Natural vs Synthetic estrogens

This morning’s excellent session on natural versus synthetic estrogens was kicked off by Alfred Mueck who discussed the pharmacology of estrogens.

Alfred began by looking at the ADME system (absorption, distribution, metabolism, elimination) for Estradiol (E2) versus Ethinylestradiol (EE).

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The ethinyl-estradioal group is the reason for EE’s high reactivity and is also responsible for protecting the hydroxyl group from oxidation which makes is a stable molecule that can be used in low dosages. In the liver passage, EE goes through the liver 20 times before it’s broken down to a non-reactive state. 

This table demonstrates why EE has been traditionally used in contraceptive pills, due to its superior stability. However many of the known risks associated with use of conventional COC are related to EE which has led to many looking for a change. EE has effects on liver proteins which leads to increased risk of venous thromboembolism, it has various strong hepatic effects which can increase risk of cholestasis, follicular nodular hyperplasia and benign and malignant hepatic tumours. In addition it impacts the CYP-P450 Enzyme system which leads to many drug interactions and can also result in an increased risk of ischemic stroke.  In the contraceptive field, we can’t reduce risk of VTE by changing the EE application form. However as E2 is metabolised to 95% in the first liver passage it presents a potentially safer option.

Now we’ve looked at the pharmacokinetics- what does clinical data actually show?

A study published by Van den Heuvel et al. showed higher VTE risk with an EE patch compared to COC. suggesting E2 may be the way forward. But other studies also showed that use of E2 could result in a poor cycle control. Although the potency of E2 with regards to endometrial proliferation is actually stronger than that of EE, due to the activity of estradiol-17beta-dehyrdogenase which is stimulated by progestins, E2 is rapidly converted to estrone (E1) which only has very weak estrogenic activity and cannot maintain stable endometrial proliferation.

So do we want to use E2 based pills? Can we reduce the VTE risk? From a pharmacological point of view Alfred believes so, Dinger J et al. Contraception 2016; 94 (4):328-229 also showed significant reduction in VTE risk with E2 based pills in the European section of the study, however the reduced risk was not significant in the overall global study. In order to have a concrete answer we need more research, currently the optimal option remains transdermal E2 to avoid the risks associated with EE.