Estetrol and its implications for contraception, venous thromboembolism, and breast cancer: an integrative review

Marques, Marcos Arêas; Sanches, Suzanna Maria Viana; Cerqueira, Monique Magnavita Borba da Fonseca; Zulchner, Marina Araujo; Oliveira, André Luiz Malavasi Longo de

doi:10.1590/1677-5449.202600121

person Marcos Arêas Marques

conception and design · analysis and interpretation · data collection · writing the article · critical revision of the article · final approval of the article · overall responsibility MSc in Medicine, Universidade Federal do Estado do Rio de Janeiro (UNIRIO); Angiologist, Vascular Surgery Service, Hospital Universitário Gaffrée e Guinle (HUGG-UNIRIO), and Angiology Service, Hospital Universitário Pedro Ernesto (HUPE), Universidade do Estado do Rio de Janeiro (UERJ).

schoolUniversidade Federal do Estado do Rio de Janeiro – UNIRIO, Hospital Universitário Gaffrée e Guinle, Rio de Janeiro, RJ, Brasil.schoolUniversidade do Estado do Rio de Janeiro – UERJ, Hospital Universitário Pedro Ernesto – HUPE, Rio de Janeiro, RJ, Brasil.

0000-0002-5329-7819

person Suzanna Maria Viana Sanches

analysis and interpretation · data collection · writing the article · critical revision of the article · final approval of the article Preceptor, Venous Thrombosis Outpatient Clinic, Hospital Geral Ernesto Simões (HGES).

schoolHospital Geral Ernesto Simões – HGES, Salvador, BA, Brasil.

0000-0002-4168-9022

person Monique Magnavita Borba da Fonseca Cerqueira

analysis and interpretation · data collection · writing the article · critical revision of the article · final approval of the article PhD in Health Sciences, Universidade Federal da Bahia (UFBA); Adjunct Professor, Department of Life Sciences, Universidade do Estado da Bahia (UNEB).

schoolUniversidade do Estado da Bahia – UNEB, Salvador, BA, Brasil.

0000-0002-9836-7788

person Marina Araujo Zulchner

analysis and interpretation · data collection · writing the article · critical revision of the article · final approval of the article Angiologist, Hospital Universitário Pedro Ernesto (HUPE), Universidade do Estado do Rio de Janeiro (UERJ).

schoolUniversidade do Estado do Rio de Janeiro – UERJ, Hospital Universitário Pedro Ernesto – HUPE, Rio de Janeiro, RJ, Brasil.

0000-0002-0182-5966

person André Luiz Malavasi Longo de Oliveira

conception and design · analysis and interpretation · writing the article · critical revision of the article · final approval of the article PhD in Health Sciences, Faculdade de Ciências Médicas (FCM), Santa Casa de São Paulo (SCSP); Physician, Human Reproduction Center, Gynecology Clinic, School of Medicine, Universidade de São Paulo (USP).

schoolUniversidade de São Paulo – USP, Faculdade de Medicina, São Paulo, SP, Brasil.

0000-0003-0972-7380

Conflicts of interest:

MAM has received honoraria from the pharmaceutical industry for lectures on anticoagulants and venous thromboembolism. ALMLO has received honoraria from the pharmaceutical industry for lectures on hormonal implants.

personCorrespondence Marcos Arêas Marques Universidade Federal do Estado do Rio de Janeiro – UNIRIO, Hospital Universitário Gaffrée e Guinle, Departamento de Cirurgia Geral e Especializada – DECIGE Rua Mariz e Barros, 775 - Maracanã CEP 20270-004 - Rio de Janeiro (RJ), Brasil Tel.: +55 (21) 2264-4742 E-mail:
mareasmarques@gmail.com

