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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
Chapter
Part of the ISGE Series book series (ISGE)

Abstract

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.

Keywords

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

Abbreviations

Ang II

Angiotensin II

CEE

Combined equine estrogen

CHD

Coronary heart disease

COCs

Combined oral contraceptives

CVD

Cardiovascular disease

DRSP

Drospirenone

DVT

Deep venous thrombophlebitis

E

Estrogen

E2

Estradiol

E4

Estetrol

eNOS

Endothelial nitric oxide synthase

ERα

Estrogen receptor alpha

ERα−/−

Estrogen receptor alpha KO

FMR

Flow-mediated arteriolar remodeling

HF

High flow

HT

Hormone therapy

LNG

Levonorgestrel

MPA

Medroxyprogesterone acetate

NEST

Native estrogen with selective actions in tissues

NF

Normal flow

NIH

National Institutes of Health

NO

Nitric oxide

PE

Pulmonary embolism

RR

Relative risk

VTE

Venous thromboembolism

WHI

Women’s Health Initiative

Notes

Acknowledgments

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.

References

  1. 1.
    Grodstein F, Stampfer MJ, Colditz GA. Postmenopausal hormone therapy and mortality. N Engl J Med. 1997;336:1769–75.PubMedCrossRefGoogle Scholar
  2. 2.
    Stampfer MJ, Colditz GA. Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev Med. 1991;20:47–63.PubMedCrossRefGoogle Scholar
  3. 3.
    Yaffe K, Sawaya G, Lieberburg I, Grady D. Estrogen therapy in postmenopausal women: effects on cognitive function and dementia. JAMA. 1998;279:688–95.PubMedCrossRefGoogle Scholar
  4. 4.
    Grady D, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med. 1992;117:1016–37.PubMedCrossRefGoogle Scholar
  5. 5.
    Henderson BE, Paganini-Hill A, Ross RK. Decreased mortality in users of estrogen replacement therapy. Arch Intern Med. 1991;151:75–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998;280:605–13.CrossRefPubMedGoogle Scholar
  7. 7.
    Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J, Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288:321–33.CrossRefPubMedGoogle Scholar
  8. 8.
    Hsia J, et al. Conjugated equine estrogens and coronary heart disease: the Women’s Health Initiative. Arch Intern Med. 2006;166:357–65.PubMedCrossRefGoogle Scholar
  9. 9.
    Rossouw JE, et al. Postmenopausal hormone therapy and cardiovascular disease by age and years since menopause. JAMA. 2007;297:1465–77.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Carrasquilla GD, et al. The association between menopausal hormone therapy and coronary heart disease depends on timing of initiation in relation to menopause onset: results based on pooled individual participant data from the Combined Cohorts of Menopausal Women — Studies of Register Based Health Outcomes in Relation to Hormonal Drugs (COMPREHEND) study [abstract S17]. Menopause. 2015;22:1373.CrossRefGoogle Scholar
  11. 11.
    Hodis HN, Mack WJ, Henderson VW. Effects of early versus late postmenopausal treatment with estradiol. N Engl J Med. 2016;374:1221–31.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Lobo Pickar JH, Stevenson JC, Mack WJ, Hodis HN. Back to the future: Hormone replacement therapy as part of a prevention strategy for women at the onset of menopause. Atherosclerosis. 2016;254:282–90.PubMedCrossRefGoogle Scholar
  13. 13.
    Manson JE, Aragaki AK, Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Chlebowski RT, Howard BV, Thomson CA, Margolis KL, Lewis CE, Stefanick ML, Jackson RD, Johnson KC, Martin LW, Shumaker SA, Espeland MA, Wactawski-Wende J, Investigators WHI. Menopausal hormone therapy and long-term all-cause and cause-specific mortality: the women’s health initiative randomized trials. JAMA. 2017;318:927–38.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Lobo RA. Hormone-replacement therapy: current thinking. Nat Rev Endocrinol. 2017;13:220–31.PubMedCrossRefGoogle Scholar
