Unique Vascular Benefits of Estetrol, a Native Fetal Estrogen with Specific Actions in Tissues (NEST)

  • J. M. FoidartEmail author
  • U. Gaspard
  • C. Pequeux
  • M. Jost
  • V. Gordenne
  • E. Tskitishvili
  • A. Gallez
  • M. C. Valera
  • P. Gourdy
  • C. Fontaine
  • D. Henrion
  • Andrea R. Genazzani
  • F. Lenfant
  • J. F. Arnal
Part of the ISGE Series book series (ISGE)


Estrogens (E), in oral contraceptives (COCs) and hormone replacement therapy (HRT) drugs used for the relief of climacteric symptoms of menopause, increase the synthesis of clotting factors, decrease the levels of coagulation inhibitors, and increase the risk of venous thromboembolic events (VTE). Ischemic stroke incidence in postmenopausal women during HRT use is also increased and is probably due to a thrombotic event. This suggests that a safer estrogen may reduce stroke and VTE incidence, with lower impact on hemostasis.

Estetrol (E4) is a relatively recently described new human-specific E produced exclusively by the fetal liver during pregnancy. This Native (human and natural) E has Selective actions in Tissues (NEST). Nest activities of E4 are the consequence of its unique dual role. It activates the nuclear estrogen receptor alpha (ERα) but antagonizes the membrane ERα in contrast to other E, which activate both types of receptors. Most beneficial effects of E on the vascular system have been ascribed to the activation of the membrane ERα of vascular endothelial cells, including enhancement of nitric oxide (NO) production, vasodilation, and prevention of atherosclerosis, of neointimal proliferation, and of hypertension. In a series of papers reviewed here, the INSERM team in Toulouse has demonstrated, by the combined use of pharmacological tools and of transgenic mice lacking either the nuclear ERα, the membrane ERα, or both, that the nuclear ERα plays a major role in controlling E activities in vessels. E4 is able to elicit the important vasculoprotective actions mediated by estradiol (E2). Phase 1 and 2 clinical studies of E4 in a contraceptive indication (in combination with drospirenone) or in postmenopausal women for the relief of climacteric complaints demonstrate that E4 has a minimal impact on hemostasis, coagulation factors, coagulation inhibitors, fibrinolysis, angiotensinogen, triglycerides, and cholesterol. Altogether, preclinical studies and phase 1 and 2 clinical data indicate that E4 could be a new E with a better safety/efficacy profile than other E for women’s healthcare.


Estrogens Estetrol Estrogen receptor alpha Vascular safety Coagulation Hemostasis HRT-hormone therapy of menopause Combined oral contraceptives (COCs) 


Ang II

Angiotensin II


Combined equine estrogen


Coronary heart disease


Combined oral contraceptives


Cardiovascular disease




Deep venous thrombophlebitis








Endothelial nitric oxide synthase


Estrogen receptor alpha


Estrogen receptor alpha KO


Flow-mediated arteriolar remodeling


High flow


Hormone therapy




Medroxyprogesterone acetate


Native estrogen with selective actions in tissues


Normal flow


National Institutes of Health


Nitric oxide


Pulmonary embolism


Relative risk


Venous thromboembolism


Women’s Health Initiative



The authors warmfully thank Professor Rogerio A. Lobo, Columbia University College of Physicians and Surgeons, and Professor Mitchell Creinin, Division of Family Planning, Department of Obstetrics and Gynecology, University of California, Davis, Sacramento, California, for helpful discussions and comments in the preparation and reviewing process of this manuscript.


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Copyright information

© International Society of Gynecological Endocrinology 2019

Authors and Affiliations

  • J. M. Foidart
    • 1
    Email author
  • U. Gaspard
    • 1
  • C. Pequeux
    • 1
  • M. Jost
    • 2
  • V. Gordenne
    • 2
  • E. Tskitishvili
    • 1
  • A. Gallez
    • 1
  • M. C. Valera
    • 3
  • P. Gourdy
    • 3
  • C. Fontaine
    • 3
  • D. Henrion
    • 4
  • Andrea R. Genazzani
    • 5
    • 6
  • F. Lenfant
    • 3
  • J. F. Arnal
    • 3
  1. 1.Laboratory of Tumor and Development Biology, GIGA-CancerUniversity of LiègeLiegeBelgium
  2. 2.Mithra PharmaceuticalsLiègeBelgium
  3. 3.I2MC, Institut National de la Santé et de la Recherche Médicale (INSERM) U 1048University of Toulouse 3ToulouseFrance
  4. 4.MITOVASC Institute, CARFI Facility, INSERM U1083, UMR CNRS, 6015University of AngersAngersFrance
  5. 5.Division of Obstetrics and Gynecology, Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
  6. 6.International School for Gynecological and Reproductive EndocrinologyInternational Society of Gynecological EndocrinologyLocarnoSwitzerland

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