Absorption, Distribution and Excretion
Estetrol is rapidly absorbed from the gastrointestinal tract. The Cmax of estetrol is 18 ng/mL according to the results of a pharmacokinetic study, with an AUC of 36.4 ng•h/mL. When estetrol and drospirenone are taken in a single product, maximum serum concentrations of approximately 48.7 ng/mL are achieved within 1-3 h. Bioavailability of the combination ranges between 76 and 85%. The Tmax can range from 0.5 to 2 hours and time to steady state is approximately 4 days, according to the results of one clinical study.
Estrogens are generally excreted as sulfated and glucuronidated derivatives. Approximately 69% of a dose of estetrol is excreted in the urine, and about 22% is excreted in the feces as unchanged drug.
Limited distribution of estetrol into red blood cells has been demonstrated.

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Metabolism / Metabolites
Estretol is heavily metabolized after oral administration. Phase 2 metabolism of estrogen forms glucuronide and sulfate conjugates with negligible in-vitro estrogenic activity. In vitro metabolism studies demonstrate that UGT2B7 catalyzes the formation of E4-16-glucuronide. Estetrol is combined with [drospirenone] in a product. The hepatic cytochrome enzyme CYP3A4 metabolizes drospirenone to two primary metabolites: the acid form of drospirenone through the opening of the lactone ring and the 4,5­ dihydrodrospirenone formed by reduction, followed by sulfation. Both metabolites are pharmacologically inactive.

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Biological Half-Life
The elimination half-life of estetrol is approximately 27 hours. Half-life may range between 19-40 hours.

Protein Binding
Estetrol is 46-50% bound to plasma proteins. Estetrol does not bind to Sex Hormone Binding Globulin (SHBG). In one study, estetrol showed moderate binding to human plasma proteins (45.5%-50.4%) and human serum albumin (58.6%) with low binding to human alpha-glycoprotein (11.2%).

[1]. Effect of estetrol, a selective nuclear estrogen receptor modulator, in mouse models of arterial and venous thrombosis. Mol Cell Endocrinol. 2018 Dec 5;477:132-139.

[2]. Estetrol Modulates Endothelial Nitric Oxide Synthesis in Human Endothelial Cells. Front Endocrinol (Lausanne). 2015 Jul 22;6:111.

Estetrol is a 3-hydroxy steroid that is 17beta-estradiol which has been substituted at the 15alpha and 16alpha positions by two additional hydroxy groups. It is a natural estrogen produced exclusively during pregnancy by the fetal liver. It has a role as an estrogen, an estrogen receptor agonist, a human metabolite, a human xenobiotic metabolite and an oral contraceptive. It is a 3-hydroxy steroid, a 17beta-hydroxy steroid, a 16alpha-hydroxy steroid, a 15alpha-hydroxy steroid and a steroid hormone. It derives from a hydride of an estrane.
Naturally or synthetically produced steroid estrogens have a wide range of pharmaceutical uses ranging from hormonal contraception to the treatment of menopausal symptoms. Estetrol (E4) is a native estrogen occurring naturally during pregnancy, but can be synthesized from a plant source and used for contraception. It is more potent and is safer than the synthetic estrogen ethinylestradiol (EE2) found in 97% of oral contraceptive pills, reducing the environmental accumulation of unwanted endocrine disrupting chemicals (EDCs) that often lead to harmful epigenetic effects. On April 15 2021, Mayne Pharma Group Limited and Mithra Pharmaceuticals were granted FDA approval for the oral contraceptive Estelle/Nextstellis, a combination of [drospirenone] and estetrol. Estetrol is the first new estrogen introduced to the USA in over 50 years and is the first approved estetrol product in the world. The combination of drospirenone and estetrol offers a new choice with a favourable safety profile for women seeking contraceptive therapy. In Canada, Nextstellis was approved for use in March 2021; it was developed by Mithra and is marketed by Searchlight Pharma.
Estetrol anhydrous is an Estrogen. The mechanism of action of estetrol anhydrous is as an Estrogen Receptor Agonist.
Therapeutic Estetrol is a synthetic steroid similar or identical to endogenous estetrol, a short-acting estrogen with both agonistic and antagonistic estrogen receptor activity. Administered orally, therapeutic estetrol binds to the estrogen receptor and as a selective estrogen receptor modulator (SERM) exhibits estrogen agonism in certain tissues and estrogen antagonism in others. Displaying weak estrogen activity in the uterus, estetrol acts as an estrogen antagonist in breast tissue. Produced solely by the human fetal liver, endogenous estetrol is the primary estrogen metabolite of estrogen biosynthesis in the human fetal liver.
A metabolite of ESTRIOL with a 15-alpha-hydroxyl group. Estetrol can be converted from estriol sulfate or DEHYDROEPIANDROSTERONE SULFATE by the fetal-placental unit.

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Drug Indication
Estetrol is indicated in combination with drospirenone for the prevention of pregnancy.

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Mechanism of Action
Estetrol is a synthetic analogue of a naturally occurring estrogen present during pregnancy, demonstrating selectivity for both estrogen receptor-α (ER-α) and ER-β and suppressing ovulation. Estetrol binds with a low to moderate affinity human estrogen receptor alpha (ER alpha) and ER beta with a preference for ER alpha. Estetrol demonstrates a unique mechanism of action via tissue selective activity, showing estrogen receptor agonist activity on the vagina, the uterus and the endometrium, and negative estrogenic activity on breast tissue.

C18H24O4

304.386

304.167

C, 71.03; H, 7.95; O, 21.02

15183-37-6

Estetrol-d4

27125

White to off-white solid powder

1.343 g/cm3

491.9ºC at 760 mmHg

233-236

231.7ºC

1.65

1.55

4

4

0

22

441

7

C[C@@]12CC[C@@H]3C4=CC=C(C=C4CC[C@H]3[C@@H]2[C@H]([C@H]([C@@H]1O)O)O)O

AJIPIJNNOJSSQC-NYLIRDPKSA-N

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

(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

15α-Hydroxyestriol; E4; Estetrol

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~328.54 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (8.21 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (8.21 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (8.21 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)