  15. 15.
    Grodstein F, Manson JE, Stampfer MJ, Rexrode K. Postmenopausal hormone therapy and stroke: role of time since menopause and age at initiation of hormone therapy. Arch Intern Med. 2008;168:861–6.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Lobo RA, Clarkson TB. Different mechanisms for benefit and risk of coronary heart disease and stroke in early postmenopausal women: a hypothetical explanation. Menopause. 2011;18:237–40.PubMedCrossRefGoogle Scholar
  17. 17.
    Sare GM, Gray LJ, Bath PM. Association between hormone replacement therapy and subsequent arterial and venous vascular events: a meta-analysis. Eur Heart J. 2008;29:2031–41.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    NHLBI. NHLBI stops trial of estrogen plus progestin due to increased breast cancer risk and lack of overall benefit. South Med J. 2002;95:795–7.CrossRefGoogle Scholar
  19. 19.
    Mohammed K, Abu Dabrh AM, Benkhadra K, Al Nofal A, Carranza Leon BG, Prokop LJ, Montori VM, Faubion SS, Murad MH. Oral vs transdermal estrogen therapy and vascular events: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2015;100:4012–20.PubMedCrossRefGoogle Scholar
  20. 20.
    Lidegaard Ø, Nielsen LH, Skovlund CW, Skjeldestad FE, Løkkegaard E. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001–9. BMJ. 2011;25:343.Google Scholar
  21. 21.
    Han L, Jensen JT. Does the progestogen used in combined hormonal contraception affect venous thrombosis risk? Obstet Gynecol Clin N Am. 2015;42:683–98.CrossRefGoogle Scholar
  22. 22.
    Kemmeren JM, Algra A, Meijers JC, Tans G, Bouma BN, Curvers J, Rosing J, Grobbee DE. Effect of second- and third-generation oral contraceptives on the protein C system in the absence or presence of the factor VLeiden mutation: a randomized trial. Blood. 2004;103:927–33.PubMedCrossRefGoogle Scholar
  23. 23.
    Oral Contraceptive and Hemostasis Study Group. The effects of seven monophasic oral contraceptive regimens on hemostatic variables: conclusions from a large randomized multicenter study. Contraception. 2003;67:173–85.CrossRefGoogle Scholar
  24. 24.
    Vandenbroucke JP, Koster T, Briët E, Reitsma PH, Bertina RM, Rosendaal FR. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet. 1994;344(8935):1453–7.PubMedCrossRefGoogle Scholar
  25. 25.
    Mantha S, Karp R, Raghavan V, Terrin N, Bauer KA, Zwicker JI. Assessing the risk of venous thromboembolic events in women taking progestin-only contraception: a meta-analysis. BMJ. 2012;345:e4944.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Regidor PA, Colli E, Schindler AE. Drospirenone as estrogen-free pill and hemostasis: coagulatory study results comparing a novel 4 mg formulation in a 24 + 4 cycle with desogestrel 75 μg per day. Gynecol Endocrinol. 2016;32:749–51.PubMedCrossRefGoogle Scholar
  27. 27.
    Dinger J, Do Minh T, Heinemann K. Impact of estrogen type on cardiovascular safety of combined oral contraceptives. Contraception. 2016;94:328–39.PubMedCrossRefGoogle Scholar
  28. 28.
    Sitruk-Ware R. New progestagens for contraceptive use. Hum Reprod Update. 2006;12:169–78.PubMedCrossRefGoogle Scholar
  29. 29.
    Wiegratz I, Lee JH, Kutschera E, Winkler UH, Kuhl H. Effect of four oral contraceptives on hemostatic parameters. Contraception. 2004;70:97–106.PubMedCrossRefGoogle Scholar
  30. 30.
