Estetrol (medication)

Last updated
Estetrol
Estetrol.svg
Estetrol 3D ball.png
Clinical data
Trade names With drospirenone: Estelle, Nextstellis
Other namesOestetrol; E4; 15α-Hydroxyestriol; Estra-1,3,5(10)-triene-3,15α,16α,17β-tetrol
Pregnancy
category
Routes of
administration 		By mouth [2] [3]
Drug class Estrogen
ATC code
  • None
Pharmacokinetic data
Bioavailability High [4]
Protein binding Moderately to albumin, not to SHBG Tooltip sex hormone-binding globulin [4] [5]
Metabolism Minimal, conjugation (glucuronidation, sulfation) [2] [6]
Metabolites Estetrol glucuronide [6] [2]
Estetrol sulfate [6]
Elimination half-life Mean: 28 hours [4] [6]
Range: 18–60 hours [4]
Excretion Urine: 79.7% (as conjugates) [2] [6]
Identifiers
  • (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
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
Chemical and physical data
Formula C18H24O4
Molar mass 304.386 g·mol−1
3D model (JSmol)
Solubility in water 1.38
  • 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=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 Yes check.svgY
  • Key:AJIPIJNNOJSSQC-NYLIRDPKSA-N Yes check.svgY
   (verify)

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. [2] [3] [7] [8] It is taken by mouth. [2] [3]

Contents

Estetrol is a naturally occurring and bioidentical estrogen, or an agonist of the estrogen receptor, the biological target of estrogens like endogenous estradiol. [2] [3] 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. [2] [4] [9] Estetrol differs in various ways both from other natural estrogens like estradiol and synthetic estrogens like ethinylestradiol, with implications for tolerability and safety. [2] [4] For instance, it appears to have minimal estrogenic effects in the breasts and liver. [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]

Estrogen dosages for menopausal hormone therapy
Route/formEstrogenLowStandardHigh
Oral Estradiol 0.5–1 mg/day1–2 mg/day2–4 mg/day
Estradiol valerate 0.5–1 mg/day1–2 mg/day2–4 mg/day
Estradiol acetate 0.45–0.9 mg/day0.9–1.8 mg/day1.8–3.6 mg/day
Conjugated estrogens 0.3–0.45 mg/day0.625 mg/day0.9–1.25 mg/day
Esterified estrogens 0.3–0.45 mg/day0.625 mg/day0.9–1.25 mg/day
Estropipate 0.75 mg/day1.5 mg/day3 mg/day
Estriol 1–2 mg/day2–4 mg/day4–8 mg/day
Ethinylestradiol a2.5–10 μg/day5–20 μg/day–
Nasal spray Estradiol 150 μg/day300 μg/day600 μg/day
Transdermal patch Estradiol 25 μg/dayb50 μg/dayb100 μg/dayb
Transdermal gel Estradiol 0.5 mg/day1–1.5 mg/day2–3 mg/day
Vaginal Estradiol 25 μg/day––
Estriol 30 μg/day0.5 mg 2x/week0.5 mg/day
IM Tooltip Intramuscular or SC injection Estradiol valerate ––4 mg 1x/4 weeks
Estradiol cypionate 1 mg 1x/3–4 weeks3 mg 1x/3–4 weeks5 mg 1x/3–4 weeks
Estradiol benzoate 0.5 mg 1x/week1 mg 1x/week1.5 mg 1x/week
SC implant Estradiol 25 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:

Side effects

Minimal side effects have been observed with estetrol in women. [4] [14] 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. [9] The medication poses a risk of endometrial hyperplasia and endometrial cancer in women similarly to other estrogens. [2] [14] As such, it is necessary to combine estetrol with a progestogen in women with intact uteruses to prevent such risks. [15] [14] The safety of estetrol alone in women with an intact uterus is currently being investigated. [16] [17]

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. [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]

Pharmacology

Pharmacodynamics

Estetrol is an agonist of the estrogen receptors (ERs), and hence is an estrogen. [2] [3] It has moderate affinity for ERα and ERβ, with Ki 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 potent nonsteroidal estrogen diethylstilbestrol showed higher affinities for ERs, with Ki 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 estrogen estriol 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 its in vivo potency 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 than ethinylestradiol, 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 high metabolic stability and favorable pharmacokinetics. [2]

