Estetrol (medication)

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;
Routes of; administration	By mouth
Drug class	Estrogen
ATC code	None;
Pharmacokinetic data
Bioavailability	High
Protein binding	Moderately to albumin, not to SHBGTooltip sex hormone-binding globulin
Metabolism	Minimal, conjugation (glucuronidation, sulfation)
Metabolites	Estetrol glucuronide; Estetrol sulfate
Elimination half-life	Mean: 28 hours; Range: 18–60 hours
Excretion	Urine: 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-decahydrocyclopenta[a]phenanthrene-3,15,16,17-tetrol;
CAS Number	15183-37-6 ;
PubChem CID	27125;
DrugBank	DB12235;
ChemSpider	25245 ;
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 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 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 ; Key:AJIPIJNNOJSSQC-NYLIRDPKSA-N ;
	(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. It is taken by mouth.

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/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
	Ethinylestradiol^a	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/day^b	50 μg/day^b	100 μg/day^b
Transdermal gel	Estradiol	0.5 mg/day	1–1.5 mg/day	2–3 mg/day
Vaginal	Estradiol	25 μg/day	–	–
Vaginal	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.

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