Editor-in-Chief responsible

Dr. Winston Bonetti Yoshida

Author/year	Number of participants	Intervention	Comparator regimen	Outcomes	Conclusion	Level of evidence *
Creinin et al., 2021⁴	1864	Open-label, multicenter, phase III study; E4 15 mg + DRSP 3 mg.	—	Contraceptive efficacy (Pearl Index); cycle control: vaginal bleeding pattern; safety: adverse events.	E4/DRSP was effective as an oral contraceptive, with a predictable bleeding pattern for most women and low rates of adverse events.	2b
Kipling et al., 2021⁵	98	Randomized, controlled, open-label, 3-arm parallel study (4:3:3); E4 15 mg/DRSP 3 mg vs EE/LNG vs EE/DRSP.	Comparator 1: EE 30 μg/LNG 150 μg. Comparator 2: EE 20 μg/DRSP 3 mg.	Effect of E4 15 mg/DRSP 3 mg on endocrine and metabolic parameters after 3 and 6 months of treatment.	E4 15 mg/DRSP 3 mg showed limited effects on metabolic and endocrine parameters, with less pronounced effects on gonadotropins, cortisol, CBG, angiotensinogen, SHBG, and triglycerides than EE-containing formulations.	1b
Gemzell‐Danielsson et al., 2021⁶	1553	Open-label, multicenter, phase III study; E4/DRSP in a 24/4 regimen for up to 13 28-day cycles.	—	Contraceptive efficacy (Pearl Index); bleeding pattern; safety.	E4/DRSP demonstrated contraceptive efficacy, a predictable bleeding pattern, and a favorable safety profile.	2b
Duijkers et al., 2021⁷	82	Randomized, open-label, single-center, parallel study; E4 15 mg/DRSP 3 mg (24/4) for three consecutive cycles.	EE 20 µg/DRSP 3 mg.	Primary: suppression of ovarian function (Hoogland score); secondary: pituitary-ovarian function, endometrial thickness, and return of ovulation.	No participant in the E4/DRSP group ovulated, whereas two participants ovulated in the EE/DRSP group; findings suggest adequate inhibition of ovulation and suppression of ovarian function (exploratory study).	1b
Apter et al., 2017⁸	396	Randomized, open-label, multicenter, dose-finding study; six cycles (24/4) in five groups: (1) E4 15 mg/DRSP 3 mg; (2) E4 15 mg/LNG 150 μg; (3) E4 20 mg/DRSP 3 mg; (4) E4 20 mg/LNG 150 μg; (5) E2V/DNG.	E2V/DNG (Qlaira^®)	Primary: bleeding pattern/cycle control (E4+DRSP or E4+LNG); secondary: satisfaction, well-being, and acceptability.	E4 15 mg/DRSP 3 mg was associated with high acceptability and satisfaction, as well as a favorable body weight-control profile.	1b
Apter et al., 2016¹¹	396	Same intervention as the dose-finding study⁸; six cycles (24/4) in five groups: (1) E4 15 mg/DRSP 3 mg; (2) E4 15 mg/LNG 150 μg; (3) E4 20 mg/DRSP 3 mg; (4) E4 20 mg/LNG 150 μg; (5) E2V/DNG.	E2V/DNG (Qlaira^®)	Primary: vaginal bleeding patterns and cycle control.	Among the four E4-containing combinations evaluated, E4 15 mg/DRSP 3 mg showed the most favorable vaginal bleeding and cycle control profile.	1b
Duijkers et al., 2015¹⁰	108	Open-label, parallel, phase II, dose-finding, pilot study; three cycles (24/4 days) in six groups: (1) E4 5 mg/DRSP 3 mg; (2) E4 10 mg/DRSP 3 mg; (3) EE 20 μg/DRSP 3 mg; (4) E4 5 mg/LNG 150 μg; (5) E4 10 mg/LNG 150 μg; (6) E4 20 mg/LNG 150 μg.	EE 20 µg/DRSP 3 mg.	Ovulation rates (Hoogland score).	When combined with a progestin, E4 adequately suppresses ovarian activity, particularly at doses ≥ 10 mg/day.	2b
Mawet et al., 2015¹²	109	Dose-finding, single-center, exploratory, controlled study; three cycles (24/4 days) in six groups: (1) E4 5 mg/DRSP 3 mg; (2) E4 10 mg/DRSP 3 mg; (3) E4 5 mg/LNG 150 μg; (4) E4 10 mg/LNG 150 μg; (5) E4 20 mg/LNG 150 μg; (6) EE 20 μg/DRSP 3 mg.	EE 20 µg/DRSP 3 mg.	Hepatic and metabolic parameters, bone markers, and growth factors.	E4-containing combinations showed limited effects on liver function, lipid metabolism, and bone and growth endocrine parameters compared with EE-containing formulations.	2b
Kluft et al., 2016⁹	48	Open-label, parallel, dose-finding, single-center study; 24/4 regimen in three groups: (1) EE 20 μg/DRSP 3 mg (Yaz®); (2) E4 5 mg/DRSP 3 mg; (3) E4 10 mg/DRSP 3 mg.	EE 20 µg/DRSP 3 mg (Yaz^®)	Markers of hepatic estrogenicity and hemostasis.	Findings suggest lower hepatic estrogenicity with E4/DRSP compared with EE/DRSP, generating the hypothesis of a lower potential risk of VTE.	2b

