Skip to content


The use of hormonal therapy has been associated with an increased risk of venous thromboembolism (VTE) and breast cancer. Recently, Gérard et al. [1] reported in a narrative review the profile of estetrol (E4), an estrogen produced by the human fetal liver, with properties that may provide a better safety profile. Unlike other estrogens, E4 activates the nuclear estrogen receptor (ER) α signaling pathway but does not activate membrane ERα signaling pathway in specific tissues. It is considered the first Native Estrogen with Selective action in Tissues (NEST) due to its differential activation of the nuclear and membrane ERα pathways. E4 does not stimulate the membrane ERα and antagonizes the estradiol-induced membrane effects. E4 has recently been approved in Europe and several countries (USA, Canada, Australia) as a new estrogenic component of a combined oral contraceptive, associated with drospirenone. The association of 15 mg of E4 plus drospirenone 3 mg has good contraceptive efficacy, safety, and user tolerability. E4 has a low impact on the liver and the breast, and a higher effect on the endometrium, vaginal epithelium, and the cardiovascular system. In comparison to other contraceptives, the association of E4/drospirenone showed less impact on several parameters, including laboratory markers of hypercoagulability. Finally, in addition to its use in contraception, E4 has the potential to be used in the treatment for menopausal symptoms.


Estrogens are used at different stages of a woman’s life. They were first synthesized almost 100 years ago with purification of estrone (E1) in 1929 and the discovery of estradiol (E2) in 1931 and estriol (E3) in 1933. E4 was first described by Diczfalusy in 1965. Natural or synthetic estrogens alone or in combination with progestogens have been used according to women’s needs during the reproductive, perimenopausal and postmenopausal periods. This use has been associated with an increased risk of venous thromboembolism and breast cancer [1]. Recently, Gerard et al. [1] performed a narrative review on the effects of E4 for oral contraception and the relief of menopausal symptoms. They analyzed the efficacy and cycle control of E4 combined to drospirenone as an oral contraceptive, and the impact on the liver (hemostasis, lipids, and renin-angiotensin-aldosterone system), the breast tissue, the cardiovascular system and metabolism. In their conclusions, the authors reinforce the importance of the estrogenic component of combined oral contraceptives (COCs). The specific estrogen/progestin combination has an impact on the total estrogenicity of the formulation, its clinical use, and linked benefit/risk balance. Both preclinical and clinical data have shown the cardiovascular safety of E4, acting as a classic estrogen that induces a series of cardiovascular/arterial benefits through the activation of the ERα nuclear pathway. At the same time, E4 may pose less risk of thromboembolic events, such as VTE due to its neutral profile on the synthesis of hemostatic proteins. Finally, E4 has shown to have a lower impact on breast tissue compared to other estrogens [1]. Regarding the use of E4 in peri- and postmenopausal periods, its use alone was effective in relieving menopausal vasomotor symptoms.

So far, COCs with a natural estrogen include estradiol valerate (E2V) plus dienogest (DNG) in a quadriphasic regimen and 17β-estradiol (E2) plus nomegestrol acetate (NOMAc) in a monophasic regimen. E2V+DNG did not change surrogate VTE markers, like prothrombin fragment 1 + 2 and D-dimer levels [2], and its VTE risk in large cohorts like INAS-SCORE were similar compared to a levonorgestrel-containing COC [3]. Similarly, E2+NOMAc had less influence on hemostasis than a levonorgestrel-containing COC [4].

It is known that the hormone replacement therapy (HRT) in postmenopausal women should always have a personalized indication. Before the prescription of HRT, the intensity of the symptoms and risks should be considered to determine the dose, route of administration and the best treatment regimen [5]. Thus, E4 has a promising profile to be a new option in the treatment of climacteric symptoms in peri- and postmenopausal women.

Prof. Edmund Baracat, MD, PhD
Gynecology Division, Department of Obstetrics and Gynecology,
Hospital das Clínicas, Faculdade de Medicina,
Universidade de São Paulo, São Paolo, Brazil


  1. Gérard C, Arnal JF, Jost M, et al. Profile of estetrol, a promising native estrogen for oral contraception and the relief of climacteric symptoms of menopause. Expert Rev Clin Pharmacol. 2022;15(2):121-137.
  2. Junge W, Mellinger U, Parke S, Serrani M. Metabolic and haemostatic effects of estradiol valerate/dienogest, a novel oral contraceptive: a randomized, open-label, single-centre study. Clin Drug Investig. 2011;31(8):573-584.
  3. Dinger J, Do Minh T, Heinemann K. Impact of estrogen type on cardiovascular safety of combined oral contraceptives. Contraception. 2016;94(4):328-39.
  4. Ågren UM, Anttila M, Mäenpää-Liukko K, et al. Effects of a monophasic combined oral contraceptive containing nomegestrol acetate and 17β-oestradiol compared with one containing levonorgestrel and ethinylestradiol on haemostasis, lipids and carbohydrate metabolism. Eur J Contracept Reprod Health Care. 2011;16(6):444-57.
  5. Sorpreso IC, Soares Júnior JM, Fonseca AM, Baracat EC. Female aging. Rev Assoc Med Bras (1992). 2015;61(6):553-6.


If you would like to add a comment or contribute to a discussion based on this issue, please contact Menopause Live Editor, Peter Chedraui at

International Menopause Society

Install International Menopause Society - DEV

Install this application on your home screen for quick and easy access when you’re on the go.

Just tap then “Add to Home Screen”