Estetrol (medication)

Source: Wikipedia, the free encyclopedia.
This article is about estetrol as a medication. For its role as a hormone, see Estetrol.
Estetrol
Skeletal formula of estetrol
Ball-and-stick model of the estetrol molecule
Clinical data
Trade namesWith drospirenone: Estelle, Nextstellis
Other namesOestetrol; E4; 15α-Hydroxyestriol; Estra-1,3,5(10)-triene-3,15α,16α,17β-tetrol
Pregnancy
category
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
JSmol)
Solubility in water1.38
  • 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 checkY
  • Key:AJIPIJNNOJSSQC-NYLIRDPKSA-N checkY
  (verify)

Estetrol (E4) is an

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]

Estetrol is a

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/form Estrogen Low Standard High
Oral Estradiol 0.5–1 mg/day 1–2 mg/day 2–4 mg/day
Estradiol valerate 0.5–1 mg/day 1–2 mg/day 2–4 mg/day
Estradiol acetate 0.45–0.9 mg/day 0.9–1.8 mg/day 1.8–3.6 mg/day
Conjugated estrogens 0.3–0.45 mg/day 0.625 mg/day 0.9–1.25 mg/day
Esterified estrogens 0.3–0.45 mg/day 0.625 mg/day 0.9–1.25 mg/day
Estropipate 0.75 mg/day 1.5 mg/day 3 mg/day
Estriol 1–2 mg/day 2–4 mg/day 4–8 mg/day
Ethinylestradiola 2.5–10 μg/day 5–20 μg/day –
Nasal spray Estradiol 150 μg/day 300 μg/day 600 μg/day
Transdermal patch Estradiol 25 μg/dayb 50 μg/dayb 100 μg/dayb
Transdermal gel
 Estradiol 0.5 mg/day 1–1.5 mg/day 2–3 mg/day
Vaginal
 Estradiol 25 μg/day – –
Estriol 30 μg/day 0.5 mg 2x/week 0.5 mg/day
SC injection
 Estradiol valerate – – 4 mg 1x/4 weeks
Estradiol cypionate 1 mg 1x/3–4 weeks 3 mg 1x/3–4 weeks 5 mg 1x/3–4 weeks
Estradiol benzoate 0.5 mg 1x/week 1 mg 1x/week 1.5 mg 1x/week
SC implant Estradiol 25 mg 1x/6 months 50 mg 1x/6 months 100 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

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

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

metabolic stability and favorable pharmacokinetics.[2]