Estetrol shows high selectivity for the ERs. [2] [21] It showed only 11 to 15% occupation of the androgen, progesterone, and glucocorticoid 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 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). [2] [21] 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. [2] [21] 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. [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 for drug interactions, including a lower potential than estradiol and particularly ethinylestradiol. [2] [21]

Affinities of estrogen receptor ligands for the ERα and ERβ
Ligand Other names Relative binding affinities (RBA, %)a Absolute binding affinities (Ki, nM)aAction
ERα ERβ ERα ERβ
Estradiol E2; 17β-Estradiol1001000.115 (0.04–0.24)0.15 (0.10–2.08)Estrogen
Estrone E1; 17-Ketoestradiol16.39 (0.7–60)6.5 (1.36–52)0.445 (0.3–1.01)1.75 (0.35–9.24)Estrogen
Estriol E3; 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
Alfatradiol 17α-Estradiol20.5 (7–80.1)8.195 (2–42)0.2–0.520.43–1.2Metabolite
16-Epiestriol 16β-Hydroxy-17β-estradiol7.795 (4.94–63)50 ? ?Metabolite
17-Epiestriol 16α-Hydroxy-17α-estradiol55.45 (29–103)79–80 ? ?Metabolite
16,17-Epiestriol 16β-Hydroxy-17α-estradiol1.013 ? ?Metabolite
2-Hydroxyestradiol 2-OH-E222 (7–81)11–352.51.3Metabolite
2-Methoxyestradiol 2-MeO-E20.0027–2.01.0 ? ?Metabolite
4-Hydroxyestradiol 4-OH-E213 (8–70)7–561.01.9Metabolite
4-Methoxyestradiol 4-MeO-E22.01.0 ? ?Metabolite
2-Hydroxyestrone 2-OH-E12.0–4.00.2–0.4 ? ?Metabolite
2-Methoxyestrone 2-MeO-E1<0.001–<1<1 ? ?Metabolite
4-Hydroxyestrone 4-OH-E11.0–2.01.0 ? ?Metabolite
4-Methoxyestrone 4-MeO-E1<1<1 ? ?Metabolite
16α-Hydroxyestrone 16α-OH-E1; 17-Ketoestriol2.0–6.535 ? ?Metabolite
2-Hydroxyestriol 2-OH-E32.01.0 ? ?Metabolite
4-Methoxyestriol 4-MeO-E31.01.0 ? ?Metabolite
Estradiol sulfate E2S; Estradiol 3-sulfate<1<1 ? ?Metabolite
Estradiol disulfate Estradiol 3,17β-disulfate0.0004 ? ? ?Metabolite
Estradiol 3-glucuronide E2-3G0.0079 ? ? ?Metabolite
Estradiol 17β-glucuronide E2-17G0.0015 ? ? ?Metabolite
Estradiol 3-gluc. 17β-sulfate E2-3G-17S0.0001 ? ? ?Metabolite
Estrone sulfate E1S; Estrone 3-sulfate<1<1>10>10Metabolite
Estradiol benzoate EB; Estradiol 3-benzoate10 ? ? ?Estrogen
Estradiol 17β-benzoate E2-17B11.332.6 ? ?Estrogen
Estrone methyl ether Estrone 3-methyl ether0.145 ? ? ?Estrogen
ent-Estradiol 1-Estradiol1.31–12.349.44–80.07 ? ?Estrogen
Equilin 7-Dehydroestrone13 (4.0–28.9)13.0–490.790.36Estrogen
Equilenin 6,8-Didehydroestrone2.0–157.0–200.640.62Estrogen
17β-Dihydroequilin 7-Dehydro-17β-estradiol7.9–1137.9–1080.090.17Estrogen
17α-Dihydroequilin 7-Dehydro-17α-estradiol18.6 (18–41)14–320.240.57Estrogen
17β-Dihydroequilenin 6,8-Didehydro-17β-estradiol35–6890–1000.150.20Estrogen
17α-Dihydroequilenin 6,8-Didehydro-17α-estradiol20490.500.37Estrogen
Δ8-Estradiol 8,9-Dehydro-17β-estradiol68720.150.25Estrogen
Δ8-Estrone 8,9-Dehydroestrone19320.520.57Estrogen
Ethinylestradiol EE; 17α-Ethynyl-17β-E2120.9 (68.8–480)44.4 (2.0–144)0.02–0.050.29–0.81Estrogen
Mestranol EE 3-methyl ether ?2.5 ? ?Estrogen
Moxestrol RU-2858; 11β-Methoxy-EE35–435–200.52.6Estrogen
Methylestradiol 17α-Methyl-17β-estradiol7044 ? ?Estrogen
Diethylstilbestrol DES; Stilbestrol129.5 (89.1–468)219.63 (61.2–295)0.040.05Estrogen
