Should Estetrol be used for oral contraception and treatment of menopause?

For those of you who aren’t familiar with Estetrol (E4), Estetrol is a native estrogenthat was discovered in 1965. In the 20 years that followed its discovery all studies focused on finding a diagnostic value of E4 looking at maternal plasma levels in abnormal pregnancy. Unfortunately all these studies failed and E4 was abandoned until the turn of the century when it was suggested E4 could be used in therapeutics, rather than as a diagnostic!  

It’s been a theme here at ESG to look at the “full circle” from past to future. It is well documented that the estrogen receptor was the first receptor that appeared in human evolution 800 million years ago. As estrogen has been around for about 500 million years it’s not surprising E1, E2 and E3 are widely found in animals. However E4 was discovered much later as its human specific, only displaying itself during the term of pregnancy from the ninth week of gestation.

It is well known that estrogen receptors are not only found in the nucleus but also in the membrane of the cell. E2 will bind to both the nucleus and membrane receptors. When it binds to the membrane receptor it activates steroid signalling which leads to increased cascade phosphorylation resulting in genomic effects. E4 on the other hand only binds to the nucleus receptor and instead acts as an antagonist at the membrane receptor.

E4 acts as an estrogen in the bone, vagina, endometrium, brain, heart and works in synergy with the endogenous estrogens to provide beneficial effects.  E4 also acts as an anti-estrogen in breast and liver tissue to block unwanted side effects of endogenous estrogens. Data has identified E4 as a selective estrogen receptor modulator.

So what about E4 as a contraceptive?

Micevych’s hypothesis suggests E4 will be able to completely stop ovulation, so contraceptives including E4 will have a double mode of action. A phase IIa study was carried out to look at the impact of E4 on ovarian activity. Data showed that E4 inhibits ovulation in association with a progestin and allows rapid and complete return to fertility. Data showed after two cycles, follicular development can also be prevented. E4 usage also resulted in less spotting during the pill intake period and a higher amount of spotting and bleeding during the pill free period.

Mawet M et al, Eur. J. Contracept. Reprod. Healthcare. 2015:1-13 showed E4 also had minimal impact on triglycerides levels and Kluti C et al. Contraception. 2016 demonstrated that E4 in combination with DRSP showed a reduced VTE risk profile when compared to a COC making E4 an attractive option for contraception.

What about for relieving symptoms of menopause?

Research also found that E4 doesn’t modify angiotensinogen plasma levels, leading to a reduced risk of hypertension. E4 also doesn’t inhibit the CYP450 so doesn’t interact with other drugs and has minimal interference with liver cells.  In the lab, E4 has shown to protect against breast cancer development and to decrease size of already existing tumours.

All this data suggests E4 is very safe and may have less risks than traditional MHT. Two large phase 3 clinical studies are being carried out in Europe/Russia and Canada/USA. A phase 2 study has also just been completed for the use of E4 in VMS, early phase I results suggest E4 usage results in a decrease in VMS symptoms. We await the phase III data to see if this could be a viable alternative to MHT!