Estetrol shows high

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)a		 Action
ERα
ERβ
ERα
ERβ
Estradiol E2; 17β-Estradiol 100 100 0.115 (0.04–0.24) 0.15 (0.10–2.08) Estrogen
Estrone E1; 17-Ketoestradiol 16.39 (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-E2 12.65 (4.03–56) 26 (14.0–44.6) 0.45 (0.35–1.4) 0.7 (0.63–0.7) Estrogen
Estetrol E4; 15α,16α-Di-OH-17β-E2 4.0 3.0 4.9 19 Estrogen
Alfatradiol 17α-Estradiol 20.5 (7–80.1) 8.195 (2–42) 0.2–0.52 0.43–1.2 Metabolite
16-Epiestriol
 16β-Hydroxy-17β-estradiol 7.795 (4.94–63) 50 ? ? Metabolite
17-Epiestriol
 16α-Hydroxy-17α-estradiol 55.45 (29–103) 79–80 ? ? Metabolite
16,17-Epiestriol
 16β-Hydroxy-17α-estradiol 1.0 13 ? ? Metabolite
2-Hydroxyestradiol 2-OH-E2 22 (7–81) 11–35 2.5 1.3 Metabolite
2-Methoxyestradiol 2-MeO-E2 0.0027–2.0 1.0 ? ? Metabolite
4-Hydroxyestradiol 4-OH-E2 13 (8–70) 7–56 1.0 1.9 Metabolite
4-Methoxyestradiol 4-MeO-E2 2.0 1.0 ? ? Metabolite
2-Hydroxyestrone 2-OH-E1 2.0–4.0 0.2–0.4 ? ? Metabolite
2-Methoxyestrone 2-MeO-E1 <0.001–<1 <1 ? ? Metabolite
4-Hydroxyestrone 4-OH-E1 1.0–2.0 1.0 ? ? Metabolite
4-Methoxyestrone 4-MeO-E1 <1 <1 ? ? Metabolite
16α-Hydroxyestrone 16α-OH-E1; 17-Ketoestriol 2.0–6.5 35 ? ? Metabolite
2-Hydroxyestriol 2-OH-E3 2.0 1.0 ? ? Metabolite
4-Methoxyestriol 4-MeO-E3 1.0 1.0 ? ? Metabolite
Estradiol sulfate E2S; Estradiol 3-sulfate <1 <1 ? ? Metabolite
Estradiol disulfate Estradiol 3,17β-disulfate 0.0004 ? ? ? Metabolite
Estradiol 3-glucuronide E2-3G 0.0079 ? ? ? Metabolite
Estradiol 17β-glucuronide
 E2-17G 0.0015 ? ? ? Metabolite
Estradiol 3-gluc. 17β-sulfate E2-3G-17S 0.0001 ? ? ? Metabolite
Estrone sulfate E1S; Estrone 3-sulfate <1 <1 >10 >10 Metabolite
Estradiol benzoate EB; Estradiol 3-benzoate 10 ? ? ? Estrogen
Estradiol 17β-benzoate E2-17B 11.3 32.6 ? ? Estrogen
Estrone methyl ether Estrone 3-methyl ether 0.145 ? ? ? Estrogen
ent-Estradiol 1-Estradiol 1.31–12.34 9.44–80.07 ? ? Estrogen
Equilin 7-Dehydroestrone 13 (4.0–28.9) 13.0–49 0.79 0.36 Estrogen
Equilenin 6,8-Didehydroestrone 2.0–15 7.0–20 0.64 0.62 Estrogen
17β-Dihydroequilin 7-Dehydro-17β-estradiol 7.9–113 7.9–108 0.09 0.17 Estrogen
17α-Dihydroequilin 7-Dehydro-17α-estradiol 18.6 (18–41) 14–32 0.24 0.57 Estrogen
17β-Dihydroequilenin 6,8-Didehydro-17β-estradiol 35–68 90–100 0.15 0.20 Estrogen
17α-Dihydroequilenin 6,8-Didehydro-17α-estradiol 20 49 0.50 0.37 Estrogen
Δ8-Estradiol 8,9-Dehydro-17β-estradiol 68 72 0.15 0.25 Estrogen
Δ8-Estrone 8,9-Dehydroestrone 19 32 0.52 0.57 Estrogen
Ethinylestradiol EE; 17α-Ethynyl-17β-E2 120.9 (68.8–480) 44.4 (2.0–144) 0.02–0.05 0.29–0.81 Estrogen
Mestranol EE 3-methyl ether ? 2.5 ? ? Estrogen
Moxestrol RU-2858; 11β-Methoxy-EE 35–43 5–20 0.5 2.6 Estrogen
Methylestradiol 17α-Methyl-17β-estradiol 70 44 ? ? Estrogen
Diethylstilbestrol DES; Stilbestrol 129.5 (89.1–468) 219.63 (61.2–295) 0.04 0.05 Estrogen
Hexestrol Dihydrodiethylstilbestrol 153.6 (31–302) 60–234 0.06 0.06 Estrogen
Dienestrol Dehydrostilbestrol 37 (20.4–223) 56–404 0.05 0.03 Estrogen