Hexestrol Dihydrodiethylstilbestrol153.6 (31–302)60–2340.060.06Estrogen
Dienestrol Dehydrostilbestrol37 (20.4–223)56–4040.050.03Estrogen
Benzestrol (B2) –114 ? ? ?Estrogen
Chlorotrianisene TACE1.74 ?15.30 ?Estrogen
Triphenylethylene TPE0.074 ? ? ?Estrogen
Triphenylbromoethylene TPBE2.69 ? ? ?Estrogen
Tamoxifen ICI-46,4743 (0.1–47)3.33 (0.28–6)3.4–9.692.5SERM
Afimoxifene 4-Hydroxytamoxifen; 4-OHT100.1 (1.7–257)10 (0.98–339)2.3 (0.1–3.61)0.04–4.8SERM
Toremifene 4-Chlorotamoxifen; 4-CT ? ?7.14–20.315.4SERM
Clomifene MRL-4125 (19.2–37.2)120.91.2SERM
Cyclofenil F-6066; Sexovid151–152243 ? ?SERM
Nafoxidine U-11,000A30.9–44160.30.8SERM
Raloxifene –41.2 (7.8–69)5.34 (0.54–16)0.188–0.5220.2SERM
Arzoxifene LY-353,381 ? ?0.179 ?SERM
Lasofoxifene CP-336,15610.2–16619.00.229 ?SERM
Ormeloxifene Centchroman ? ?0.313 ?SERM
Levormeloxifene 6720-CDRI; NNC-460,0201.551.88 ? ?SERM
Ospemifene Deaminohydroxytoremifene0.82–2.630.59–1.22 ? ?SERM
Bazedoxifene – ? ?0.053 ?SERM
Etacstil GW-56384.3011.5 ? ?SERM
ICI-164,384 –63.5 (3.70–97.7)1660.20.08Antiestrogen
Fulvestrant ICI-182,78043.5 (9.4–325)21.65 (2.05–40.5)0.421.3Antiestrogen
Propylpyrazoletriol PPT49 (10.0–89.1)0.120.4092.8ERα agonist
16α-LE2 16α-Lactone-17β-estradiol14.6–570.0890.27131ERα agonist
16α-Iodo-E2 16α-Iodo-17β-estradiol30.22.30 ? ?ERα agonist
Methylpiperidinopyrazole MPP110.05 ? ?ERα antagonist
Diarylpropionitrile DPN0.12–0.256.6–1832.41.7ERβ agonist
8β-VE2 8β-Vinyl-17β-estradiol0.3522.0–8312.90.50ERβ agonist
Prinaberel ERB-041; WAY-202,0410.2767–72 ? ?ERβ agonist
ERB-196 WAY-202,196 ?180 ? ?ERβ agonist
Erteberel SERBA-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-Prenylnaringenin 8-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
Zeranol α-Zearalanol48–111 ? ? ?Xenoestrogen
Taleranol β-Zearalanol16 (13–17.8)140.80.9Xenoestrogen
Zearalenone ZEN7.68 (2.04–28)9.45 (2.43–31.5) ? ?Xenoestrogen
Zearalanone ZAN0.51 ? ? ?Xenoestrogen
Bisphenol A BPA0.0315 (0.008–1.0)0.135 (0.002–4.23)19535Xenoestrogen
Endosulfan EDS<0.001–<0.01<0.01 ? ?Xenoestrogen
Kepone Chlordecone0.0069–0.2 ? ? ?Xenoestrogen
o,p'-DDT –0.0073–0.4 ? ? ?Xenoestrogen
p,p'-DDT –0.03 ? ? ?Xenoestrogen
Methoxychlor p,p'-Dimethoxy-DDT0.01 (<0.001–0.02)0.01–0.13 ? ?Xenoestrogen
HPTE Hydroxychlor; p,p'-OH-DDT1.2–1.7 ? ? ?Xenoestrogen
Testosterone T; 4-Androstenolone<0.0001–<0.01<0.002–0.040>5000>5000Androgen
Dihydrotestosterone DHT; 5α-Androstanolone0.01 (<0.001–0.05)0.0059–0.17221–>500073–1688Androgen
Nandrolone 19-Nortestosterone; 19-NT0.010.2376553Androgen
Dehydroepiandrosterone DHEA; Prasterone0.038 (<0.001–0.04)0.019–0.07245–1053163–515Androgen
5-Androstenediol A5; Androstenediol6173.60.9Androgen
4-Androstenediol –0.50.62319Androgen
4-Androstenedione A4; Androstenedione<0.01<0.01>10000>10000Androgen
3α-Androstanediol 3α-Adiol0.070.326048Androgen
3β-Androstanediol 3β-Adiol3762Androgen
Androstanedione 5α-Androstanedione<0.01<0.01>10000>10000Androgen
Etiocholanedione 5β-Androstanedione<0.01<0.01>10000>10000Androgen
Methyltestosterone 17α-Methyltestosterone<0.0001 ? ? ?Androgen
Ethinyl-3α-androstanediol 17α-Ethynyl-3α-adiol4.0<0.07 ? ?Estrogen
Ethinyl-3β-androstanediol 17α-Ethynyl-3β-adiol505.6 ? ?Estrogen
