Advertisement

Estetrol and Its Effects on the Damaged Brain

  • Ekaterine Tskitishvili
  • Jean Michel Foidart
Chapter
Part of the ISGE Series book series (ISGE)

Abstract

Estrogens play an important role not only in the reproductive system but in the central nervous system as well. Major events of ontogenesis that occur earlier in pregnancy are connected to the formation of estrogen receptors and expression of estrogens leading to the normal physiological development of the central nervous system, though development of the brain by itself is a complex process and lasts during the whole pregnancy. Estetrol (E4) is a recently described natural estrogen with four hydroxyl groups that is synthesized exclusively during pregnancy by the human fetal liver. Its role in the central nervous system is not fully understood. Our studies showed for the first time and proved impressive antioxidative effects of E4 in vitro and proved its tremendous neuroprotective, promyelinating, neurogenic, and cerebro-angiogenic properties in vivo. E4 decreases brain damage markers (S100B and GFAP) in blood assuming that E4 attenuates neonatal hypoxic-ischemic encephalopathy in vivo. We have also shown that the combined use of E4 with other steroids does not have any priority over the single use of E4. E4’s antioxidative actions mostly depend on ERα and ERβ, whereas neurogenesis and possibly promyelinating activities might be realized through ERβ. Taken together our studies suggest importance of E4 treatment possibly not only in neonates but in adults with different neurological diseases like that opening new directions for the use of E4 in clinical practice in neurological diseases.

Keywords

Estetrol Estrogen receptors Neonatal hypoxic-ischemic encephalopathy Neurogenesis Cerebro-angiogenesis Myelination Hippocampus Cortex S100B GFAP 