Benzestrol (B2) – 114 ? ? ? Estrogen
Chlorotrianisene TACE 1.74 ? 15.30 ? Estrogen
Triphenylethylene TPE 0.074 ? ? ? Estrogen
Triphenylbromoethylene TPBE 2.69 ? ? ? Estrogen
Tamoxifen ICI-46,474 3 (0.1–47) 3.33 (0.28–6) 3.4–9.69 2.5 SERM
Afimoxifene 4-Hydroxytamoxifen; 4-OHT 100.1 (1.7–257) 10 (0.98–339) 2.3 (0.1–3.61) 0.04–4.8 SERM
Toremifene 4-Chlorotamoxifen; 4-CT ? ? 7.14–20.3 15.4 SERM
Clomifene MRL-41 25 (19.2–37.2) 12 0.9 1.2 SERM
Cyclofenil F-6066; Sexovid 151–152 243 ? ? SERM
Nafoxidine U-11,000A 30.9–44 16 0.3 0.8 SERM
Raloxifene – 41.2 (7.8–69) 5.34 (0.54–16) 0.188–0.52 20.2 SERM
Arzoxifene LY-353,381 ? ? 0.179 ? SERM
Lasofoxifene CP-336,156 10.2–166 19.0 0.229 ? SERM
Ormeloxifene Centchroman ? ? 0.313 ? SERM
Levormeloxifene 6720-CDRI; NNC-460,020 1.55 1.88 ? ? SERM
Ospemifene Deaminohydroxytoremifene 0.82–2.63 0.59–1.22 ? ? SERM
Bazedoxifene – ? ? 0.053 ? SERM
Etacstil GW-5638 4.30 11.5 ? ? SERM
ICI-164,384
 – 63.5 (3.70–97.7) 166 0.2 0.08 Antiestrogen
Fulvestrant ICI-182,780 43.5 (9.4–325) 21.65 (2.05–40.5) 0.42 1.3 Antiestrogen
Propylpyrazoletriol PPT 49 (10.0–89.1) 0.12 0.40 92.8 ERα agonist
16α-LE2 16α-Lactone-17β-estradiol 14.6–57 0.089 0.27 131 ERα agonist
16α-Iodo-E2 16α-Iodo-17β-estradiol 30.2 2.30 ? ? ERα agonist
Methylpiperidinopyrazole MPP 11 0.05 ? ? ERα antagonist
Diarylpropionitrile DPN 0.12–0.25 6.6–18 32.4 1.7 ERβ agonist
8β-VE2 8β-Vinyl-17β-estradiol 0.35 22.0–83 12.9 0.50 ERβ agonist
Prinaberel ERB-041; WAY-202,041 0.27 67–72 ? ? ERβ agonist
ERB-196 WAY-202,196 ? 180 ? ? ERβ agonist
Erteberel SERBA-1; LY-500,307 ? ? 2.68 0.19 ERβ agonist
SERBA-2 – ? ? 14.5 1.54 ERβ agonist
Coumestrol – 9.225 (0.0117–94) 64.125 (0.41–185) 0.14–80.0 0.07–27.0 Xenoestrogen
Genistein – 0.445 (0.0012–16) 33.42 (0.86–87) 2.6–126 0.3–12.8 Xenoestrogen
Equol – 0.2–0.287 0.85 (0.10–2.85) ? ? Xenoestrogen
Daidzein – 0.07 (0.0018–9.3) 0.7865 (0.04–17.1) 2.0 85.3 Xenoestrogen
Biochanin A – 0.04 (0.022–0.15) 0.6225 (0.010–1.2) 174 8.9 Xenoestrogen
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-PN 4.4 ? ? ? Xenoestrogen
Quercetin – <0.001–0.01 0.002–0.040 ? ? 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-Zearalanol 48–111 ? ? ? Xenoestrogen
Taleranol β-Zearalanol 16 (13–17.8) 14 0.8 0.9 Xenoestrogen
Zearalenone ZEN 7.68 (2.04–28) 9.45 (2.43–31.5) ? ? Xenoestrogen
Zearalanone ZAN 0.51 ? ? ? Xenoestrogen
Bisphenol A BPA 0.0315 (0.008–1.0) 0.135 (0.002–4.23) 195 35 Xenoestrogen
Endosulfan EDS <0.001–<0.01 <0.01 ? ? Xenoestrogen
Kepone
 Chlordecone 0.0069–0.2 ? ? ? Xenoestrogen
o,p'-DDT
 – 0.0073–0.4 ? ? ? Xenoestrogen
p,p'-DDT
 – 0.03 ? ? ? Xenoestrogen
Methoxychlor p,p'-Dimethoxy-DDT 0.01 (<0.001–0.02) 0.01–0.13 ? ? Xenoestrogen
HPTE Hydroxychlor; p,p'-OH-DDT 1.2–1.7 ? ? ? Xenoestrogen
Testosterone T; 4-Androstenolone <0.0001–<0.01 <0.002–0.040 >5000 >5000 Androgen
Dihydrotestosterone DHT; 5α-Androstanolone 0.01 (<0.001–0.05) 0.0059–0.17 221–>5000 73–1688 Androgen
Nandrolone 19-Nortestosterone; 19-NT 0.01 0.23 765 53 Androgen
