, 2015|access-date=2020-11-10|website=Mithra}}</ref> As of June 2018, it is in [[Phases of clinical research#Phase II|phase II]] [[Clinical trial|clinical trials]] for [[breast cancer]] and [[prostate cancer]].{{cn|date=March 2021}}

In addition to a single-drug formulation, estetrol is being developed in combination with the [[progestin]] [[drospirenone]] for hormonal contraception (use as a [[birth control pill]]) to prevent pregnancy. Drospirenone is a potent [[antimineralocorticoid]] and [[antiandrogen]] in addition to [[progestogen]], and in relation to this, is said to have a [[progesterone (medication)|progesterone]]-like medication profile.<ref name="pmid17472544">{{cite journal | vauthors = Rapkin AJ, Winer SA | title = Drospirenone: a novel progestin | journal = Expert Opin Pharmacother | volume = 8 | issue = 7 | pages = 989–99 | date = May 2007 | pmid = 17472544 | doi = 10.1517/14656566.8.7.989 | s2cid = 6954183 }}</ref><ref name="pmid15134826">{{cite journal | vauthors = Oelkers W | title = Drospirenone, a progestogen with antimineralocorticoid properties: a short review | journal = Mol. Cell. Endocrinol. | volume = 217 | issue = 1–2 | pages = 255–61 | date = March 2004 | pmid = 15134826 | doi = 10.1016/j.mce.2003.10.030 | s2cid = 19936032 }}</ref><ref name="AdisInsight-E4/DRSP" /> The clinical development program for [[hormonal contraception]] of the [[estetrol/drospirenone]] combination has been completed, and as of 2020, the dossier is under review by both the [[European Medicines Agency]] (EMA) and the U.S. [[Food and Drug Administration]] (FDA).<ref name="NCT04209543">{{ClinicalTrialsGov|NCT04209543|Estetra. (2020) Estetrol for the Treatment of Moderate to Severe Vasomotor Symptoms in Postmenopausal Women (E4Comfort Study I).}}</ref><ref name="NCT04090957">{{ClinicalTrialsGov|NCT04090957|Estetra. (2019) Estetrol for the Treatment of Moderate to Severe Vasomotor Symptoms in Postmenopausal Women (E4Comfort).}}</ref>

Estetrol has been studied in humans at [[oral administration|oral]] doses of 0.1 to 1000mg.<ref name="pmid18464023" /><ref name="pmid18464021" /><ref name="pmid27451327" /> Dosages of between 2 and 40&nbsp;mg/day estetrol have been studied in postmenopausal women and found to be effective in the alleviation of [[menopausal symptoms]].<ref name="pmid27451327" />

===Overdose===

High single doses of estetrol of 1000&nbsp;mg have been studied in women and were found to be well-[[tolerability|tolerated]].<ref name="pmid18464021" /> Estetrol is 10 to 20&nbsp;times less potent orally than the highly potent estrogen [[ethinylestradiol]].<ref name="pmid18464021" /> During [[pregnancy]], estetrol levels increase to high concentrations of about 723&nbsp;pg/mL on average in the mother and about 9,034&nbsp;pg/mL on average in the [[fetus]] (measured via [[umbilical cord]] blood) by term.<ref name="pmid18464026">{{cite journal | vauthors = Coelingh Bennink F, Holinka CF, Visser M, Coelingh Bennink HJ | title = Maternal and fetal estetrol levels during pregnancy | journal = Climacteric | volume = 11 | issue = Suppl 1 | pages = 69–72 | date = 2008 | pmid = 18464026 | doi = 10.1080/13697130802056321 | s2cid = 20399632 }}</ref> Estetrol levels are 10 to 20&nbsp;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 fetal [[liver]]).<ref name="pmid18464021" /><ref name="pmid18464026" /> The production of high amounts of estetrol during pregnancy suggests that it may be a reasonably safe compound at such concentrations.<ref name="pmid18462934">{{cite journal | vauthors = Holinka CF, Diczfalusy E, Coelingh Bennink HJ | title = Estetrol: a unique steroid in human pregnancy | journal = J. Steroid Biochem. Mol. Biol. | volume = 110 | issue = 1–2 | pages = 138–43 | date = May 2008 | pmid = 18462934 | doi = 10.1016/j.jsbmb.2008.03.027 | s2cid = 28007341 }}</ref>

