estetrol (medication) estetrol (medication) estetrol (e4) is an estrogen medication and naturally occurring steroid hormone which is used in combination with a progestin in combined birth control pills and is under development for various other indications. these investigational uses include menopausal hormone therapy to treat symptoms such as vaginal atrophy, hot flashes, and bone loss and the treatment of breast cancer and prostate cancer. it is taken by mouth. this article is about estetrol as a medication. for its role as a hormone, see estetrol. estetrolclinical datatrade nameswith drospirenone: estelle, nextstellisother namesoestetrol; e4; 15α-hydroxyestriol; estra-1,3,5(10)-triene-3,15α,16α,17β-tetrolpregnancycategory au: b3 routes ofadministrationby mouthdrug classestrogenatc codenonepharmacokinetic databioavailabilityhighprotein bindingmoderately to albumin, not to shbgmetabolismminimal, conjugation (glucuronidation, sulfation)metabolitesestetrol glucuronideestetrol sulfateelimination half-lifemean: 28 hoursrange: 18–60 hoursexcretionurine: 79.7% (as conjugates)identifiers iupac name (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 cas number15183-37-6 ypubchem cid27125drugbankdb12235chemspider25245 yuniienb39r14vfkeggd11513chebichebi:142773chemblchembl1230314pdb ligand4oh (pdbe, rcsb pdb)chemical and physical dataformulac18h24o4molar mass304.386 g·mol−13d model (jsmol)interactive imagesolubility in water1.38 smiles c12cc3(1((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 ykey:ajipijnnojssqc-nylirdpksa-n y (verify) estetrol is a naturally occurring and bioidentical estrogen, or an agonist of the estrogen receptor, the biological target of estrogens like endogenous estradiol. due to its estrogenic activity, estetrol has antigonadotropic effects and can inhibit fertility and suppress sex hormone production and levels in both women and men. estetrol differs in various ways both from other natural estrogens like estradiol and synthetic estrogens like ethinylestradiol, with implications for tolerability and safety. for instance, it appears to have minimal estrogenic effects in the breasts and liver. estetrol interacts with nuclear erα in a manner identical to that of the other estrogens and distinct from that observed with selective estrogen receptor modulators (serms). estetrol was first discovered in 1965, and basic research continued up until 1984. 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. as of 2021, estetrol is in mid- to late-stage clinical development for a variety of indications. estrogen dosages for menopausal hormone therapy route/formestrogenlowstandardhigh oralestradiol0.5–1 mg/day1–2 mg/day2–4 mg/day estradiol valerate0.5–1 mg/day1–2 mg/day2–4 mg/day estradiol acetate0.45–0.9 mg/day0.9–1.8 mg/day1.8–3.6 mg/day conjugated estrogens0.3–0.45 mg/day0.625 mg/day0.9–1.25 mg/day esterified estrogens0.3–0.45 mg/day0.625 mg/day0.9–1.25 mg/day estropipate0.75 mg/day1.5 mg/day3 mg/day estriol1–2 mg/day2–4 mg/day4–8 mg/day ethinylestradiola2.5–10 μg/day5–20 μg/day– nasal sprayestradiol150 μg/day300 μg/day600 μg/day transdermal patchestradiol25 μg/dayb50 μg/dayb100 μg/dayb transdermal gelestradiol0.5 mg/day1–1.5 mg/day2–3 mg/day vaginalestradiol25 μg/day–– estriol30 μg/day0.5 mg 2x/week0.5 mg/day im or sc injectionestradiol valerate––4 mg 1x/4 weeks estradiol cypionate1 mg 1x/3–4 weeks3 mg 1x/3–4 weeks5 mg 1x/3–4 weeks estradiol benzoate0.5 mg 1x/week1 mg 1x/week1.5 mg 1x/week sc