Dehydroepiandrosterone DHEA; Prasterone 0.038 (<0.001–0.04) 0.019–0.07 245–1053 163–515 Androgen
5-Androstenediol
 A5; Androstenediol 6 17 3.6 0.9 Androgen
4-Androstenediol – 0.5 0.6 23 19 Androgen
4-Androstenedione
 A4; Androstenedione <0.01 <0.01 >10000 >10000 Androgen
3α-Androstanediol 3α-Adiol 0.07 0.3 260 48 Androgen
3β-Androstanediol 3β-Adiol 3 7 6 2 Androgen
Androstanedione 5α-Androstanedione <0.01 <0.01 >10000 >10000 Androgen
Etiocholanedione 5β-Androstanedione <0.01 <0.01 >10000 >10000 Androgen
Methyltestosterone 17α-Methyltestosterone <0.0001 ? ? ? Androgen
Ethinyl-3α-androstanediol
 17α-Ethynyl-3α-adiol 4.0 <0.07 ? ? Estrogen
Ethinyl-3β-androstanediol
 17α-Ethynyl-3β-adiol 50 5.6 ? ? Estrogen
Progesterone P4; 4-Pregnenedione <0.001–0.6 <0.001–0.010 ? ? Progestogen
Norethisterone NET; 17α-Ethynyl-19-NT 0.085 (0.0015–<0.1) 0.1 (0.01–0.3) 152 1084 Progestogen
Norethynodrel
 5(10)-Norethisterone 0.5 (0.3–0.7) <0.1–0.22 14 53 Progestogen
Tibolone 7α-Methylnorethynodrel 0.5 (0.45–2.0) 0.2–0.076 ? ? Progestogen
Δ4-Tibolone 7α-Methylnorethisterone 0.069–<0.1 0.027–<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)
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
(%)
ERTooltip Estrogen receptor ARTooltip Androgen receptor PRTooltip Progesterone receptor GRTooltip Glucocorticoid receptor MRTooltip Mineralocorticoid receptor SHBGTooltip Sex hormone-binding globulin
CBG
Tooltip Corticosteroid binding globulin
Estradiol 100 7.9 2.6 0.6 0.13 8.7–12 <0.1
Estradiol benzoate ? ? ? ? ? <0.1–0.16 <0.1
Estradiol valerate 2 ? ? ? ? ? ?
Estrone 11–35 <1 <1 <1 <1 2.7 <0.1
Estrone sulfate 2 2 ? ? ? ? ?
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 100–112 1–3 15–25 1–3 <1 0.18 <0.1
Mestranol 1 ? ? ? ? <0.1 <0.1
Methylestradiol 67 1–3 3–25 1–3 <1 ? ?
Moxestrol 12 <0.1 0.8 3.2 <0.1 <0.2 <0.1
Diethylstilbestrol ? ? ? ? ? <0.1 <0.1
Notes: Reference
CBG
Tooltip Corticosteroid-binding globulin. Sources: See template.
Selected biological properties of endogenous estrogens in rats
Estrogen
RBA
Tooltip relative binding affinity (%)		 Uterine weight (%)
Uterotrophy
 LHTooltip Luteinizing hormone levels (%)
RBA
Tooltip relative binding affinity (%)
Control – 100 – 100 –
Estradiol (E2) 100 506 ± 20 +++ 12–19 100
Estrone (E1) 11 ± 8 490 ± 22 +++ ? 20
Estriol (E3) 10 ± 4 468 ± 30 +++ 8–18 3
Estetrol (E4) 0.5 ± 0.2 ? Inactive ? 1
17α-Estradiol 4.2 ± 0.8 ? ? ? ?
2-Hydroxyestradiol 24 ± 7 285 ± 8 +b 31–61 28
2-Methoxyestradiol 0.05 ± 0.04 101 Inactive ? 130
4-Hydroxyestradiol 45 ± 12 ? ? ? ?
4-Methoxyestradiol 1.3 ± 0.2 260 ++ ? 9
4-Fluoroestradiola 180 ± 43 ? +++ ? ?
2-Hydroxyestrone 1.9 ± 0.8 130 ± 9 Inactive 110–142 8
2-Methoxyestrone 0.01 ± 0.00 103 ± 7 Inactive 95–100 120
4-Hydroxyestrone 11 ± 4 351 ++ 21–50 35
4-Methoxyestrone 0.13 ± 0.04 338 ++ 65–92 12
16α-Hydroxyestrone 2.8 ± 1.0 552 ± 42 +++ 7–24 <0.5
2-Hydroxyestriol 0.9 ± 0.3 302 +b ? ?
2-Methoxyestriol 0.01 ± 0.00 ? Inactive ? 4
Notes: Values are mean ± SD or range. ER RBA =
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