Progesterone P4; 4-Pregnenedione<0.001–0.6<0.001–0.010 ? ?Progestogen
Norethisterone NET; 17α-Ethynyl-19-NT0.085 (0.0015–<0.1)0.1 (0.01–0.3)1521084Progestogen
Norethynodrel 5(10)-Norethisterone0.5 (0.3–0.7)<0.1–0.221453Progestogen
Tibolone 7α-Methylnorethynodrel0.5 (0.45–2.0)0.2–0.076 ? ?Progestogen
Δ4-Tibolone 7α-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
Estrogen Relative binding affinities (%)
ER Tooltip Estrogen receptor AR Tooltip Androgen receptor PR Tooltip Progesterone receptor GR Tooltip Glucocorticoid receptor MR Tooltip Mineralocorticoid receptor SHBG Tooltip Sex hormone-binding globulin CBG Tooltip Corticosteroid binding globulin
Estradiol 1007.92.60.60.138.7–12<0.1
Estradiol benzoate  ? ? ? ? ?<0.1–0.16<0.1
Estradiol valerate 2 ? ? ? ? ? ?
Estrone 11–35<1<1<1<12.7<0.1
Estrone sulfate 22 ? ? ? ? ?
Estriol 10–15<1<1<1<1<0.1<0.1
Equilin 40 ? ? ? ? ?0
Alfatradiol 15<1<1<1<1 ? ?
Epiestriol 20<1<1<1<1 ? ?
Ethinylestradiol 100–1121–315–251–3<10.18<0.1
Mestranol 1 ? ? ? ?<0.1<0.1
Methylestradiol 671–33–251–3<1 ? ?
Moxestrol 12<0.10.83.2<0.1<0.2<0.1
Diethylstilbestrol  ? ? ? ? ?<0.1<0.1
Notes: Reference ligands (100%) were progesterone for the PR Tooltip progesterone receptor, testosterone for the AR Tooltip androgen receptor, estradiol for the ER Tooltip estrogen receptor, dexamethasone for the GR Tooltip glucocorticoid receptor, aldosterone for the MR Tooltip mineralocorticoid receptor, dihydrotestosterone for SHBG Tooltip sex hormone-binding globulin, and cortisol for CBG Tooltip Corticosteroid-binding globulin. Sources: See template.
Selected biological properties of endogenous estrogens in rats
Estrogen ER Tooltip Estrogen receptor RBA Tooltip relative binding affinity (%) Uterine weight (%) Uterotrophy LH Tooltip Luteinizing hormone levels (%) SHBG Tooltip Sex hormone-binding globulin RBA Tooltip relative binding affinity (%)
Control–100–100–
Estradiol (E2) 100506 ± 20+++12–19100
Estrone (E1) 11 ± 8490 ± 22+++ ?20
Estriol (E3) 10 ± 4468 ± 30+++8–183
Estetrol (E4)0.5 ± 0.2 ?Inactive ?1
17α-Estradiol 4.2 ± 0.8 ? ? ? ?
2-Hydroxyestradiol 24 ± 7285 ± 8+b31–6128
2-Methoxyestradiol 0.05 ± 0.04101Inactive ?130
4-Hydroxyestradiol 45 ± 12 ? ? ? ?
4-Methoxyestradiol 1.3 ± 0.2260++ ?9
4-Fluoroestradiol a180 ± 43 ?+++ ? ?
2-Hydroxyestrone 1.9 ± 0.8130 ± 9Inactive110–1428
2-Methoxyestrone 0.01 ± 0.00103 ± 7Inactive95–100120
4-Hydroxyestrone 11 ± 4351++21–5035
4-Methoxyestrone 0.13 ± 0.04338++65–9212
16α-Hydroxyestrone 2.8 ± 1.0552 ± 42+++7–24<0.5
2-Hydroxyestriol 0.9 ± 0.3302+b ? ?
2-Methoxyestriol 0.01 ± 0.00 ?Inactive ?4
Notes: Values are mean ± SD or range. ERRBA = Relative binding affinity to estrogen receptors of rat uterine cytosol. Uterine weight = Percentage change in uterine wet weight of ovariectomized rats after 72 hours with continuous administration of 1 μg/hour via subcutaneously implanted osmotic pumps. LH levels = Luteinizing hormone levels relative to baseline of ovariectomized rats after 24 to 72 hours of continuous administration via subcutaneous implant. Footnotes:a = Synthetic (i.e., not endogenous). b = Atypical uterotrophic effect which plateaus within 48 hours (estradiol's uterotrophy continues linearly up to 72 hours). Sources: See template.