===Interactions===

Estetrol shows minimal to no [[enzyme inhibition|inhibition]] or [[enzyme induction|induction]] of [[cytochrome P450]] [[enzyme]]s.<ref name="pmid18464023" /><ref name="pmid18464025" /> In addition, estetrol undergoes minimal phase I [[metabolism]] by CYP450 enzymes, but is conjugated via [[glucuronidation]] and to a lesser extent [[sulfation]] and then [[Excretion|excreted]].<ref name="pmid18464023" /><ref name="pmid18464025" /> As such, estetrol is expected to harbor a low risk for [[drug interaction]]s.<ref name="pmid18464023" /><ref name="pmid18464025" />

== See also ==

* [[Birth control pill formulations]]

* [[List of combined sex-hormonal preparations#Estrogens and progestogens|Estrogens and progestogens]]

* [[Drospirenone/estetrol]]

==References==

{{Reflist}}

==Further reading==

{{refbegin|30em}}

* {{cite journal | vauthors = Sakamoto H, Ohtani K, Satoh K | title = [Estetrol (E4)] | language = ja | journal = Nihon Rinsho. Japanese Journal of Clinical Medicine | volume = 53 | issue = Su Pt 2 | pages = 566–568 | date = March 1995 | pmid = 8753305 }}

* {{cite journal | vauthors = Holinka CF, Diczfalusy E, Coelingh Bennink HJ | title = Estetrol: a unique steroid in human pregnancy | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 110 | issue = 1–2 | pages = 138–143 | date = May 2008 | pmid = 18462934 | doi = 10.1016/j.jsbmb.2008.03.027 | s2cid = 28007341 }}

* {{cite journal | vauthors = Coelingh Bennink HJ, Holinka CF, Diczfalusy E | title = Estetrol review: profile and potential clinical applications | journal = Climacteric | volume = 11 | issue = Suppl 1 | pages = 47–58 | date = 2008 | pmid = 18464023 | doi = 10.1080/13697130802073425 | s2cid = 24003341 }}

* {{cite journal | vauthors = Warmerdam EG, Visser M, Coelingh Bennink HJ, Groen M | title = A new route of synthesis of estetrol | journal = Climacteric | volume = 11 | issue = Suppl 1 | pages = 59–63 | date = 2008 | pmid = 18464024 | doi = 10.1080/13697130802054078 | s2cid = 42017011 }}

* {{cite journal | vauthors = Visser M, Foidart JM, Coelingh Bennink HJ | title = In vitro effects of estetrol on receptor binding, drug targets and human liver cell metabolism | journal = Climacteric | volume = 11 | issue = Suppl 1 | pages = 64–68 | date = 2008 | pmid = 18464025 | doi = 10.1080/13697130802050340 | s2cid = 11027782 }}

* {{cite journal | vauthors = Coelingh Bennink F, Holinka CF, Visser M, Coelingh Bennink HJ | title = Maternal and fetal estetrol levels during pregnancy | journal = Climacteric | volume = 11 | issue = Suppl 1 | pages = 69–72 | date = 2008 | pmid = 18464026 | doi = 10.1080/13697130802056321 | s2cid = 20399632 }}

* {{cite journal | vauthors = Visser M, Coelingh Bennink HJ | title = Clinical applications for estetrol | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 114 | issue = 1–2 | pages = 85–89 | date = March 2009 | pmid = 19167495 | doi = 10.1016/j.jsbmb.2008.12.013 | s2cid = 32081001 }}

* {{cite journal | vauthors = Krøll J | title = Estetrol, molecular chaperones, and the epigenetics of longevity and cancer resistance | journal = Rejuvenation Research | volume = 17 | issue = 2 | pages = 157–158 | date = April 2014 | pmid = 23992378 | doi = 10.1089/rej.2013.1483 }}

{{refend}}

== External links ==

* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/rn/15183-37-6 | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Estetrol }}

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