Estetrol e suas implicações na contracepção, no tromboembolismo venoso e no câncer de mama: uma revisão integrativa
Estetrol and its implications for contraception, venous thromboembolism, and breast cancer: an integrative review
Marcos Arêas Marques; Suzanna Maria Viana Sanches; Monique Magnavita Borba da Fonseca Cerqueira; Marina Araujo Zulchner; André Luiz Malavasi Longo de Oliveira
Resumo
Palavras-chave
Abstract
Combined oral contraceptives (COCs) provide benefits beyond contraception but are associated with risks such as venous thromboembolism (VTE) and breast cancer. This integrative review aimed to evaluate the efficacy and safety of estetrol (E4)-containing COCs regarding their risk of VTE and breast cancer. The PubMed database was searched for preclinical and clinical studies published through 2025. Data extraction followed a structured protocol, resulting in the inclusion of 15 studies in the review. Available evidence suggests that E4 has limited effects on the liver and the coagulation cascade, in addition to being associated with less breast tissue proliferation compared to other estrogens. However, clinical evidence regarding hard outcomes, including the long-term incidence of VTE and breast cancer, remains limited. Current evidence suggests a promising efficacy and safety profile but remains insufficient to rule out the risks of VTE and breast cancer.
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Referências
1 Oliveira ALML, Marques MA. Profilaxia de tromboembolismo venoso na gestação. J Vasc Bras. 2016;15(4):293-301.
2 Fitzpatrick D, Pirie K, Reeves G, Green J, Beral V. Combined and progestagen-only hormonal contraceptives and breast cancer risk: a UK nested case-control study and meta-analysis. PLoS Med. 2023;20(3):e1004188.
3 Hadizadeh F, Koteci A, Karlsson T, Ek WE, Johansson Å. Hormonal contraceptive formulations and breast cancer risk in adolescents and premenopausal women. JAMA Oncol. 2025;11(12):1497-506.
4 Creinin MD, Westhoff CL, Bouchard C, et al. Estetrol-drospirenone combination oral contraceptive: North American phase 3 efficacy and safety results. Contraception. 2021;104(3):222-8.
5 Klipping C, Duijkers I, Mawet M, et al. Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone. Contraception. 2021;103(4):213-21.
6 Gemzell‐Danielsson K, Apter D, Zatik J, et al. Estetrol‐Drospirenone combination oral contraceptive: a clinical study of contraceptive efficacy, bleeding pattern and safety in Europe and Russia. BJOG. 2022;129(1):63-71.
7 Duijkers I, Klipping C, Kinet V, Jost M, Bastidas A, Foidart JM. Effects of an oral contraceptive containing estetrol and drospirenone on ovarian function. Contraception. 2021;103(6):386-93.
8 Apter D, Zimmerman Y, Beekman L, et al. Estetrol combined with drospirenone: an oral contraceptive with high acceptability, user satisfaction, well-being and favourable body weight control. Eur J Contracept Reprod Health Care. 2017;22(4):260-7.
9 Kluft C, Zimmerman Y, Mawet M, et al. Reduced hemostatic effects with drospirenone-based oral contraceptives containing estetrol vs. ethinyl estradiol. Contraception. 2017;95(2):140-7.
10 Duijkers IJM, Klipping C, Zimmerman Y, et al. Inhibition of ovulation by administration of estetrol in combination with drospirenone or levonorgestrel: results of a phase II dose-finding pilot study. Eur J Contracept Reprod Health Care. 2015;20(6):476-89.
11 Apter D, Zimmerman Y, Beekman L, et al. Bleeding pattern and cycle control with estetrol-containing combined oral contraceptives: results from a phase II, randomised, dose-finding study (FIESTA). Contraception. 2016;94(4):366-73.
12 Mawet M, Maillard C, Klipping C, Zimmerman Y, Foidart JM, Bennink HJTC. Unique effects on hepatic function, lipid metabolism, bone and growth endocrine parameters of estetrol in combined oral contraceptives. Eur J Contracept Reprod Health Care. 2015;20(6):463-75.
13 Creinin MD, Foidart JM, Gemzell-Danielsson K, et al. Estetrol/Drospirenone safety in a population with cardiovascular risk factors. Contraception. 2025;146:110861.
14 Chen MJ, Jensen JT, Kaunitz AM, et al. Tolerability and safety of the estetrol/drospirenone combined oral contraceptive: Pooled analysis of two multicenter, open-label phase 3 trials. Contraception. 2022;116:44-50.
15 Jensen JT, Kaunitz AM, Achilles SL, et al. Pooled efficacy results of estetrol/drospirenone combined oral contraception phase 3 trials. Contraception. 2022;116:37-43.