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). [2] [22] It has comparable efficacy to ethinylestradiol on bone turnover and hot flashes and to estradiol valerate on vaginal atrophy. [2] [6] [14] In addition, estetrol has stimulatory effects on the endometrium and poses a risk of endometrial hyperplasia and endometrial cancer similar to other estrogens. [2] [14] 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. [2] [10] [6] [22] 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] [22]

Estetrol has a low estrogenic effect in breast/mammary gland, and when administered in combination with estradiol, antagonizes the effects of estradiol. [2] [22] 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 . [10] In animal models, 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. [2] [22] [23] 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. [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 SHBG in vitro. [5] 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, triglycerides, estrogen-sensitive coagulation proteins, insulin-like growth factor 1 (IGF-1), and insulin-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). [24] [25] For comparison, it has been reported that a dosage of estradiol that is of similar potency to ethinylestradiol in terms of FSH Tooltip 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. [26] Estetrol has shown only minor effects on hemostatic biomarkers, including both on coagulation and fibrinolysis. [6] [27] 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. [2] 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. [26] [6]

Estetrol has potent estrogenic effects in the brain in terms of relief of hot flashes, antigonadotropic effects, and ovulation inhibition. [2] 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. [22] [28] [29] Estetrol has mixed effects in the vascular system similarly. [22] [30] 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 endothelial nitric oxide synthase activation and acceleration of endothelial healing. [22] [30]

Relative oral potencies of estrogens
Estrogen HF Tooltip Hot flashes VE Tooltip Vaginal epithelium UCa Tooltip Urinary calcium FSH Tooltip Follicle-stimulating hormone LH Tooltip Luteinizing hormone HDL Tooltip High-density lipoprotein-C Tooltip Cholesterol SHBG Tooltip Sex hormone-binding globulin CBG Tooltip Corticosteroid-binding globulin AGT Tooltip AngiotensinogenLiver
Estradiol 1.01.01.01.01.01.01.01.01.01.0
Estrone  ? ? ?0.30.3 ? ? ? ? ?
Estriol 0.30.30.10.30.30.2 ? ? ?0.67
Estrone sulfate  ?0.90.90.8–0.90.90.50.90.5–0.71.4–1.50.56–1.7
Conjugated estrogens 1.21.52.01.1–1.31.01.53.0–3.21.3–1.55.01.3–4.5
Equilin sulfate  ? ?1.0 ? ?6.07.56.07.5 ?
Ethinylestradiol 12015040060–150100400500–600500–6003502.9–5.0
Diethylstilbestrol  ? ? ?2.9–3.4 ? ?26–2825–37205.7–7.5
Sources and footnotes
Notes: Values are ratios, with estradiol as standard (i.e., 1.0). Abbreviations:HF = Clinical relief of hot flashes. VE = Increased proliferation of vaginal epithelium. UCa = Decrease in UCa Tooltip urinary calcium. FSH = Suppression of FSH Tooltip follicle-stimulating hormone levels. LH = Suppression of LH Tooltip luteinizing hormone levels. HDL-C, SHBG, CBG, and AGT = Increase in the serum levels of these liver proteins. Liver = Ratio of liver estrogenic effects to general/systemic estrogenic effects (hot flashes/gonadotropins). Sources: See template.

