Letter to the editor regarding ‘Estetrol (E4): the new estrogenic component of combined oral contraceptives’

It was a pleasure to read this review on the use of the natural fetal estrogen Estetrol (E4) as the estrogen in combined oral contraception [1].

I would like to add two important pieces of information to this review.

Firstly, with regard to the history of E4 described in the first two sentences of the review: ‘Estetrol (E4) is a natural fetal estrogenic steroid discovered in 1965 (by Egon Diczfalusy) at the Karolinska Institutet in Stockholm (Sweden). It was studied for a period of 20 years originally as a biomarker of fetal well-being during pregnancy before being abandoned as a weak estrogen: research into the potential physiological effects and applications of E4 resumed in 2001’. The last part of this sentence underestimates the 15 years of extensive R&D that went into E4 at Pantarhei Bioscience that took place from the discovery of E4 as a potential new natural estrogenic drug by the author of this Letter in 2001 until the out-licensing of E4 in 2015 by Pantarhei to Mithra Pharmaceuticals in Belgium. By 2015 Pantarhei had already performed pilot efficacy and dose finding studies for both the hormonal oral contraceptive (OC) application and for menopausal hormone therapy (MHT); both applications currently in development by Mithra.

Secondly, regarding the literature on E4, the authors of this review paper have limited their references to 17 papers and did not cite several important papers including: (1) the very first preclinical paper on ovulation inhibition comparing E4 with EE in the rat published in Contraception in 2008 [2]; (2) the Supplement of Climacteric from 2008, with guest editors Herjan JT Coelingh Bennink, Christian F Holinka and Egon Diczfalusy, containing a series of papers reporting the results of preclinical studies with E4 between 2001 and 2008 [3]; (3) the DMBA study published in HMBCI in 2012, that reported for the first time the unique anti-tumor effect of E4 on breast tumors in the rat [4]. These are just a selection of some key studies that are important contributions to the development of E4 as a component of combined oral contraceptives, although there are more, and it seems to me that even when restricting the review to oral contraception some of these papers should have qualified for inclusion.

In relation to the contraceptive development of E4, it seems relevant to know that at present, Pantarhei Oncology is developing high dose E4 (HDE4) for the treatment of advanced breast and prostate cancer with daily doses of 40 mg E4. For both applications first pilot efficacy and safety studies have been performed successfully and papers are in preparation.

Declaration of interest

The author of this Letter has no financial interest in the contraceptive development of estetrol, but has employment at Pantarhei Oncology, the company developing estetrol for oncological aplications. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.