implantestradiol25 mg 1x/6 months50 mg 1x/6 months100 mg 1x/6 months footnotes: a = no longer used or recommended, due to health concerns. b = as a single patch applied once or twice per week (worn for 3–4 days or 7 days), depending on the formulation. note: dosages are not necessarily equivalent. sources: see template. available forms 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 effects have been observed with estetrol in women. in men, decreased libido (in 40%) and nipple tenderness (in 35%) have been observed with high-dose (20–40 mg/day) estetrol for four weeks. the medication poses a risk of endometrial hyperplasia and endometrial cancer in women similarly to other estrogens. as such, it is necessary to combine estetrol with a progestogen in women with intact uteruses to prevent such risks. the safety of estetrol alone in women with an intact uterus is currently being investigated. estetrol-containing birth control pills, similarly to estradiol-containing birth control pills, may have a lower risk of venous thromboembolism (vte) than ethinylestradiol-containing birth control pills based on studies of coagulation. 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. pharmacology pharmacodynamics estetrol is an agonist of the estrogen receptors (ers), and hence is an estrogen. it has moderate affinity for erα and erβ, with ki values of 4.9 nm and 19 nm, respectively. as such, estetrol has 4- to 5-fold preference for erα over erβ. for comparison, the potent nonsteroidal estrogen diethylstilbestrol showed higher affinities for ers, with ki values of 0.286 nm for erα and 0.199 nm for erβ. similarly, estetrol has low affinity for ers relative to estradiol, and thus both estetrol and the related estrogen estriol require substantially higher concentrations than estradiol to produce similar effects. the affinity of estetrol for ers is about 0.3% (rat) to 6.25% (human) of that of estradiol, and its in vivo potency in animals is about 2 to 3% of that of estradiol. in women, estetrol has been found to be approximately 10 to 20 times less potent orally than ethinylestradiol, the most potent oral estrogen available. 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. estetrol shows high selectivity for the ers. it showed only 11 to 15% occupation of the androgen, progesterone, and glucocorticoid receptors at a very high concentration of 10 μm. in addition, estetrol showed no affinity (>10 μm) for a set of 124 receptors and enzymes, with the sole exception of very weak affinity for the α1b-adrenergic receptor (23% inhibition of prazosin binding at a concentration of 10 μm). due to its high selectivity for the ers, estetrol is anticipated to have a low risk of undesirable off-target activity and associated side effects. furthermore, estetrol showed no inhibition of the major cytochrome p450 enzymes cyp1a2, cyp2c9, cyp2c19, cyp2d6, and cyp3a4 at a very high concentration of 10 μm, unlike estradiol and ethinylestradiol. conversely, estetrol moderately stimulated cyp3a4 (by 23%), while estradiol strongly stimulated cyp3a4 (by 83%) and ethinylestradiol moderately inhibited the enzyme (by 45%). these findings suggest that estetrol has a low potential for drug interactions, including a lower potential than estradiol and particularly ethinylestradiol. affinities of estrogen receptor ligands for the erα and erβ ligandother namesrelative binding affinities (rba, %)aabsolute binding affinities (ki, nm)aaction erαerβerαerβ estradiole2; 17β-estradiol1001000.115 (0.04–0.24)0.15 (0.10–2.08)estrogen estronee1; 17-ketoestradiol16.39 (0.7–60)6.5 (1.36–52)0.445 (0.3–1.01)1.75 (0.35–9.24)estrogen estriole3; 16α-oh-17β-e212.65 (4.03–56)26 (14.0–44.6)0.45 (0.35–1.4)0.7 (0.63–0.7)estrogen estetrole4; 15α,16α-di-oh-17β-e24.03.04.919estrogen alfatradiol17α-estradiol20.5 (7–80.1)8.195 (2–42)0.2–0.520.43–1.2metabolite 16-epiestriol16β-hydroxy-17β-estradiol7.795 (4.94–63)50 ? ?metabolite 17-epiestriol16α-hydroxy-17α-estradiol55.45 (29–103)79–80 ? ?metabolite 16,17-epiestriol16β-hydroxy-17α-estradiol1.013 ? ?metabolite 2-hydroxyestradiol2-oh-e222 (7–81)11–352.51.3metabolite 2-methoxyestradiol2-meo-e20.0027–2.01.0 ? ?metabolite 4-hydroxyestradiol4-oh-e213 (8–70)7–561.01.9metabolite 4-methoxyestradiol4-meo-e22.01.0 ? ?metabolite 2-hydroxyestrone2-oh-e12.0–4.00.2–0.4 ? ?metabolite 2-methoxyestrone2-meo-e1<0.001–<1<1 ? ?metabolite 4-hydroxyestrone4-oh-e11.0–2.01.0 ? ?metabolite 4-methoxyestrone4-meo-e1<1<1 ? ?metabolite 16α-hydroxyestrone16α-oh-e1; 17-ketoestriol2.0–6.535 ? ?metabolite 2-hydroxyestriol2-oh-e32.01.0 ? ?metabolite 4-methoxyestriol4-meo-e31.01.0 ? ?metabolite estradiol sulfatee2s; estradiol 3-sulfate<1<1 ? ?metabolite estradiol disulfateestradiol 3,17β-disulfate0.0004 ? ? ?metabolite estradiol 3-glucuronidee2-3g0.0079 ? ? ?metabolite estradiol 17β-glucuronidee2-17g0.0015 ? ? ?metabolite estradiol 3-gluc. 17β-sulfatee2-3g-17s0.0001 ? ? ?metabolite estrone sulfatee1s; estrone 3-sulfate<1<1>10>10metabolite estradiol benzoateeb; estradiol 3-benzoate10 ? ? ?estrogen estradiol 17β-benzoatee2-17b11.332.6 ? ?estrogen estrone methyl etherestrone 3-methyl ether0.145 ? ? ?estrogen ent-estradiol1-estradiol1.31–12.349.44–80.07 ? ?estrogen equilin7-dehydroestrone13 (4.0–28.9)13.0–490.790.36estrogen equilenin6,8-didehydroestrone2.0–157.0–200.640.62estrogen 17β-dihydroequilin7-dehydro-17β-estradiol7.9–1137.9–1080.090.17estrogen 17α-dihydroequilin7-dehydro-17α-estradiol18.6 (18–41)14–320.240.57estrogen 17β-dihydroequilenin6,8-didehydro-17β-estradiol35–6890–1000.150.20estrogen 17α-dihydroequilenin6,8-didehydro-17α-estradiol20490.500.37estrogen δ8-estradiol8,9-dehydro-17β-estradiol68720.150.25estrogen δ8-estrone8,9-dehydroestrone19320.520.57estrogen ethinylestradiolee; 17α-ethynyl-17β-e2120.9 (68.8–480)44.4 (2.0–144)0.02–0.050.29–0.81estrogen mestranolee 3-methyl ether ?2.5 ? ?estrogen moxestrolru-2858; 11β-methoxy-ee35–435–200.52.6estrogen methylestradiol17α-methyl-17β-estradiol7044 ? ?estrogen diethylstilbestroldes; stilbestrol129.5 (89.1–468)219.63 (61.2–295)0.040.05estrogen hexestroldihydrodiethylstilbestrol153.6 (31–302)60–2340.060.06estrogen dienestroldehydrostilbestrol37 (20.4–223)56–4040.050.03estrogen benzestrol (b2)–114 ? ? ?estrogen chlorotrianisenetace1.74 ?15.30 ?estrogen triphenylethylenetpe0.074 ? ? ?estrogen triphenylbromoethylenetpbe2.69 ? ? ?estrogen tamoxifenici-46,4743 (0.1–47)3.33 (0.28–6)3.4–9.692.5serm afimoxifene4-hydroxytamoxifen; 4-oht100.1 (1.7–257)10 (0.98–339)2.3 (0.1–3.61)0.04–4.8serm toremifene4-chlorotamoxifen; 4-ct ? ?7.14–20.315.4serm clomifenemrl-4125 (19.2–37.2)120.91.2serm cyclofenilf-6066; sexovid151–152243 ? ?serm nafoxidineu-11,000a30.9–44160.30.8serm raloxifene–41.2 (7.8–69)5.34 (0.54–16)0.188–0.5220.2serm arzoxifenely-353,381 ? ?0.179 ?serm lasofoxifenecp-336,15610.2–16619.00.229 ?serm ormeloxifenecentchroman ? ?0.313 ?serm levormeloxifene6720-cdri; nnc-460,0201.551.88 ? ?serm ospemifenedeaminohydroxytoremifene0.82–2.630.59–1.22 ? ?serm bazedoxifene– ? ?0.053 ?serm etacstilgw-56384.3011.5 ? ?serm ici-164,384–63.5 (3.70–97.7)1660.20.08antiestrogen fulvestrantici-182,78043.5 (9.4–325)21.65 (2.05–40.5)0.421.3antiestrogen propylpyrazoletriolppt49 (10.0–89.1)0.120.4092.8erα agonist 16α-le216α-lactone-17β-estradiol14.6–570.0890.27131erα agonist 16α-iodo-e216α-iodo-17β-estradiol30.22.30 ? ?erα agonist methylpiperidinopyrazolempp110.05 ? ?erα antagonist diarylpropionitriledpn0.12–0.256.6–1832.41.7erβ agonist 8β-ve28β-vinyl-17β-estradiol0.3522.0–8312.90.50erβ agonist prinaberelerb-041; way-202,0410.2767–72 ? ?erβ agonist erb-196way-202,196 ?180 ? ?erβ agonist erteberelserba-1; ly-500,307 ? ?2.680.19erβ agonist serba-2– ? ?14.51.54erβ agonist coumestrol–9.225 (0.0117–94)64.125 (0.41–185)0.14–80.00.07–27.0xenoestrogen genistein–0.445 (0.0012–16)33.42 (0.86–87)2.6–1260.3–12.8xenoestrogen equol–0.2–0.2870.85 (0.10–2.85) ? ?xenoestrogen daidzein–0.07 (0.0018–9.3)0.7865 (0.04–17.1)2.085.3xenoestrogen biochanin a–0.04 (0.022–0.15)0.6225 (0.010–1.2)1748.9xenoestrogen kaempferol–0.07 (0.029–0.10)2.2 (0.002–3.00) ? ?xenoestrogen naringenin–0.0054 (<0.001–0.01)0.15 (0.11–0.33) ? ?xenoestrogen 8-prenylnaringenin8-pn4.4 ? ? ?xenoestrogen quercetin–<0.001–0.010.002–0.040 ? ?xenoestrogen ipriflavone–<0.01<0.01 ? ?xenoestrogen miroestrol–0.39 ? ? ?xenoestrogen deoxymiroestrol–2.0 ? ? ?xenoestrogen β-sitosterol–<0.001–0.0875<0.001–0.016 ? ?xenoestrogen resveratrol–<0.001–0.0032 ? ? ?xenoestrogen α-zearalenol–48 (13–52.5) ? ? ?xenoestrogen β-zearalenol–0.6 (0.032–13) ? ? ?xenoestrogen zeranolα-zearalanol48–111 ? ? ?xenoestrogen taleranolβ-zearalanol16 (13–17.8)140.80.9xenoestrogen zearalenonezen7.68 (2.04–28)9.45 (2.43–31.5) ? ?xenoestrogen zearalanonezan0.51 ? ? ?xenoestrogen bisphenol abpa0.0315 (0.008–1.0)0.135 (0.002–4.23)19535xenoestrogen endosulfaneds<0.001–<0.01<0.01 ? ?xenoestrogen keponechlordecone0.0069–0.2 ? ? ?xenoestrogen o,p'-ddt–0.0073–0.4 ? ? ?xenoestrogen p,p'-ddt–0.03 ? ? ?xenoestrogen methoxychlorp,p'-dimethoxy-ddt0.01 (<0.001–0.02)0.01–0.13 ? ?xenoestrogen hptehydroxychlor; p,p'-oh-ddt1.2–1.7 ? ? ?xenoestrogen testosteronet; 4-androstenolone<0.0001–<0.01<0.002–0.040>5000>5000androgen dihydrotestosteronedht; 5α-androstanolone0.01 (<0.001–0.05)0.0059–0.17221–>500073–1688androgen nandrolone19-nortestosterone; 19-nt0.010.2376553androgen dehydroepiandrosteronedhea; prasterone0.038 (<0.001–0.04)0.019–0.07245–1053163–515androgen 5-androstenediola5; androstenediol6173.60.9androgen 4-androstenediol–0.50.62319androgen 4-androstenedionea4; androstenedione<0.01<0.01>10000>10000androgen 3α-androstanediol3α-adiol0.070.326048androgen 3β-androstanediol3β-adiol3762androgen androstanedione5α-androstanedione<0.01<0.01>10000>10000androgen etiocholanedione5β-androstanedione<0.01<0.01>10000>10000androgen methyltestosterone17α-methyltestosterone<0.0001 ? ? ?androgen ethinyl-3α-androstanediol17α-ethynyl-3α-adiol4.0<0.07 ? ?estrogen ethinyl-3β-androstanediol17α-ethynyl-3β-adiol505.6 ? ?estrogen progesteronep4; 4-pregnenedione<0.001–0.6<0.001–0.010 ? ?progestogen norethisteronenet; 17α-ethynyl-19-nt0.085 (0.0015–<0.1)0.1 (0.01–0.3)1521084progestogen norethynodrel5(10)-norethisterone0.5 (0.3–0.7)<0.1–0.221453progestogen tibolone7α-methylnorethynodrel0.5 (0.45–2.0)0.2–0.076 ? ?progestogen δ4-tibolone7α-methylnorethisterone0.069–<0.10.027–<0.1 ? ?progestogen 3α-hydroxytibolone–2.5 (1.06–5.0)0.6–0.8 ? ?progestogen 3β-hydroxytibolone–1.6 (0.75–1.9)0.070–0.1 ? ?progestogen footnotes: a = (1) binding affinity values are of the format "median (range)" (# (#–#)), "range" (#–#), or "value" (#) depending on the values available. the full sets of values within the ranges can be found in the wiki code. (2) binding affinities were determined via displacement studies in a variety of in-vitro systems with labeled estradiol and human erα and erβ proteins (except the erβ values from kuiper et al. (1997), which are rat erβ). sources: see template page. relative affinities of estrogens for steroid hormone receptors and blood proteins estrogenrelative binding affinities (%) erarprgrmrshbgcbg estradiol1007.92.60.60.138.7–12<0.1 estradiol benzoate ? ? ? ? ?<0.1–0.16<0.1 estradiol valerate2 ? ? ? ? ? ? estrone11–35<1<1<1<12.7<0.1 estrone sulfate22 ? ? ? ? ? estriol10–15<1<1<1<1<0.1<0.1 equilin40 ? ? ? ? ?0 alfatradiol15<1<1<1<1 ? ? epiestriol20<1<1<1<1 ? ? ethinylestradiol100–1121–315–251–3<10.18<0.1 mestranol1 ? ? ? ?<0.1<0.1 methylestradiol671–33–251–3<1 ? ? moxestrol12<0.10.83.2<0.1<0.2<0.1 diethylstilbestrol ? ? ? ? ?<0.1<0.1 notes: reference ligands (100%) were progesterone for the pr, testosterone for the ar, estradiol for the er, dexamethasone for the gr, aldosterone for the mr, dihydrotestosterone for shbg, and cortisol for cbg. sources: see template. selected biological properties of endogenous estrogens in rats estrogener rba (%)uterine weight (%)uterotrophylh levels (%)shbg rba (%) control–100–100– estradiol (e2)100506 ± 20+++12–19100 estrone (e1)11 ± 8490 ± 22+++ ?20 estriol (e3)10 ± 4468 ± 30+++8–183 estetrol (e4)0.5 ± 0.2 ?inactive ?1 17α-estradiol4.2 ± 0.8 ? ? ? ? 2-hydroxyestradiol24 ± 7285 ± 8+b31–6128 2-methoxyestradiol0.05 ± 0.04101inactive ?130 4-hydroxyestradiol45 ± 12 ? ? ? ? 4-methoxyestradiol1.3 ± 0.2260++ ?9 4-fluoroestradiola180 ± 43 ?+++ ? ? 2-hydroxyestrone1.9 ± 0.8130 ± 9inactive110–1428 2-methoxyestrone0.01 ± 0.00103 ± 7inactive95–100120 4-hydroxyestrone11 ± 4351++21–5035 4-methoxyestrone0.13 ± 0.04338++65–9212 16α-hydroxyestrone2.8 ± 1.0552 ± 42+++7–24<0.5 2-hydroxyestriol0.9 ± 0.3302+b ? ? 2-methoxyestriol0.01 ± 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: see template. differences from other estrogens estetrol has potent estrogenic effects in bone, vagina, uterus (both myometrium and endometrium), arteries, and certain areas of the brain like the pituitary gland and hypothalamus (in terms of hot flash relief, antigonadotropic effects, and ovulation inhibition). it has comparable efficacy to ethinylestradiol on bone turnover and hot flashes and to estradiol valerate on vaginal atrophy. in addition, estetrol has stimulatory effects on the endometrium and poses a risk of endometrial hyperplasia and endometrial cancer similar to other estrogens. conversely, the effects of estetrol in certain other tissues such as breast/mammary gland, liver, vascular tissue, and various brain areas differ, with weakly estrogenic or even antiestrogenic effects occurring in such tissues. 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. estetrol has a low estrogenic effect in breast/mammary gland, and when administered in combination with estradiol, antagonizes the effects of estradiol. relative to estradiol, estetrol shows 100-fold lower potency in stimulating the proliferation of human breast epithelial cells in vitro and of mouse mammary gland cells in vivo. in animal models, estetrol shows antiestrogenic effects, antagonizing the stimulatory effects