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. [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 of ovulation and hence are involved in its hormonal contraceptive effects in women. [2] [31] [4] In addition, the antigonadotropic effects of estetrol cause suppression of gonadal sex hormone production. [9] In healthy men, 40 mg/day estetrol suppressed total testosterone levels by 60% and estradiol 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. [32] Suppression of testosterone levels is the primary basis for the use of estetrol in the treatment of prostate cancer. [9] [32]

Pharmacokinetics

Estetrol levels following a single dose of different doses of oral estetrol (E4) in postmenopausal women Levels of estetrol after a single dose of different doses of oral estetrol in postmenopausal women.png
Estetrol levels following a single dose of different doses of oral estetrol (E4) in postmenopausal women

The oral bioavailability of estetrol in rats was 70% relative to subcutaneous injection. [2] The high oral bioavailability of estetrol [33] is in contrast to estradiol, estrone, and estriol (all very low, in the range of 5% and below), but is more similar to ethinylestradiol (38–48%). [4] [26] Estetrol shows a high and linear dose–response relationship across oral doses of 0.1 to 100 mg in humans, and shows low interindividual variability. [2] [4] Upon oral administration, estetrol is very rapidly absorbed, with maximal 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 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. [2] In accordance, estetrol shows clear central effects such as alleviation of hot flashes and antigonadotropic effects in humans. [14] [31] [9] In terms of plasma protein binding, estetrol is bound moderately to albumin, and is not bound to SHBG. [4] [5] This is in contrast to estradiol, which binds to SHBG with high affinity, 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, the plasma distribution or availability for target tissues of estetrol is not limited or otherwise influenced by SHBG. [3]

Estetrol is metabolized slowly and minimally, and is not transformed 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 of phase I estrogen metabolism in humans. [4] The medication is conjugated via glucuronidation and to a lesser extent via sulfation. [2] [6] The biological 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] [34] Estetrol is excreted mostly or completely in urine, virtually entirely in the form of conjugates (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]

Chemistry

Estetrol, also known as 15α-hydroxyestriol or as estra-1,3,5(10)-triene-3,15α,16α,17β-tetrol, is a naturally occurring estrane steroid and a derivative of estrin (estra-1,3,5(10)-triene). [2] [3] It has four hydroxyl groups, which is the basis for its abbreviation of E4. [2] [3] For comparison, estriol (E3) has three hydroxyl groups, estradiol (E2) has two hydroxyl groups, and estrone (E1) has one hydroxyl group and one ketone. [2]

Synthesis

Chemical syntheses of estetrol have been published. [35]

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. [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 [36] [37] 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.

Society and culture

Estetrol 15 mg in combination with drospirenone 3 mg has been approved for the use of hormonal contraception in Europe, [38] [39] the US, [40] Canada [41] and Australia [42] and is pending approval in other countries.

Generic names

Estetrol is the generic name of the drug and its INN Tooltip International Nonproprietary Name. [43]

Research

Estetrol is under development for use alone for a variety of indications. Applications include menopausal hormone therapy among others. [2] [3] The phase III clinical development of estetrol for vasomotor symptoms and genitourinary symptoms of menopause has been initiated in October 2019. [44] As of June 2018, it is in phase II clinical trials for breast cancer and prostate cancer.[ citation needed ]

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-like medication profile. [45] [46] [8] 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). [16] [17]

Estetrol has been studied in humans at oral 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 of menopausal symptoms. [14]

Overdose

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 estrogen ethinylestradiol. [4] During pregnancy, 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 the fetus (measured via umbilical cord blood) by term. [47] 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 fetal liver). [4] [47] The production of high amounts of estetrol during pregnancy suggests that it may be a reasonably safe compound at such concentrations. [34]

Interactions

Estetrol shows minimal to no inhibition or induction of cytochrome P450 enzymes. [2] [21] In addition, estetrol undergoes minimal phase I metabolism by CYP450 enzymes, but is conjugated via glucuronidation and to a lesser extent sulfation and then excreted. [2] [21] As such, estetrol is expected to harbor a low risk for drug interactions. [2] [21]

See also

Related Research Articles

<span class="mw-page-title-main">Progestogen (medication)</span> Medication producing effects similar to progesterone

A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of medication which produces effects similar to those of the natural female sex hormone progesterone in the body. A progestin is a synthetic progestogen. Progestogens are used most commonly in hormonal birth control and menopausal hormone therapy. They can also be used in the treatment of gynecological conditions, to support fertility and pregnancy, to lower sex hormone levels for various purposes, and for other indications. Progestogens are used alone or in combination with estrogens. They are available in a wide variety of formulations and for use by many different routes of administration. Examples of progestogens include natural or bioidentical progesterone as well as progestins such as medroxyprogesterone acetate and norethisterone.

