Bleeding pattern and cycle control with estetrol-containing combined oral contraceptives: results from a phase II, randomised, dose-finding study (FIESTA)

Apter, Dan; Zimmerman, Yvette; Beekman, Louise; Mawet, Marie; Maillard, Catherine; Foidart, Jean-Michel; Coelingh Bennink, Herjan J.T.

doi:10.1016/j.contraception.2016.04.015

Cited by 77Reproductive Health and ContraceptionMenstrual Health and DisordersEstrogen and related hormone effects

Bleeding pattern and cycle control with estetrol-containing combined oral contraceptives: results from a phase II, randomised, dose-finding study (FIESTA)

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Apter, Dan, Zimmerman, Yvette, Beekman, Louise, Mawet, Marie, Maillard, Catherine, Foidart, Jean-Michel, Coelingh Bennink, Herjan J.T.·2016·Contraception

DOI 10.1016/j.contraception.2016.04.015

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Abstract

OBJECTIVES: This study aims to assess vaginal bleeding patterns and cycle control of oral contraceptives containing estetrol (E4) combined with either drospirenone (DRSP) or levonorgestrel (LNG). STUDY DESIGN: An open-label, multicentre, randomised, dose-finding study lasting six cycles in healthy women aged 18-35 years was used. Four treatments (15 mg or 20 mg E4, combined with either 3 mg DRSP or 150 mcg LNG) were administered in a 24/4-day regimen. A marketed dosing regimen of estradiol valerate with dienogest (E2V/DNG) served as reference since it contains (like E4) a natural oestrogen. RESULTS: A total of 396 women were randomised, of whom 389 received study medication, and 316 completed the study. By cycle 6, the frequencies of unscheduled bleeding and/or spotting and absence of withdrawal bleeding were the lowest in the 15 mg E4/DRSP group (33.8% and 3.5%, respectively). In the E2V/DNG reference group, these frequencies were 47.8% and 27.1%, respectively. By cycle 6, the frequency of women with absence of withdrawal bleeding was <20% for all E4 treatment groups: 3.5-3.8% combined with DRSP and 14.0-18.5% combined with LNG. By cycle 6, unscheduled intracyclic bleeding was reported by <20% of women in the 20 mg E4/LNG group (18.9%) and in the 15 mg E4/DRSP group (16.9%). CONCLUSION: This study showed that, of the four treatment modalities investigated, the 15 mg E4/DRSP combination has the most favourable bleeding pattern and cycle control. IMPLICATIONS: Due to its favourable bleeding pattern and cycle control, the 15 mg E4/DRSP combination is the preferred combination for further phase III clinical development.

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E4 has been studied in contraception, menopause, osteoporosis, and breast cancer.
“Chemically synthesized E4 is identical to the natural hormone and has been studied in contraception, menopause, osteoporosis, and breast cancer [9-11] .”
From Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone (2021) · cites this paper as [9]
The Introduction and Abstract describe a phase II study of E4-containing oral contraceptives, supporting the contraception part of the claim. Our copy does not report studies of E4 for menopause, osteoporosis, or breast cancer; the References mention exposure in postmenopausal women but do not establish a menopause study. Page numbers were not available in the indexed passages. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Chemically synthesized E4 is identical to the natural hormone.
“Chemically synthesized E4 is identical to the natural hormone and has been studied in contraception, menopause, osteoporosis, and breast cancer [9-11] .”
From Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone (2021) · cites this paper as [9]
The Introduction identifies E4 as a natural oestrogen synthesised by the human foetal liver. It does not say that chemically synthesised E4 is identical to the naturally occurring hormone; that central comparison is unsupported by this paper. (LLM, conf=0.77)
Experimental — accuracy not yet measured
E4 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 [9]
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 [9]
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 [9]
The Results (section 3.1) report a 91.1% completion rate for the 15 mg E4/DRSP group, and the Discussion describes favorable cycle control and low discontinuation. Neither passage reports user satisfaction or a satisfaction assessment, so our copy does not establish the attributed claim (searched: satisfaction, acceptability). (LLM, conf=0.74)
Experimental — accuracy not yet measured

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POSTER ABSTRACTS
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Bleeding Patterns with Use of an Oral Contraceptive Containing Estetrol and Drospirenone: Pooled Analysis of Phase-3 Clinical Trials
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Authors: Apter, D., Zimmerman, Y., Beekman, L., Mawet, M., Maillard, C., Foidart, J.-M., & Coelingh Bennink, H. J. T.
Affiliations: Väestöliitto (FI)
Pantarhei Bioscience (Netherlands) (NL)
University of Liège (BE)
Corresponding author: Mawet, Marie
ORCID: Apter, Dan
Zimmerman, Yvette
Mawet, Marie
Foidart, Jean-Michel
Venue: Contraception
Publisher: Elsevier BV
Published: 2016-10
Volume: 94
Issue: 4
Pages: 366-373
ISSN: 0010-7824 (ISSN-L)
DOI: 10.1016/j.contraception.2016.04.015
OpenAlex: W2346414905
Cited by: 77
References: 26
Citations by year: 2026: 7 · 2025: 4 · 2024: 9 · 2023: 9 · 2022: 11 · 2021: 11 · 2020: 5 · 2019: 5 · 2018: 6 · 2017: 5 · 2016: 5
FWCI: 6.94
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
Locations: Contraception (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
ORBi (University of Liège) (submittedVersion, other-oa)
Funders: Estetra SPRL
Walloon Government (C6139)
Topics: Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Health and Contraception
Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Menstrual Health and Disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Keywords: estetrol, E4, combined oral contraceptives, drospirenone, levonorgestrel, vaginal bleeding, cycle control, withdrawal bleeding, unscheduled bleeding, estradiol valerate, dienogest, dose-finding
MeSH terms: Androstenes, Contraceptive Agents, Female, Contraceptives, Oral, Combined, Dose-Response Relationship, Drug, Estetrol, Estradiol, Female, Humans, Metrorrhagia, Nandrolone, Levonorgestrel

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Bleeding pattern and cycle control with estetrol-containing combined oral contraceptives: results from a phase II, randomised, dose-finding study (FIESTA)

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