Estetrol

Clinical data
Trade names	With drospirenone: Estelle, Nextstellis
Other names	Oestetrol; E4; 15α-Hydroxyestriol; Estra-1,3,5(10)-triene-3,15α,16α,17β-tetrol
Pregnancy category	AU: B3[1]
Routes of administration	By mouth[2][3]
Drug class	Estrogen
ATC code	None
Pharmacokinetic data
Bioavailability	High[4]
Protein binding	Moderately to albumin, not to SHBGTooltip 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
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 Number	15183-37-6 Y
PubChem CID	27125
DrugBank	DB12235
ChemSpider	25245 Y
UNII	ENB39R14VF
KEGG	D11513
ChEBI	CHEBI:142773
ChEMBL	ChEMBL1230314
PDB ligand	4OH (PDBe, RCSB PDB)
Chemical and physical data
Formula	C18H24O4
Molar mass	304.386 g·mol−1
3D model (JSmol)	Interactive image
Solubility in water	1.38
SMILES 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 Y Key:AJIPIJNNOJSSQC-NYLIRDPKSA-N Y
(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]

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]

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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
IMTooltip Intramuscular or 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 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 K_i values of 4.9 nM and 19 nM, respectively.^[2][21] As such, estetrol has 4- to 5-fold preference for ERα over ERβ.^[2][21] For comparison, the potent nonsteroidal estrogen diethylstilbestrol showed higher affinities for ERs, with K_i values of 0.286 nM for ERα and 0.199 nM for ERβ.^[21] Similarly, estetrol has low affinity for ERs relative to estradiol, and thus both estetrol and the related 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 α_1B-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]

Zdroj:https://en.wikipedia.org?pojem=Estetrol_(medication)
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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