16 Kaunitz AM, Achilles SL, Zatik J, et al. Pooled analysis of two phase 3 trials evaluating the effects of a novel combined oral contraceptive containing estetrol/drospirenone on bleeding patterns in healthy women. Contraception. 2022;116:29-36.
17 Gérard C, Foidart JM. Estetrol: from preclinical to clinical pharmacology and advances in the understanding of the molecular mechanism of action. Drugs R D. 2023;23(2):77-92.
18 Gallez A, Silva ID, Wuidar V, Foidart JM, Péqueux C. Estetrol and mammary gland: friends or foes? J Mammary Gland Biol Neoplasia. 2021;26(3):297-308.
19 Gallez A, Blacher S, Maquoi E, et al. Estetrol combined to progestogen for menopause or contraception indication is neutral on breast cancer. Cancers. 2021;13(10):2486.
20 Battipaglia C, Genazzani AD, Nappi RE, La Marca A. Insights on estetrol, the native estrogen: from contraception to hormone replacement therapy. Minerva Obstet Gynecol. 2024;76(6):590-603. PMid:39283289.
21 Gemzell-Danielsson K, Cagnacci A, Chabbert-Buffet N, et al. A novel estetrol-containing combined oral contraceptive: European expert panel review. Eur J Contracept Reprod Health Care. 2022;27(5):373-83.
22 Cirillo F, Spinelli A, Talia M, et al. Estetrol/GPER/SERPINB2 transduction signaling inhibits the motility of triple-negative breast cancer cells. J Transl Med. 2024;22(1):450.
23 Gérard C, Mestdagt M, Tskitishvili E, et al. Combined estrogenic and anti-estrogenic properties of estetrol on breast cancer may provide a safe therapeutic window for the treatment of menopausal symptoms. Oncotarget. 2015;6(19):17621-36.
24 Jozan S, Kreitmann B, Bayard F. Different effects of oestradiol, oestriol, oestetrol and of oestrone on human breast cancer cells (MCF-7) in long term tissue culture. Acta Endocrinol. 1981;98(1):73-80.
25 Liu S, Ruan X, Schultz S, et al. Oestetrol stimulates proliferation and oestrogen receptor expression in breast cancer cell lines: comparison of four oestrogens. Eur J Contracept Reprod Health Care. 2015;20(1):29-35.
26 Singer CF, Bennink HJTC, Natter C, et al. Antiestrogenic effects of the fetal estrogen estetrol in women with estrogen-receptor positive early breast cancer. Carcinogenesis. 2014;35(11):2447-51.
27 Schmidt M, Lenhard H, Hoenig A, et al. Tumor suppression, dose-limiting toxicity and wellbeing with the fetal estrogen estetrol in patients with advanced breast cancer. J Cancer Res Clin Oncol. 2021;147(6):1833-42.
28 Kobayashi T, Hirayama M, Nogami M, et al. Impact of estetrol combined with drospirenone on blood coagulation and fibrinolysis in patients with endometriosis: a multicenter, randomized, open-label, active-controlled, parallel-group study. Clin Appl Thromb Hemost. 2024;30:10760296241286514.
29 Douxfils J, Gaspard U, Taziaux M, et al. Impact of estetrol (E4) on hemostasis, metabolism and bone turnover in postmenopausal women. Climacteric. 2023;26(1):55-63.
30 Douxfils J, Klipping C, Duijkers I, et al. Evaluation of the effect of a new oral contraceptive containing estetrol and drospirenone on hemostasis parameters. Contraception. 2020;102(6):396-402.
31 Morimont L, Jost M, Gaspard U, Foidart JM, Dogné JM, Douxfils J. Low thrombin generation in users of a contraceptive containing estetrol and drospirenone. J Clin Endocrinol Metab. 2022;108(1):135-43.
32 Douxfils J, Morimont L, Gaspard U, Utian WH, Foidart JM. Estetrol is not a SERM but a NEST and has a specific safety profile on coagulation. Thromb Res. 2023;232:148-50.
33 Didembourg M, Locquet M, Raskin L, et al. Lower reporting of venous thromboembolisms events with natural estrogen-based combined oral contraceptives compared to ethinylestradiol-containing pills: a disproportionality analysis of the Eudravigilance database. Contraception. 2025;142:110727.
34 Sobreira ML, Marques MA, Paschôa AF, et al. Diretrizes sobre trombose venosa profunda da Sociedade Brasileira de Angiologia e Cirurgia Vascular. J Vasc Bras. 2024;23:e20230107. PMid:39286300.
Submetido em:
07/02/2026
Aceito em:
21/05/2026
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