    van Vliet HA, Frolich M, Christella M, Thomassen LG, Doggen CJ, Rosendaal FR, Rosing J, Helmerhorst FM. Association between sex hormone-binding globulin levels and activated protein C resistance in explaining the risk of thrombosis in users of oral contraceptives containing different progestogens. Hum Reprod. 2005;20:563–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Raps M, Helmerhorst F, Fleischer K, Thomassen S, Rosendaal F, Rosing J, Ballieux B, VAN Vliet H. Sex hormone-binding globulin as a marker for the thrombotic risk of hormonal contraceptives. J Thromb Haemost. 2012;10:992–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Rosing J, Middeldorp S, Curvers J, Christella M, Thomassen LG, Nicolaes GA, Meijers JC, Bouma BN, Büller HR, Prins MH, Tans G. Low-dose oral contraceptives and acquired resistance to activated protein C: a randomised cross-over study. Lancet. 1999;354:2036–40.PubMedCrossRefGoogle Scholar
  33. 33.
    Odlind V, Milsom I, Persson I, Victor A. Can changes in sex hormone binding globulin predict the risk of venous thromboembolism with combined oral contraceptive pills? Acta Obstet Gynecol Scand. 2002;81:482–90.PubMedGoogle Scholar
  34. 34.
    Hickey M, Hart R, Keelan JA. The relationship between umbilical cord estrogens and perinatal characteristics. Cancer Epidemiol Biomark Prev. 2014;23:946–5.CrossRefGoogle Scholar
  35. 35.
    Kundu N, Wachs M, Iverson GB, Petersen LP. Comparison of serum unconjugated estriol and estetrol in normal and complicated pregnancies. Obstet Gynecol. 1981;58(3):276–81.PubMedGoogle Scholar
  36. 36.
    Arnal JF, Lenfant F, Metivier R, Flouriot G, Henrion D, Adlanmerini M, Fontaine C, Gourdy P, Chambon P, Katzenellenbogen B, Katzenellenbogen J. Membrane and nuclear estrogen receptor alpha actions: from tissue specificity to medical implications. Physiol Rev. 2017;3:1045–87.CrossRefGoogle Scholar
  37. 37.
    Abot A, Fontaine C, Buscato M, Solinhac R, Flouriot G, Fabre A, Drougard A, Rajan S, Laine M, Milon A, Muller I, Henrion D, Adlanmerini M, Valéra MC, Gompel A, Gerard C, Péqueux C, Mestdagt M, Raymond-Letron I, Knauf C, Ferriere F, Valet P, Gourdy P, Katzenellenbogen BS, Katzenellenbogen JA, Lenfant F, Greene GL, Foidart JM, Arnal JF. The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor α modulation, uncoupling nuclear and membrane activation. EMBO Mol Med. 2014;10:1328–46.CrossRefGoogle Scholar
  38. 38.
    Gourdy P, Guillaume M, Fontaine C, Adlanmerini M, Montagner A, Laurell H, Lenfant F, Arnal JF. Estrogen receptor subcellular localization and cardiometabolism. Mol Metab. 2018;15:56–69.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Brouchet L, Krust A, Dupont S, Chambon P, Bayard F, Arnal JF. Estradiol accelerates reendothelialization in mouse carotid artery through estrogen receptor-alpha but not estrogen receptor-beta. Circulation. 2001;103:423–8.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Wu Q, Chambliss K, Umetani M, Mineo C, Shaul PW. Non-nuclear estrogen receptor signaling in the endothelium. J Biol Chem. 2011;286:14737–43.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Adlanmerini M, Solinhac R, Abot A, Fabre A, Raymond-Letron I, Guihot AL, Boudou F, Sautier L, Vessieres E, Kim SH, et al. Mutation of the palmitoylation site of estrogen receptor alpha in vivo reveals tissue-specific roles for membrane versus nuclear actions. Proc Natl Acad Sci U S A. 2014;111:E283–90.PubMedCrossRefGoogle Scholar
  42. 42.
    Chambliss KL, Wu Q, Oltmann S, Konaniah ES, Umetani M, Korach KS, Thomas GD, Mineo C, Yuhanna IS, Kim SH, et al. Non-nuclear estrogen receptor alpha signaling promotes cardiovascular protection but not uterine or breast cancer growth in mice. J Clin Invest. 2010;120:2319–30.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Vanhoutte PM. Nitric oxide: from good to bad. Ann Vasc Dis. 2018;11:41–51.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Vanhoutte PM, Zhao Y, Xu A, Leung SW. Thirty years of saying no: sources, fate, actions, and misfortunes of the endothelium-derived vasodilator mediator. Circ Res. 2016;119:375–96.PubMedCrossRefGoogle Scholar
  45. 45.
    Yamazaki Y, Kondo Y, Kamiyama Y. Estimation of shear-stress-induced endothelial nitric oxide production from flow-mediated dilation. Conf Proc IEEE Eng Med Biol Soc. 2013;2013:4521–4.PubMedGoogle Scholar
  46. 46.
    Levine MG, Miodovnik M, Clark KE. Uterine vascular effects of estetrol in nonpregnant ewes. Am J Obstet Gynecol. 1984;148(6):735–8.PubMedCrossRefGoogle Scholar
  47. 47.
    Hilgers RH, Oparil S, Wouters W, Coelingh Bennink HJ. Vasorelaxing effects of estetrol in rat arteries. Endocrinology. 2012;215:97–106.CrossRefGoogle Scholar
  48. 48.
    Arnal JF, Fontaine C, Billon-Gales A, Favre J, Laurell H, Lenfant F, Gourdy P. Estrogen receptors and endothelium. Arterioscler Thromb Vasc Biol. 2010;30:1506–12.PubMedCrossRefGoogle Scholar
  49. 49.
    Chambliss KL, Shaul PW. Estrogen modulation of endothelial nitric oxide synthase. Endocr Rev. 2002;23:665–86.PubMedCrossRefGoogle Scholar
  50. 50.
    Mallat Z, Tedgui A. Cytokines as regulators of atherosclerosis in murine models. Curr Drug Targets. 2007;8:1264–72.PubMedCrossRefGoogle Scholar
  51. 51.
    Weber C, Zernecke A, Libby P. The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models. Nat Rev Immunol. 2008;8:802–15.PubMedCrossRefGoogle Scholar
  52. 52.
    Tarhouni K, Guihot AL, Freidja ML, Toutain B, Henrion B, Baufreton C, Pinaud F, Procaccio V, Grimaud L, Ayer A, Loufrani L, Lenfant F, Arnal JF, Henrion D. Key role of estrogens and endothelial estrogen receptor alpha in blood flow-mediated remodeling of resistance arteries. Arterioscler Thromb Vasc Biol. 2013;33:605–11.PubMedCrossRefGoogle Scholar
  53. 53.
    Billon-Gales A, Fontaine C, Douin-Echinard V, Delpy L, Berges H, Calippe B, Lenfant F, Laurell H, Guery JC, Gourdy P, Arnal JF. Endothelial estrogen receptor-alpha plays a crucial role in the atheroprotective action of 17beta-estradiol in low-density lipoprotein receptor-deficient mice. Circulation. 2009;120:2567–76.PubMedCrossRefGoogle Scholar
  54. 54.
    Billon-Gales A, Krust A, Fontaine C, Abot A, Flouriot G, Toutain C, Berges H, Gadeau AP, Lenfant F, Gourdy P, et al. Activation function 2 (AF2) of estrogen receptor-{alpha} is required for the atheroprotective action of estradiol but not to accelerate endothelial healing. Proc Natl Acad Sci U S A. 2011;108:13311–6.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Guivarc’h E, Buscato M, Guihot A.L, Favre J, Vessières E, Grimaud L, Wakim J, Melhem NJ, Zahreddine R, Adlanmerini M., Loufrani M, Knauf C, Katzenellenbogen JA, Katzenellenbogen BS, Foidart JM, Gourdy P, Lenfant F, Arnal JF, Henrion D, Fontaine C Predominant role of nuclear versus membrane estrogen receptor (ER)α in arterial protection: implications for ERα modulation in cardiovascular prevention/safety. J Am Heart Assoc. 2018.  https://doi.org/10.1161/JAHA.118.008950.
  56. 56.
    Hui DY. Intimal hyperplasia in murine models. Curr Drug Targets. 2008;9:251–60.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Smirnova NF, Gayral S, Pedros C, Loirand G, Vaillant N, Malet N, Kassem S, Calise D, Goudounèche D, Wymann MP, Hirsch E, Gadeau AP, Martinez LO, Saoudi A, Laffargue M. Targeting PI3Kγ activity decreases vascular trauma-induced intimal hyperplasia through modulation of the Th1 response. J Exp Med. 2014;211:1779–92.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Costa MA, Simon DI. Molecular basis of restenosis and drug eluting stents. Circulation. 2005;111:2257–73.PubMedCrossRefGoogle Scholar
