Estradiol-containing birth control pill

Combined birth control pills that contain natural estradiol or an estradiol ester (e.g., estradiol valerate) include:^[1][2][3]

• Estradiol valerate and cyproterone acetate (brand name Femilar) – introduced in Finland (only) in 1993^[3]
• Estradiol valerate and dienogest (brand names Qlaira, Natazia) – introduced in Europe in 2009 and the U.S.Tooltip United States in 2010^[4]
• Estradiol and nomegestrol acetate (brand name Zoely) – introduced in Europe in 2011^[5]

Estradiol-containing oral contraceptive
Background
Type	Hormonal
First use	1993 (Finland)
Pregnancy rates (first year)
Perfect use	?
Typical use	?
Usage
Reversibility	Yes
User reminders	?
Advantages and disadvantages
STI protection	No

Estradiol, mainly as esters including estradiol valerate, estradiol cypionate, and estradiol enanthate, is also the exclusive estrogen used in combined injectable contraceptives.^[6]

As of 2021, more than 95% of prescriptions are for combined hormonal birth control forms containing the synthetic estrogen ethinylestradiol (EE).^[7] Hence, estradiol-based birth control pills are still not widely used.^[7]

Side effects

Birth control pills containing estradiol have less impact on liver protein synthesis than ethinylestradiol-containing birth control pills, and it is thought that for this reason, they may pose less of a risk of venous thromboembolism (VTE).^[8][9] In accordance, although birth control pills containing estradiol valerate/dienogest are associated with a significantly increased risk of VTE, they are associated with a significantly lower risk of venous thromboembolism than birth control pills containing ethinylestradiol and a progestin.^[10] The risk of VTE with estradiol/nomegestrol acetate birth control pills is under study.^[11]

Incidence of irregular vaginal bleeding may be higher with estradiol-containing birth control pills in relation to the fact that estradiol is a weaker estrogen than ethinylestradiol in the endometrium.^[3]

Pharmacology

The pharmacodynamics and pharmacokinetics of estradiol in the context of use in birth control pills have been studied and reviewed.^[12][2][9]

Research

Experimental estradiol-containing birth control pills that were studied but never marketed include:^[3]

• Estradiol/norethisterone (Netagen, Netagen 403)
• Estradiol/estriol/norethisterone (Netagen 423)
• Estradiol/estriol/norethisterone acetate
• Estradiol/desogestrel
• Estradiol cyclooctyl acetate/desogestrel
• Estradiol/ethinylestradiol/dienogest

A large randomized controlled trial of a birth control pill containing ethinylestradiol/norethisterone acetate versus a birth control pill containing estradiol/estriol/norethisterone acetate has been conducted.^[13]

See also

• Birth control pill formulations
• Estetrol/drospirenone

References

1. De Leo V, Musacchio MC, Cappelli V, Piomboni P, Morgante G (2016). "Hormonal contraceptives: pharmacology tailored to women's health". Human Reproduction Update. 22 (5): 634–46. doi:10.1093/humupd/dmw016. PMID 27307386.
2. Stanczyk FZ, Archer DF, Bhavnani BR (2013). "Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment". Contraception. 87 (6): 706–27. doi:10.1016/j.contraception.2012.12.011. PMID 23375353.
3. Fruzzetti F, Bitzer J (2010). "Review of clinical experience with estradiol in combined oral contraceptives". Contraception. 81 (1): 8–15. doi:10.1016/j.contraception.2009.08.010. PMID 20004267.
4. Guida M, Bifulco G, Di Spiezio Sardo A, Scala M, Fernandez LM, Nappi C (2010). "Review of the safety, efficacy and patient acceptability of the combined dienogest/estradiol valerate contraceptive pill". International Journal of Women's Health. 2: 279–90. doi:10.2147/IJWH.S6954. PMC 2990895. PMID 21151673.
5. Burke A (2013). "Nomegestrol acetate-17b-estradiol for oral contraception". Patient Preference and Adherence. 7: 607–19. doi:10.2147/PPA.S39371. PMC 3702550. PMID 23836965.
6. "WJPPS | ABSTRACT" (PDF). World Journal of Pharmacy and Pharmaceutical Sciences.
7. Mawet, M; Gaspard, Ulysse; Foidart, JM (2021). "Estetrol as estrogen in a combined oral contraceptive, from the first in-human study to the contraceptive efficacy" (PDF). European Gynecology and Obstetrics. 3 (1): 13–21. On the other side, only three different estrogens have been used in COC since 1961: the first one was the pro-drug mestranol rapidly replaced by its potent active form, ethinylestradiol (EE). Ethinylestradiol has remained the only estrogen used in COC during more than four decades. After initial unsuccessful attempts, estradiol (E2) was finally introduced into two COCs in the early 2010': in the form of the pro-drug E2 valerate in combination with dienogest (E2V/DNG) and in the form of E2 in combination with nomegestrol acetate [4, 5]. However, these E2-containing COCs are less prescribed as over 95% of combined hormonal contraceptive users still utilize an EE-containing product.
8. Nelson AL (2015). "An update on new orally administered contraceptives for women". Expert Opinion on Pharmacotherapy. 16 (18): 2759–72. doi:10.1517/14656566.2015.1100173. PMID 26512437. S2CID 207481206.
9. Jensen, Jeffrey; Bitzer, Johannes; Serrani, Marco (2013). "Comparison of the pharmacologic and clinical profiles of new combined oral contraceptives containing estradiol". Open Access Journal of Contraception. 4: 39–50. doi:10.2147/OAJC.S50693. ISSN 1179-1527.
10. Fruzzetti F, Cagnacci A (2018). "Venous thrombosis and hormonal contraception: what's new with estradiol-based hormonal contraceptives?". Open Access J Contracept. 9: 75–79. doi:10.2147/OAJC.S179673. PMC 6239102. PMID 30519125.
11. Douxfils J, Morimont L, Bouvy C (October 2020). "Oral Contraceptives and Venous Thromboembolism: Focus on Testing that May Enable Prediction and Assessment of the Risk". Semin Thromb Hemost. 46 (8): 872–886. doi:10.1055/s-0040-1714140. PMID 33080636. S2CID 224821517.
12. Kuhnz W, Gansau C, Mahler M (September 1993). "Pharmacokinetics of estradiol, free and total estrone, in young women following single intravenous and oral administration of 17β-estradiol". Arzneimittelforschung. 43 (9): 966–73. ISSN 0004-4172. PMID 8240460.
13. "A randomized, double-blind study of two combined oral contraceptives containing the same progestogen, but different estrogens. World Health Organization Task Force on Oral Contraception". Contraception. 21 (5): 445–59. May 1980. doi:10.1016/0010-7824(80)90010-4. PMID 7428356.