What molecule am I?
Estetrol, also called E4, is a steroid hormone closely related to sex hormones in the estrogen family, including former Molecule of the Week estradiol1. Along with estradiol and other hormones, estetrol occurs in the fetal liver during early pregnancy and in the mother in “exponentially growing concentrations during gestation”. Fetal concentrations are ≈10 times higher than maternal concentrations.
Estetrol was discovered in 1965 by Egon Diczfalusy and colleagues at the Karolinska Institute (Stockholm) during a study of the metabolism of estradiol in early infancy. But Diczfalusy did not realize at the time that estetrol could be a valuable drug; it was largely ignored for 35 years.
In 2000, Herjan Coelingh Bennink at the Dutch contraceptive manufacturer Organon2, recognizing estetrol’s occurrence in pregnant women and fetuses, believed that it should be explored as a safe therapeutic agent. Studies on estetrol as an oral contraceptive at Bennink-founded Pantarhei Bioscience (Zeist, The Netherlands) and later at Mithra Pharmaceuticals (Liège, Belgium) demostrated that it is as effective as the leading product, ethinylestradiol, without its adverse side effects.
Mithra conducted clinical trials on a combination of estetrol and drospirenone3, a progestin commonly included in estrogen-based contraceptives. In 2021, the estetrol–drospirenone combination, tradenamed Estelle, was approved by the US Food and Drug Administration. It is marketed by Mayne Pharma, an Australian company with facilities in North Carolina.
Estetrol is difficult to synthesize. The commercial manufacturing method begins with a soy-derived phytosterol and requires eight synthetic steps. Mithra recently announced that it chose Seqens (Écully, France) to produce estetrol at its 129-year-old manufacturing plant in Villeneuve-la-Garenne, France.
1. CAS Reg. No. 50-28-2.
2. Not to be confused with a recently launched American company with the same name.
3. CAS Reg. No. 67392-87-4.
Estetrol hazard information*
|Hazard class**||GHS code and hazard statement|
|Acute toxicity, oral, category 5||H303—May be harmful if swallowed|
|Carcinogenicity, category 2||H351—Suspected of causing cancer|
|Reproductive toxicity, category 1B||H360—May damage fertility or the unborn child|
|Short-term (acute) aquatic hazard, category 3||H402—Harmful to aquatic life|
|Long-term (chronic) aquatic hazard, category 3||H412—Harmful to aquatic life with long-lasting effects|
*The hazard statements given here are the most severe reported. Most safety data sheets contain fewer hazard statements or state that estetrol is not a hazardous substance or mixture.
**Globally Harmonized System (GHS) of Classification and Labeling of Chemicals. Explanation of pictograms.
Estetrol fast facts
|CAS Reg. No.||15183-37-6|
|Molar mass||304.38 g/mol|
|Appearance||White crystals or powder|
|Melting point||244 °C|
|Water solubility||1.4 g/L|
Herbicides atrazine1 and 2,4-dichlorophenoxyacetic acid2 were the Molecules of the Week for May 10, 2010 and August 12, 2012, respectively. Both have been heavily used in commercial agriculture for decades and have increasingly come under environmental restrictions.
Now, after many years of neglect, the US Environmental Protection Agency is reassessing the use of these and many other pesticides in terms of their compliance under the Endangered Species Act of 1973. In response, manufacturers and farmers’ groups have complained that the new mitigation measures make it difficult to find alternative products so close to this year’s growing season.
1. CAS Reg. No. 1912-24-9.
2. CAS Reg. No. 94-57-5.
Learn more about this molecule from CAS, the most authoritative and comprehensive source for chemical information.
Molecule of the Week needs your suggestions!
If your favorite molecule is not in our archive, please send us a message. The molecule can be notable for its current or historical importance or for any quirky reason. Thank you!
Stay Ahead of the Chemistry Curve
Learn how ACS can help you stay ahead in the world of chemistry.