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,

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.

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,

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		 VETooltip Vaginal epithelium UCaTooltip Urinary calcium FSHTooltip Follicle-stimulating hormone LHTooltip Luteinizing hormone HDLTooltip High-density lipoprotein-CTooltip Cholesterol SHBGTooltip Sex hormone-binding globulin
CBG
Tooltip Corticosteroid-binding globulin
AGT
Tooltip Angiotensinogen		 Liver
Estradiol 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0
Estrone ? ? ? 0.3 0.3 ? ? ? ? ?
Estriol 0.3 0.3 0.1 0.3 0.3 0.2 ? ? ? 0.67
Estrone sulfate ? 0.9 0.9 0.8–0.9 0.9 0.5 0.9 0.5–0.7 1.4–1.5 0.56–1.7
Conjugated estrogens 1.2 1.5 2.0 1.1–1.3 1.0 1.5 3.0–3.2 1.3–1.5 5.0 1.3–4.5
Equilin sulfate
 ? ? 1.0 ? ? 6.0 7.5 6.0 7.5 ?
Ethinylestradiol 120 150 400 60–150 100 400 500–600 500–600 350 2.9–5.0
Diethylstilbestrol ? ? ? 2.9–3.4 ? ? 26–28 25–37 20 5.7–7.5
Sources and footnotes
Notes: Values are ratios, with estradiol as standard (i.e., 1.0). Abbreviations: HF = Clinical relief of
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

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[2]

The oral bioavailability of estetrol in rats was 70% relative to

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

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

See also: List of estrogens § Estriol derivatives
Structures of major endogenous estrogens
Chemical structures of major endogenous estrogens
Estrone (E1)
Estriol (E3)
Estetrol (E4)
The image above contains clickable links
Note the
hydroxyl (–OH) groups
: estrone (E1) has one, estradiol (E2) has two, estriol (E3) has three, and estetrol (E4) has four.

