An overview of the development of combined oral contraceptives containing estradiol: focus on estradiol valerate/dienogest
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Natural estrogens such as estradiol (E(2)) or its valerate ester (E(2)V) offer an alternative to ethinyl estradiol (EE). E(2)-containing combined oral contraceptives (COCs) have demonstrated sufficient ovulation inhibition and acceptable contraceptive efficacy. However, earlier formulations were generally associated with unacceptable bleeding profiles. Two E(2)V-containing preparations have been approved to date for contraceptive use: E(2)V/cyproterone acetate (CPA) (Femilar(®); only approved in Finland and only in women >40 years or women aged 35-40 years in whom a COC containing EE is not appropriate) and E(2)V/dienogest (DNG; Qlaira(®)/Natazia(®)). The objective of the current review is to provide an overview of the development of COCs containing natural estrogen, highlighting past issues and challenges faced by earlier formulations, as well as the current status and future directions. The majority of information to date pertains to the development of E(2)V/DNG.
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Compared to EE, the effect of the natural human hormone estradiol (E2) on hepatic metabolism is reduced.
“Compared to EE, the effect of the natural human hormone estradiol (E2) on hepatic metabolism is reduced [ 2 , 3 ].”
From Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone (2021) · cites this paper as [2]
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Cattoni, A., Parissone, F., Porcari, I., Molinari, S., Masera, N., Franchi, M. P., Cesaro, S., Gaudino, R., Passoni, P., & Balduzzi, A. (2021) · Yearbook of pediatric endocrinology · doi:10.1530/ey.18.9.7 · Cited by 1 · see citing works
Theoestrogen component of currently used steroidal contraceptives
Crook, D. (2013) · Cambridge University Press eBooks · doi:10.1017/cbo9781107323469.007
The Best Prophet of the Future is the Past: Oral Contraception and Novel Components
SHULMAN, L. P. (2014) · Journal of Women s Health · doi:10.1089/jwh.2014.4733
Individualizing Selection of Hormonal Contraception
Raney, E. C., Scott, S. C., & Cauthon, K. A. B. (2014) · Osteopathic Family Physician · doi:10.1016/ofp.v6i4.338
Real clinical practice and contraception for young women with children
Aganezova, N. V., & Станиславович, А. С. (2021) · GYNECOLOGY · doi:10.26442/20795696.2021.1.200629
NERY, L. C. D. E. S., BRAZ, L. C. S., Ferreira, L. L. D. M., VIEIRA, F. P., da Silva, L. L., Blanc, H. N. H., & Raimundo, J. M. (2021) · Anais da Academia Brasileira de Ciências · doi:10.1590/0001-3765202120201924 · Cited by 1 · see citing works
Stracquadanio, M. (2019) · Springer eBooks · doi:10.1007/978-3-030-29223-2_4
Optimizing oral contraceptive timing: Daytime intake reduces doses and enhances efficacy
Gavina, B. L. A., Lee, T., Cawiding, O. R., Choi, S., Choi, S., Kim, S., & Kim, J. K. (2026) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1014040
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Aspectos práticos quanto à escolha do contraceptivo oral combinado
Machado, R. B., MONTEIRO, I. M. U., Brito, M. B., & Lubianca, J. N. (2021) · Femina · doi:10.61622/0100-725449902101
Algorithm for prescribing hormonal contraception and menopausal hormone therapy in perimenopause
Baranov, I. I., Andreeva, E. N., Yureneva, S. V., Yarmolinskaya, M. I., Balan, V. E., Ивановна, А. Е., Aganezova, N. V., Bezhenar, V. F., Густоварова, Т. А., Dobrokhotova, J. E., et al. (2026) · Bulletin of Reproductive Health · doi:10.14341/brh12801
- Authors
- Fruzzetti, F., Trémollieres, F., & Bitzer, J.
- Affiliations
- University Hospital of Basel (CH)
- Corresponding author
- Fruzzetti, Franca
- Venue
- Gynecological Endocrinology
- Publisher
- Informa UK Limited
- Published
- 2012-04-02
- Volume
- 28
- Issue
- 5
- Pages
- 400-408
- ISSN
- 0951-3590 (ISSN-L)
- 1473-0766
- PMC
- PMC3399636
- OpenAlex
- W2150882666
- Cited by
- 56
- References
- 52
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 3 · 2023: 2 · 2022: 3 · 2021: 10 · 2020: 3 · 2019: 3 · 2018: 3 · 2017: 2 · 2016: 5 · 2015: 4 · 2014: 7 · 2013: 5 · 2012: 1
- FWCI
- 0.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gynecological Endocrinology (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Bayer HealthCare
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Health and Contraception
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Menopause: Health Impacts and Treatments
- Keywords
- estradiol valerate, dienogest, combined oral contraceptives, natural estrogens, cyproterone acetate, bleeding profile, ovulation inhibition, contraceptive efficacy, drug development history
- MeSH terms
- Contraceptives, Oral, Combined, Estradiol, Female, Humans, Nandrolone, History, 20th Century
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