Comparison of contraceptive pills reveals differences in adverse metabolic effects of different forms of estrogen

A joint study by the University of Oulu and University of Helsinki compared the effects of two different types of estrogen on blood inflammatory markers and lipid levels. Ethinyl estradiol, used in many combined oral contraceptives (COCs), increased chronic inflammation, while estradiol valerate, which is similar to natural estrogen, had barely any effect on inflammation.

The COCs compared by the researchers contained either ethinyl estradiol or estradiol valerate combined with the progestin dienogest. In the research frame, the effect of progestin was standardised, which facilitated direct comparison of the effects of different types of estrogen. Similar comparisons between these two types of estrogen have never been done before.

Fifty-nine healthy women aged between 18 and 34 years participated in the study, using a COC containing either ethinyl estradiol or estradiol valerate, or a product containing only progestin, continuously for nine weeks.

The COC containing ethinyl estradiol increased chronic inflammation. The result was not surprising, as ethinyl estradiol has previously been observed to slightly increase inflammatory markers.

A completely new observation was that estradiol valerate barely increased inflammatory markers and had metabolic effects comparable to COCs containing only progestin.

An overwhelming majority of the currently available COCs contain ethinyl estradiol. “There are dozens of COCs with ethinyl estradiol combinations available in the market, whereas there are only three COCs used in Finland that contain natural estradiol or estradiol valerate,” says Marika Kangasniemi from the University of Oulu, head researcher of the study.

Although the study gives a strong indication to favour estradiol valerate in COCs, further research is still needed. More information is also needed on the long-term effects of COCs. Protracted chronic inflammation is known to predispose women to cardiovascular diseases.

“Because women use COCs for up to decades, it could be useful to favour COCs with fewer adverse metabolic effects. In particular, this should be taken into account for women who already have many metabolic risk factors, such as obesity or polycystic ovary syndrome. However, more medical research with these patient groups is needed,” says Kangasniemi.

Millions of women around the world use COCs for birth control or to treat an illness. The choice of COC is influenced by a number of individual factors, such as the woman’s age and the potential adverse effects of COCs. The effectiveness of ethinyl estradiol in achieving good control of bleeding has been considered one of its advantages. A more natural estrogen may be favoured for older women because it is thought to involve a lower risk of thrombosis.  

The study was published in the prestigious Journal of Clinical Endocrinology & Metabolism.

Research publication: Marika H Kangasniemi, Anniina Haverinen, Kaisu Luiro, J Kalervo Hiltunen, Elina K Komsi, Riikka K Arffman, Oskari Heikinheimo, Juha S Tapanainen, Terhi T Piltonen. Estradiol Valerate in COC Has More Favorable Inflammatory Profile Than Synthetic Ethinyl Estradiol: A Randomized Trial. The Journal of Clinical Endocrinology & Metabolism, Volume 105, Issue 7, July 2020, dgaa186,

Updated 18.6. There are only three (previously: two) COCs used in Finland that contain natural estradiol or estradiol valerate.


Last updated: 30.6.2020