Estetrol: From Preclinical to Clinical Pharmacology and Advances in the Understanding of the Molecular Mechanism of Action

Abstract

Estetrol (E4) is the most recently described natural estrogen. It is produced by the human fetal liver during pregnancy and its physiological function remains unclear. E4 is the estrogenic component of a recently approved combined oral contraceptive. It is also in development for use as menopausal hormone therapy. In the context of these developments, the pharmacological activity of E4, alone or in combination with a progestin, has been extensively characterized in preclinical models as well as in clinical studies in women of reproductive age and postmenopausal women. Despite the clinical benefits, the use of oral estrogens for contraception or menopause is also associated with unwanted effects, such as an increased risk of breast cancer and thromboembolic events, due to their impact on non-target tissues. Preclinical and clinical data for E4 point to a tissue-specific activity and a more selective pharmacological profile compared with other estrogens, including a low impact on the liver and hemostasis balance. This review summarizes the characterization of the pharmacological properties of E4 as well as recent advances made in the understanding of the molecular mechanisms of action driving its activity. How the unique mode of action and the different metabolism of E4 might support its favorable benefit-risk ratio is also discussed.

Fig. 1

Chemical structure of the natural estrogens estrone (E1), estradiol (E2), estriol (E3) and estetrol (E4)

Fig. 2

Thrombin generation curves in the absence and presence of APC in healthy pooled plasma (blue) and women using different combined oral contraceptives. The area under the curve represents the ETP parameter. In the presence of APC, ETP is higher with the use of combined oral contraceptives (e.g. EE/DRSP, EE/DSG) compared with HPP, leading to a resistance towards APC. APC activated protein C, DRSP drospirenone, DSG desogestrel, EE ethinylestradiol, ETP endogenous thrombin potential, E4 estetrol, HPP healthy pooled plasma, LNG levonogestrel. Source: Morimont et al. [21]

Fig. 3

Schematic representation of genomic and non-genomic signaling pathways induced by estrogens. Classical estrogen signaling occurs via ERs belonging to the nuclear receptors protein family and mainly functioning as ligand-dependent transcription factors to modulate the transcription of target genes. Alternatively, estrogens may activate non-genomic signaling via ERs located at the plasma membrane. Non-genomic signaling events include the activation of kinase cascades in the cytoplasm and the production of second messengers that ultimately induce cellular responses. Genomic and non-genomic signaling pathways also interact and influence each other. ER estrogen receptor

Fig. 4

Schematic representation of the main pharmacological properties of E4 based on available preclinical and early clinical data. SHBG sex hormone binding globulin