Estetrol, also known as 15α-hydroxyestriol or as estra-1,3,5(10)-triene-3,15α,16α,17β-tetrol, is a

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

Legal status

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

INNTooltip International Nonproprietary Name.[43]

Research

Estetrol is under development for use alone for a variety of indications. Applications include

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

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

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

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

References

  1. ^ "Updates to the Prescribing Medicines in Pregnancy database". Therapeutic Goods Administration (TGA). 21 December 2022. Retrieved 2 January 2023.
  2. ^
    S2CID 24003341
    .
  3. ^
    S2CID 32081001
    .
  4. ^
    S2CID 23568599
    .
  5. ^
    S2CID 22715507
    .
  6. ^
    PMID 26212489.{{cite journal}}: CS1 maint: DOI inactive as of January 2024 (link
    )
  7. ^ a b "Estetrol - Mithra Pharmaceuticals - AdisInsight".
  8. ^ a b c d "Drospirenone/estetrol - Mithra Pharmaceuticals". AdisInsight. Springer Nature Switzerland AG.
  9. ^
    ISSN 1569-9056
    .
  10. ^
    PMID 25359896
    .
  11. PMID 25214462
    .
  12. ^ a b 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
  13. ^
    PMID 14303250
    .
  14. ^
    PMID 27451327
    .
  15. S2CID 25111733
    .
  16. ^ a b Clinical trial number NCT04209543 for "Estetra. (2020) Estetrol for the Treatment of Moderate to Severe Vasomotor Symptoms in Postmenopausal Women (E4Comfort Study I)." at ClinicalTrials.gov
  17. ^ a b Clinical trial number NCT04090957 for "Estetra. (2019) Estetrol for the Treatment of Moderate to Severe Vasomotor Symptoms in Postmenopausal Women (E4Comfort)." at ClinicalTrials.gov
  18. PMID 34956081
    .
  19. S2CID 224821517
    .
  20. 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. ^
    S2CID 11027782
    .
  22. ^
    PMID 26056044
    .
  23. S2CID 35660932
    .
  24. S2CID 205931204
    .
  25. PMID 27593335
    .
  26. ^
    S2CID 24616324
    .
  27. S2CID 221843478
    .
  28. S2CID 21359519
    .
  29. S2CID 32178988
    .
  30. ^
    PMID 25214462
    .
  31. ^
    PMID 26394847.{{cite journal}}: CS1 maint: DOI inactive as of January 2024 (link
    )
  32. ^
    PMID 29931320
    .
  33. S2CID 23568599
    .
  34. ^
    S2CID 28007341
    .
  35. 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
  38. ^ "Drovelis EMEA authorisation". European Medicines Agency (EMA). Retrieved 4 November 2021.
  39. ^ "Lydisilka EMEA authorisation". European Medicines Agency (EMA). Retrieved 4 November 2021.
  40. ^ "Nextstellis Approval FDA". U.S. Food & Drug Administration (FDA). Retrieved 4 November 2021.
  41. ^ "Nextstellis Approval Health Canada". Health Canada, Government of Canada. 25 April 2012. Retrieved 4 November 2021.
  42. ^ "Nexstellis Approval ARTG". Australian Government, Department of Health. Retrieved 6 June 2022.[permanent dead link]
  43. ^ "Essential Medicines and Health Products Information Portal" (PDF).[dead link]
  44. ^ "News". Mithra. Archived from the original on October 1, 2015. Retrieved 2020-11-10.
  45. S2CID 6954183
    .
  46. S2CID 19936032
    .
  47. ^
    S2CID 20399632
    .

Further reading

External links

  • "Estetrol". Drug Information Portal. U.S. National Library of Medicine.
Retrieved from "https://en.wikipedia.org/w/index.php?title=Estetrol_(medication)&oldid=1214011780"