Author/year	N	Intervention	Comparator regimen	Outcomes	Conclusion	Level of evidence *
Singer et al., 2014²⁶	30	Pilot randomized clinical trial: E4 20 mg vs placebo in the perioperative setting of early-stage breast cancer; preoperative and postoperative biopsies performed.	Placebo	Tumor proliferation and apoptosis markers: Ki-67, ERα, ERβ, Bax, Bcl-2; systemic IGF-1 levels.	E4 demonstrated antiestrogenic effects in breast cancer cells, with increased apoptosis, ERα downregulation, and decreased systemic IGF-1 levels, suggesting the safety of E4 in the evaluated setting.	1b
Schmidt et al., 2021²⁷	12	Open-label, multicenter, phase IB/IIA pilot dose-escalation study (3 + 3 cohort design): oral E4 20, 40, or 60 mg daily for 12 weeks in patients with heavily treated advanced breast cancer.	—	Primary: DLT and estimation of the maximum recommended and optimal doses; secondary: safety, tolerability, quality of life related to estrogen-deficiency symptoms, and preliminary assessment of antitumor response.	High doses of E4 were reported to be safe and well tolerated over 12 weeks, with signs of antitumor activity and no DLT, suggesting a potentially favorable cardiovascular risk profile and the possibility of maintaining or improving quality of life.	4

Author/year	Number of participants	Intervention	Comparator regimen	Outcomes	Conclusion	Level of evidence *
Douxfils et al., 2020³⁰	101	Randomized clinical trial: combined oral contraceptive containing E4 15 mg + DRSP 3 mg administered for six 28-day cycles in healthy women.	EE 20 μg + DRSP 3 mg	Hemostasis parameters, including activated protein C resistance, prothrombin fragment 1+2 (F1+2), SHBG, and other thromboembolic risk markers, assessed after 3 and 6 cycles.	The effect of E4/DRSP on hemostasis parameters was smaller or similar to that of EE/LNG and lower than that of EE/DRSP, suggesting a more favorable hemostasis profile. The findings indicate a possible reduction in thromboembolic risk associated with the estrogen component.	1b
Kluft et al., 2017⁹	48	Open-label clinical trial: E4 (5 or 10 mg) + DRSP 3 mg administered for three cycles in healthy women.	EE 20 μg + DRSP 3 mg	Markers of hemostasis and hepatic estrogenicity (SHBG, angiotensinogen, APCr, D-dimer, and F1+2).	E4/DRSP showed a lower hemostatic impact and no apparent procoagulant effect compared with EE/DRSP, suggesting a potentially more favorable thrombotic profile.	2b
Kobayashi et al., 2024²⁸	86	Multicenter randomized clinical trial: E4 15 mg + DRSP 3 mg administered for 12 weeks in patients with endometriosis.	EE 20 μg + DRSP 3 mg	Coagulation and fibrinolysis markers (APCsr/nAPCsr, D-dimer, F1+2, protein S, TFPI, and SHBG).	E4/DRSP had a lower impact on coagulation and fibrinolytic markers than EE/DRSP, suggesting a more favorable thrombotic profile, including in a population with a higher baseline risk of VTE.	1b
Douxfils et al., 2023²⁹	180	Double-blind randomized clinical trial: E4 2.5–15 mg/day administered for 12 weeks.	Placebo	Hemostasis markers (nAPCsr, D-dimer, and F1+2), SHBG, lipid profile, glucose metabolism, and bone remodeling markers.	E4 had limited impact on hemostasis, with only minor and clinically irrelevant changes, and potentially beneficial effects in metabolic and bone parameters, suggesting a favorable thrombotic profile in postmenopausal women.	1b

[1] CBG = corticosteroid-binding globulin; DNG = dienogest; DRSP = drospirenone; E2V = estradiol valerate; E4 = estetrol; EE = ethinyl estradiol; LNG = levonorgestrel; SHBG = sex hormone-binding globulin; VTE = venous thromboembolism. 24/4 regimen: 24 consecutive days of active tablets followed by 4 days of placebo tablets.

[TFN100] ^*
Level of evidence according to the Oxford Centre for Evidence-Based Medicine classification.