  59. 59.
    Chandrasekar B, Sirois MG, Geoffroy P, Lauzier D, Nattel S, Tanguay JF. Local delivery of 17beta-estradiol improves reendothelialization and decreases inflammation after coronary stenting in a porcine model. Thromb Haemost. 2005;94:1042–7.PubMedCrossRefGoogle Scholar
  60. 60.
    Smirnova NF, Fontaine C, Buscato M, Lupieri A, Vinel A, Valera MC, Guillaume M, Malet N, Foidart JM, Raymond-Letron I, Lenfant F, Gourdy P, Katzenellenbogen BS, Katzenellenbogen JA, Laffargue M, Arnal JF. The activation function-1 of estrogen receptor alpha prevents arterial neointima development through a direct effect on smooth muscle cells. Circ Res. 2015;117:770–8.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Bouvet C, Belin de Chantemèle E, Guihot AL, Vessieres E, Bocquet A, Dumont O, Jardel A, Loufrani L, Moreau P, Henrion D. Flow-induced remodeling in resistance arteries from obese Zucker rats is associated with endothelial dysfunction. Hypertension. 2007;50:248–54.PubMedCrossRefGoogle Scholar
  62. 62.
    Dumont O, Loufrani L, Henrion D. Key role of the NO-pathway and matrix metalloprotease-9 in high blood flow-induced remodeling of rat resistance arteries. Arterioscler Thromb Vasc Biol. 2007;27:317–24.PubMedCrossRefGoogle Scholar
  63. 63.
    Pourageaud F, De Mey JG. Vasomotor responses in chronically hyperperfused and hypoperfused rat mesenteric arteries. Am J Phys. 1998;274:H1301–7.Google Scholar
  64. 64.
    Carmeliet P. Angiogenesis in life, disease and medicine. Nature. 2005;438:932–6.PubMedCrossRefGoogle Scholar
  65. 65.
    Silvestre JS, Smadja DM, Levy BI. Postischemic revascularization: from cellular and molecular mechanisms to clinical applications. Physiol Rev. 2013;93:1743–802.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Dumont O, Kauffenstein G, Guihot AL, Guerineau NC, Abraham P, Loufrani L, Henrion D. Time-related alteration in flow- (shear stress-) mediated remodeling in resistance arteries from spontaneously hypertensive rats. Int J Hypertens. 2014;2014:859793.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Tuttle JL, Sanders BM, Burkhart HM, Fath SW, Kerr KA, Watson WC, Herring BP, Dalsing MC, Unthank JL. Impaired collateral artery development in spontaneously hypertensive rats. Microcirculation. 2002;9:343–51.PubMedCrossRefGoogle Scholar
  68. 68.
    Belin de Chantemele EJ, Vessieres E, Guihot AL, Toutain B, Maquignau M, Loufrani L, Henrion D. Type 2 diabetes severely impairs structural and functional adaptation of rat resistance arteries to chronic changes in blood flow. Cardiovasc Res. 2009;81:788–96.PubMedCrossRefGoogle Scholar
  69. 69.
    Freidja ML, Tarhouni K, Toutain B, Fassot C, Loufrani L, Henrion D. The age-breaker alt-711 restores high blood flow-dependent remodeling in mesenteric resistance arteries in a rat model of type 2 diabetes. Diabetes. 2012;61:1562–72.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Dumont O, Pinaud F, Guihot AL, Baufreton C, Loufrani L, Henrion D. Alteration in flow (shear stress)-induced remodelling in rat resistance arteries with aging: Improvement by a treatment with hydralazine. Cardiovasc Res. 2008;77:600–8.PubMedCrossRefGoogle Scholar
  71. 71.
    Tarhouni K, Guihot AL, Vessieres E, Toutain B, Procaccio V, Grimaud L, Loufrani L, Lenfant F, Arnal JF, Henrion D. Determinants of flow-mediated outward remodeling in female rodents: respective roles of age, estrogens, and timing. Arterioscler Thromb Vasc Biol. 2014;34:1281–9.PubMedCrossRefGoogle Scholar