<span class="mw-page-title-main">Ethinylestradiol</span> Estrogen medication

Ethinylestradiol (EE) is an estrogen medication which is used widely in birth control pills in combination with progestins. In the past, EE was widely used for various indications such as the treatment of menopausal symptoms, gynecological disorders, and certain hormone-sensitive cancers. It is usually taken by mouth but is also used as a patch and vaginal ring.

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

Estradiol valerate (EV), sold for use by mouth under the brand name Progynova and for use by injection under the brand names Delestrogen and Progynon Depot among others, is an estrogen medication. It is used in hormone therapy for menopausal symptoms and low estrogen levels, hormone therapy for transgender people, and in hormonal birth control. It is also used in the treatment of prostate cancer. The medication is taken by mouth or by injection into muscle or fat once every 1 to 4 weeks.

<span class="mw-page-title-main">Desogestrel</span> Medication

Desogestrel is a progestin medication which is used in birth control pills for women. It is also used in the treatment of menopausal symptoms in women. The medication is available and used alone or in combination with an estrogen. It is taken by mouth.

<span class="mw-page-title-main">Drospirenone</span> Medication drug

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

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

Norethisterone acetate (NETA), also known as norethindrone acetate and sold under the brand name Primolut-Nor among others, is a progestin medication which is used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication available in low-dose and high-dose formulations and is used alone or in combination with an estrogen. It is ingested orally.

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

Norgestimate, sold under the brand names Ortho Tri-Cyclen and Previfem among others, is a progestin medication which is used in birth control pills for women and in menopausal hormone therapy. The medication is available in combination with an estrogen and is not available alone. It is taken by mouth.

<span class="mw-page-title-main">Norethisterone</span> Progestin medication

Norethisterone, also known as norethindrone and sold under many brand names, is a progestin medication used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication is available in both low-dose and high-dose formulations and both alone and in combination with an estrogen. It is used by mouth or, as norethisterone enanthate, by injection into muscle.

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

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<span class="mw-page-title-main">Estrogen (medication)</span> Type of medication

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<span class="mw-page-title-main">Estriol (medication)</span> Chemical compound

