Inhibition of ovulation by administration of estetrol in combination with drospirenone or levonorgestrel: Results of a phase II dose-finding pilot study
Open accessAbstract
OBJECTIVES: The aim of the study was to evaluate the efficacy of different dosages of estetrol (E4) combined with one of two progestins in suppressing the pituitary-ovarian axis and ovulation in healthy premenopausal women. METHODS: This was an open, parallel, phase II, dose-finding, pilot study performed in healthy women aged 18 to 35 years with a documented ovulatory cycle before treatment. For three consecutive cycles in a 24/4-day regimen, participants received 5 mg or 10 mg E4/3 mg drospirenone (DRSP); 5 mg, 10 mg or 20 mg E4/150 μg levonorgestrel; or 20 μg ethinylestradiol (EE)/3 mg DRSP as comparator. Pituitary-ovarian axis activity and the occurrence of ovulation were evaluated by monitoring follicular size, serum levels of follicle-stimulating hormone, luteinising hormone, estradiol and progesterone during treatment cycles 1 and 3. Endometrial thickness was evaluated throughout the trial, and the return of ovulation was evaluated after the last intake of medication. RESULTS: A total of 109 women were included in the trial. No ovulation occurred in any treatment group. Ovarian activity inhibition seemed proportional to the E4 dosage: the highest suppression was observed in the 20 mg E4 group and was very similar to that observed with EE/DRSP. Endometrial thickness was suppressed to the same extent in all groups. Post-treatment ovulation occurred in all participants between 17 and 21 days after the last active treatment. The study combinations were well tolerated and safe. CONCLUSIONS: Combined with a progestin, E4 adequately suppresses ovarian activity, particularly when given at a dosage above 10 mg/day.
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E4 in combination with DRSP is associated with a favorable vaginal bleeding, safety and tolerability profile.
“E4 in combination with DRSP inhibits ovulation and is associated with a favorable vaginal bleeding, safety and tolerability profile, and with high user satisfaction [ 9 , 12 , 13 ].”
From Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone (2021) · cites this paper as [12]
The Results section on safety and tolerability says the E4/DRSP study combinations were well tolerated and that no serious adverse events occurred. However, the Discussion’s “Unanswered questions and future research” section says this small, short study was not designed to evaluate bleeding patterns or safety adequately. It therefore does not establish a favorable vaginal-bleeding profile or a fully characterized safety profile. (LLM, conf=0.90)
Experimental — accuracy not yet measuredE4 in combination with DRSP inhibits ovulation.
“E4 in combination with DRSP inhibits ovulation and is associated with a favorable vaginal bleeding, safety and tolerability profile, and with high user satisfaction [ 9 , 12 , 13 ].”
From Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone (2021) · cites this paper as [12]
E4 in combination with DRSP is associated with high user satisfaction.
“E4 in combination with DRSP inhibits ovulation and is associated with a favorable vaginal bleeding, safety and tolerability profile, and with high user satisfaction [ 9 , 12 , 13 ].”
From Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone (2021) · cites this paper as [12]
The Results section on safety and tolerability says the E4/DRSP combinations were well tolerated, but it does not report user satisfaction. The Discussion section on unanswered questions says a larger study is needed to assess acceptability; searches for satisfaction and acceptability found no satisfaction result in this paper. (LLM, conf=0.78)
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Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone
Klipping, C., Duijkers, I., Mawet, M., Maillard, C., Bastidas, A., Jost, M., & Foidart, J.-M. (2021) · Contraception · doi:10.1016/j.contraception.2021.01.001 · Cited by 108 · see citing works
Self-citationApter, D., Zimmerman, Y., Beekman, L., Mawet, M., Maillard, C., Foidart, J.-M., & Coelingh Bennink, H. J. T. (2016) · Contraception · doi:10.1016/j.contraception.2016.04.015 · Cited by 77 · see citing works
Self-citationApter, D., Zimmerman, Y., Beekman, L., Mawet, M., Maillard, C., Foidart, J.-M., & Coelingh Bennink, H. J. T. (2017) · The European Journal of Contraception & Reproductive Health Care · doi:10.1080/13625187.2017.1336532 · Cited by 57 · see citing works
Self-citationCoelingh Bennink, H. J. T., Verhoeven, C., Zimmerman, Y., Visser, M., Foidart, J.-M., & Gemzell-Danielsson, K. (2017) · Menopause · doi:10.1097/gme.0000000000000823 · Cited by 45 · see citing works
Self-citation
- Authors
- Duijkers, I. J. M., Klipping, C., Zimmerman, Y., Appels, N., Jost, M., Maillard, C., Mawet, M., Foidart, J.-M., & Coelingh Bennink, H. J. T.
- Affiliations
- *Dinox BV, Groningen, the Netherlands
- Pantarhei Bioscience (Netherlands) (NL)
- Estetra SPRL, Liège, Belgium
- University of Liège (BE)
- Pantarhei Bioscience BV, Zeist, the Netherlands
- Corresponding author
- Mawet, Marie
- Venue
- The European Journal of Contraception & Reproductive Health Care
- Publisher
- Informa UK Limited
- Published
- 2015-08-20
- Volume
- 20
- Issue
- 6
- Pages
- 476-489
- ISSN
- 1362-5187 (ISSN-L)
- 1473-0782
- PMC
- PMC4673580
- OpenAlex
- W1889867145
- Cited by
- 61
- References
- 1
- Citations by year
- 2026: 7 · 2025: 3 · 2024: 9 · 2023: 7 · 2022: 9 · 2021: 9 · 2020: 4 · 2019: 1 · 2018: 4 · 2017: 6 · 2016: 2
- FWCI
- 4.29
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- The European Journal of Contraception & Reproductive Health Care (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Open Repository and Bibliography (University of Liège) (submittedVersion)
- PubMed
- 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 › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- estetrol, E4, drospirenone, levonorgestrel, ovulation inhibition, progestins, dose-finding, premenopausal women, endometrial thickness, follicle-stimulating hormone, luteinizing hormone, estradiol, progesterone, ethinyl estradiol
- MeSH terms
- Adolescent, Adult, Mineralocorticoid Receptor Antagonists, Androstenes, Contraceptives, Oral, Combined, Dose-Response Relationship, Drug, Endometrium, Estetrol, Estradiol, Ethinyl Estradiol, Female, Follicle Stimulating Hormone, Ovarian Follicle, Humans, Luteinizing Hormone, Ovulation, Pilot Projects, Pituitary Gland, Progesterone, Ultrasonography, Levonorgestrel, Ovulation Inhibition, Young Adult
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