  72. 72.
    Barton M, Meyer MR. Postmenopausal hypertension: mechanisms and therapy. Hypertension. 2009;54:11–8.PubMedCrossRefGoogle Scholar
  73. 73.
    Regitz-Zagrosek V, Kararigas G. Mechanistic pathways of sex differences in cardiovascular disease. Physiol Rev. 2017;97:1–37.PubMedCrossRefGoogle Scholar
  74. 74.
    Barsha G, Denton KM, Mirabito Colafella KM. Sex- and age-related differences in arterial pressure and albuminuria in mice. Biol Sex Differ. 2016;7:57.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Sampson AK, Moritz KM, Jones ES, Flower RL, Widdop RE, Denton KM. Enhanced angiotensin II type 2 receptor mechanisms mediate decreases in arterial pressure attributable to chronic low-dose angiotensin II in female rats. Hypertension. 2008;52:666–71.PubMedCrossRefGoogle Scholar
  76. 76.
    Valera MC, Gratacap MP, Gourdy P, Lenfant F, Cabou C, Toutain CE, Marcellin M, Saint Laurent N, Sie P, Sixou M, Arnal JF, Payrastre B. Chronic estradiol treatment reduces platelet responses and protects mice from thromboembolism through the hematopoietic estrogen receptor alpha. Blood. 2012;120:1703–12.PubMedCrossRefGoogle Scholar
  77. 77.
    Kluft C, Zimmerman Y, Mawet M, Klipping C, Duijkers IJ, Neuteboom J, Foidart JM, Bennink HC. Reduced hemostatic effects with drospirenone-based oral contraceptives containing estetrol vs. ethinyl estradiol. Contraception. 2017;95:140–7.PubMedCrossRefGoogle Scholar
  78. 78.
    Shapiro S. Oral contraceptives, hormone therapy and cardiovascular risk. Climacteric. 2008;11:355–63.PubMedCrossRefGoogle Scholar
  79. 79.
    Jirouskova M, Shet AS, Johnson GJ. A guide to murine platelet structure, function, assays, and genetic alterations. J Thromb Haemost. 2007;5:661–9.PubMedCrossRefGoogle Scholar
  80. 80.
    Valéra MC, Noirrit-Esclassan E, Dupuis M, Fontaine C, Lenfant F, Briaux A, Cabou C, Garcia C, Lairez O, Foidart JM, Payrastre B, Arnal JF. Effect of estetrol, a selective nuclear estrogen receptor modulator, in mouse models of arterial and venous thrombosis. Mol Cell Endocrinol. 2018;477:132–9. S0303-7207(18) 30196-5PubMedCrossRefGoogle Scholar
  81. 81.
    Geddings J, Aleman MM, Wolberg A, von Bruhl ML, Massberg S, Mackman N. Strengths and weaknesses of a new mouse model of thrombosis induced by inferior vena cava stenosis: communication from the SSC of the ISTH. J Thromb Haemost. 2014;12:571–3.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Donnem T, Reynolds AR, Kuczynski EA, Gatter K, Vermeulen PB, Kerbel RS, Harris AL, Pezzella F. Non-angiogenic tumours and their influence on cancer biology. Nat Rev Cancer. 2018;18:323–36.PubMedCrossRefGoogle Scholar
  83. 83.
    Péqueux C, Raymond-Letron I, Blacher S, Boudou F, Adlanmerini M, Fouque MJ, Rochaix P, Noël A, Foidart JM, Krust A, Chambon P, Brouchet L, Arnal JF, Lenfant F. Stromal estrogen receptor-α promotes tumor growth by normalizing an increased angiogenesis. Cancer Res. 2012;72:3010–9.PubMedCrossRefGoogle Scholar
  84. 84.
    EMA. European Medicines Agency, Committee for Medicinal Products for Human Use. Guideline on clinical investigation of steroid contraceptives in women. London: EMA; 2005. EMEA/CPMP/EWP/519/98 rev 1Google Scholar
  85. 85.
    Benoit T, Valera MC, Fontaine C, Buscato M, Lenfant F, Raymond-Letron I, Tremollieres F, Soulie M, Foidart JM, Game X, Arnal JF. Estetrol, a fetal selective estrogen receptor modulator, acts on the vagina of mice through nuclear estrogen receptor α activation. Am J Pathol. 2017;187:2499–507.PubMedCrossRefGoogle Scholar

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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