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References

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  20. ↑ Grandi G, Facchinetti F, Bitzer J (February 2022). "Confirmation of the safety of combined oral contraceptives containing oestradiol on the risk of venous thromboembolism". Eur J Contracept Reprod Health Care. 27 (2): 83–84. doi: 10.1080/13625187.2022.2029397 . PMID   35133236. S2CID   246651102. 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.
  21. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Visser M, Foidart JM, Coelingh Bennink HJ (2008). "In vitro effects of estetrol on receptor binding, drug targets and human liver cell metabolism". Climacteric. 11 (Suppl 1): 64–68. doi:10.1080/13697130802050340. PMID   18464025. S2CID   11027782.
  22. 1 2 3 4 5 6 7 8 Gérard C, Mestdagt M, Tskitishvili E, Communal L, Gompel A, Silva E, Arnal JF, Lenfant F, Noel A, Foidart JM, Péqueux C (July 2015). "Combined estrogenic and anti-estrogenic properties of estetrol on breast cancer may provide a safe therapeutic window for the treatment of menopausal symptoms". Oncotarget. 6 (19): 17621–36. doi:10.18632/oncotarget.4184. PMC   4627333 . PMID   26056044.
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  25. ↑ Kluft C, Zimmerman Y, Mawet M, Klipping C, Duijkers IJ, Neuteboom J, et al. (February 2017). "Reduced hemostatic effects with drospirenone-based oral contraceptives containing estetrol vs. ethinyl estradiol". Contraception. 95 (2): 140–147. doi:10.1016/j.contraception.2016.08.018. hdl: 2268/247756 . PMID   27593335.
  26. 1 2 3 Kuhl H (August 2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration". Climacteric. 8 (Suppl 1): 3–63. doi:10.1080/13697130500148875. PMID   16112947. S2CID   24616324.
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  28. ↑ Pluchino N, Santoro AN, Casarosa E, Giannini A, Genazzani A, Russo M, Russo N, Petignat P, Genazzani AR (September 2014). "Effect of estetrol administration on brain and serum allopregnanolone in intact and ovariectomized rats". J. Steroid Biochem. Mol. Biol. 143: 285–90. doi:10.1016/j.jsbmb.2014.04.011. PMID   24787659. S2CID   21359519.
  29. ↑ Pluchino N, Drakopoulos P, Casarosa E, Freschi L, Petignat P, Yaron M, Genazzani AR (March 2015). "Effect of estetrol on Beta-Endorphin level in female rats". Steroids. 95: 104–10. doi:10.1016/j.steroids.2015.01.003. PMID   25595451. S2CID   32178988.
  30. 1 2 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 (October 2014). "The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor α modulation, uncoupling nuclear and membrane activation". EMBO Mol Med. 6 (10): 1328–46. doi:10.15252/emmm.201404112. PMC   4287935 . PMID   25214462.
  31. 1 2 Duijkers IJ, Klipping C, Zimmerman Y, Appels N, Jost M, Maillard C, et al. (2015). "Inhibition of ovulation by administration of estetrol in combination with drospirenone or levonorgestrel: Results of a phase II dose-finding pilot study". The European Journal of Contraception & Reproductive Health Care. 20 (6): 476–489. doi:10.3109/13625187.2015.1074675 (inactive 31 January 2024). PMC   4673580 . PMID   26394847.{{cite journal}}: CS1 maint: DOI inactive as of January 2024 (link)
  32. 1 2 Coelingh Bennink HJ, Zimmerman Y, Verhoeven C, Dutman AE, Mensinga T, Kluft C, Reisman Y, Debruyne FM (June 2018). "A Dose Escalating Study with the Fetal Estrogen Estetrol in Healthy Males". J. Clin. Endocrinol. Metab. 103 (9): 3239–3249. doi: 10.1210/jc.2018-00147 . PMID   29931320.
  33. ↑ Visser M, Holinka CF, Coelingh Bennink HJ (2008). "First human exposure to exogenous single-dose oral estetrol in early postmenopausal women". Climacteric. 11 1 (sup1): 31–40. doi:10.1080/13697130802056511. PMID   18464021. S2CID   23568599.
  34. 1 2 Holinka CF, Diczfalusy E, Coelingh Bennink HJ (May 2008). "Estetrol: a unique steroid in human pregnancy". J. Steroid Biochem. Mol. Biol. 110 (1–2): 138–43. doi:10.1016/j.jsbmb.2008.03.027. PMID   18462934. S2CID   28007341.
  35. ↑ Warmerdam EG, Visser M, Coelingh Bennink HJ, Groen M (2008). "A new route of synthesis of estetrol". Climacteric. 11 (Suppl 1): 59–63. doi:10.1080/13697130802054078. PMID   18464024. S2CID   42017011.
  36. ↑ Clinical trial number NCT02817841 for "E4 FREEDOM (Female Response Concerning Efficacy and Safety of Estetrol/Drospirenone as Oral Contraceptive in a Multicentric Study) - United States/Canada Study" at ClinicalTrials.gov
  37. ↑ Clinical trial number NCT02817828 NCT02817828 for "Estetra. (2019) E4 FREEDOM (Female Response Concerning Efficacy and Safety of Estetrol/Drospirenone as Oral Contraceptive in a Multicentric Study) - EU/Russia Study." at ClinicalTrials.gov
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  45. ↑ Rapkin AJ, Winer SA (May 2007). "Drospirenone: a novel progestin". Expert Opin Pharmacother. 8 (7): 989–99. doi:10.1517/14656566.8.7.989. PMID   17472544. S2CID   6954183.
  46. ↑ Oelkers W (March 2004). "Drospirenone, a progestogen with antimineralocorticoid properties: a short review". Mol. Cell. Endocrinol. 217 (1–2): 255–61. doi:10.1016/j.mce.2003.10.030. PMID   15134826. S2CID   19936032.
  47. 1 2 Coelingh Bennink F, Holinka CF, Visser M, Coelingh Bennink HJ (2008). "Maternal and fetal estetrol levels during pregnancy". Climacteric. 11 (Suppl 1): 69–72. doi:10.1080/13697130802056321. PMID   18464026. S2CID   20399632.

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