References

  1. 1.
    Charles H. Rodeck, Martin J. Whittle, Fetal medicine: basic science and clinical practice. 2nd edition, 2009, Elsevier Health Sciences, London.Google Scholar
  2. 2.
    Shiota K. Prenatal development of the human central nervous system, normal and abnormal. Donald School J Ultrasound Obstet Gynecol. 2015;9(1):61–6.CrossRefGoogle Scholar
  3. 3.
    Gonzalez M, Cabrera-Socorro A, Perez-Garcia CG, Fraser JD, Lopez FJ, Alonso R, et al. Distribution patterns of estrogen receptor alpha and beta in the human cortex and hippocampus during development and adulthood. J Comp Neurol. 2007;503(6):790–802.  https://doi.org/10.1002/cne.21419.CrossRefPubMedGoogle Scholar
  4. 4.
    Hart SA, Patton JD, Woolley CS. Quantitative analysis of ER alpha and GAD colocalization in the hippocampus of the adult female rat. J Comp Neurol. 2001;440:144–55.  https://doi.org/10.1002/cne.1376.CrossRefPubMedGoogle Scholar
  5. 5.
    Shughrue PJ, Merchenthaler I. Evidence for novel estrogen binding sites in the rat hippocampus. Neuroscience. 2000;99:605–12.  https://doi.org/10.1210/endo.139.12.6525.CrossRefPubMedGoogle Scholar
  6. 6.
    O’Keefe JA, Li Y, Burgess LH, Handa RJ. Estrogen receptor mRNA alterations in the developing rat hippocampus. Brain Res Mol Brain Res. 1995;30:115–24.  https://doi.org/10.1016/0169-328X(94)00284-L.CrossRefPubMedGoogle Scholar
  7. 7.
    Solum DT, Handa RJ. Localization of estrogen receptor alpha (ER-alpha) in pyramidal neurons of the developing rat hippocampus. Brain Res Dev Brain Res. 2001;28:165–75.  https://doi.org/10.1016/S0165-3806(01)00171-7.CrossRefGoogle Scholar
  8. 8.
    Nomura M, Korach KS, Pfaff DW, Ogawa S. Estrogen receptor b (ERb) protein levels in neurons depend on estrogen receptor a (ERa) gene expression and on its ligand in a brain region-specific manner. Mol Brain Res. 2003;110(2003):7–14.  https://doi.org/10.1016/S0169-328X(02)00544-2.CrossRefPubMedGoogle Scholar
  9. 9.
    Van der Knaap MS, Valk J. Magnetic resonance of myelin, myelination and myelin disorders. 2nd ed. Berlin: Springer; 1995.CrossRefGoogle Scholar
  10. 10.
    Oakey RE. The progressive increase in oestrogen production in human pregnancy: an appraisal of the factors responsible. Vitam Horm. 1970;28:1.PubMedGoogle Scholar
  11. 11.
    Levitz M, Young BK. Estrogens in pregnancy. Vitam Horm. 1977;35:109.CrossRefGoogle Scholar
  12. 12.
    Brann DW, Dhandapani K, Wakade C, Mahesh VB, Khan MM. Neurotrophic and neuroprotective actions of estrogen: basic mechanisms and clinical implications. Steroids. 2007;72:381–405.  https://doi.org/10.1016/j.steroids.2007.02.003.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    McCarty MM. Estradiol and the developing brain. Physiol Rev. 2008;88(1):91–124.CrossRefGoogle Scholar
  14. 14.
    Lee HS, Han J, Baim HJ, Kim KW. Brain angiogenesis in developmental and pathological processes: regulation, molecular and cellular communication at the neurovascular interface. FEBS J. 2009;276(17):4622–35.  https://doi.org/10.1111/j.1742-4658.2009.07174.x.CrossRefPubMedGoogle Scholar
  15. 15.
    Park JA, Choi KS, Kim SY, Kim KW. Coordinated interaction of the vascular and nervous systems: from molecule- to cell-based approaches. Biochem Biophys Res Commun. 2003;311:247–53.  https://doi.org/10.1016/j.bbrc.2003.09.129.CrossRefPubMedGoogle Scholar
  16. 16.
    Gordon GR, Mulligan SJ, MacVicar BA. Astrocyte control of the cerebrovasculature. Glia. 2007;55:1214–21.  https://doi.org/10.1002/glia.20543.CrossRefPubMedGoogle Scholar
  17. 17.
    Mulligan SJ, MacVicar BA. Calcium transients in astrocyte endfeet cause cerebrovascular constrictions. Nature. 2004;431:195–9.  https://doi.org/10.1038/nature02827.CrossRefGoogle Scholar
  18. 18.
    Zonta M, Angulo MC, Gobbo S, Rosengarten B, Hossmann KA, Pozzan T, et al. Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nat Neurosci. 2003;6:43–50.  https://doi.org/10.1038/nn980.CrossRefPubMedGoogle Scholar
  19. 19.
    Krause DN, Duckles SP, Pelligrino DA. Influence of sex steroid hormones on cerebrovascular function. J Appl Physiol. 2006;101(4):1252–61.  https://doi.org/10.1152/japplphysiol.01095.2005.CrossRefPubMedGoogle Scholar
  20. 20.
    Barouk S, Hintz T, Li P, Duffy AM, MacLusky NJ, Scharfman HE. 17β-estradiol increases astrocytic vascular endothelial growth factor (VEGF) in adult female rat hippocampus. Endocrinology. 2011;152(5):1745–51.  https://doi.org/10.1210/en.2010-1290.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Jin K, Zhu Y, Sun Y, Mao XO, Xie L, Greenberg DA. Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc Natl Acad Sci U S A. 2002;99(18):11946–50.  https://doi.org/10.1073/pnas.182296499.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Zhu Y, Jin K, Mao XO, Greenberg DA. Vascular endothelial growth factor promotes proliferation of cortical neuron precursors by regulating E2F expression. FASEB J. 2003;17(2):186–93.  https://doi.org/10.1096/fj.02-0515com.CrossRefPubMedGoogle Scholar
  23. 23.
    Ogunshola OO, Stewart WB, Mihalcik V, Solli T, Madri JA, Ment LR. Neuronal VEGF expression correlates with angiogenesis in postnatal developing rat brain. Brain Res Dev Brain Res. 2000;119(1):139–53.  https://doi.org/10.1016/S0165-3806(99)00125-X.CrossRefPubMedGoogle Scholar
  24. 24.
    Haigh JJ, Morelli PI, Gerhardt H, Haigh K, Tsien J, Damert A, et al. Cortical and retinal defects caused by dosage-dependent reductions in VEGFA paracrine signaling. Dev Biol. 2003;262:225–41.  https://doi.org/10.1016/S0012-1606(03)00356-7.CrossRefPubMedGoogle Scholar
  25. 25.
    Raab S, Beck H, Gaumann A, Yüce A, Gerber HP, Plate K, et al. Impaired brain angiogenesis and neuronal apoptosis induced by conditional homozygous inactivation of vascular endothelial growth factor. Thromb Haemost. 2004;91:595–605.  https://doi.org/10.1160/TH03-09-0582.CrossRefPubMedGoogle Scholar
  26. 26.
    Wise PM. Estrogens and neuroprotection. Trends Endocrinol Metab. 2002;6:229–30.CrossRefGoogle Scholar
  27. 27.
    Dubal DB, Wisel PM. Estrogen and neuroprotection: from clinical observations to molecular mechanisms. Dialogues Clin Neurosci. 2002;4(2):149–61.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Cho JJ, Iannucci FA, Fraile M, Franco J, Alesius TN, Stefano GB. The role of the estrogen in neuroprotection: implications for neurodegenerative diseases. Neuro Endocrinol Lett. 2003;24:141–7.PubMedGoogle Scholar
  29. 29.
    Garcia-Segura LM, Azcoitia I, DonCarlos LL. Neuroprotection by estradiol. Prog Neurobiol. 2001;63:29–60.  https://doi.org/10.1016/S0301-0082(00)00025-3.CrossRefPubMedGoogle Scholar
  30. 30.
    Gold SM, Voskuhl RR. Estrogen treatment in multiple sclerosis. J Neurol Sci. 2009;286(1–2):99–103.  https://doi.org/10.1016/j.jns.2009.05.028.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Samantaray S, Matzelle DD, Ray SK, Banik NL. Physiological low dose of estrogen-protected neurons in experimental spinal cord injury. Ann N Y Acad Sci. 2010;1199:86–9.  https://doi.org/10.1111/j.1749-6632.2009.05360.x.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Suzuki S, Brown CM, Wise PM. Neuroprotective effects of estrogens following ischemic stroke. Front Neuroendocrinol. 2009;30:201–11.  https://doi.org/10.1016/j.yfrne.2009.04.007.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Henderson VW, Benke KS, Green RC, Cupples LA, Farrer LA, MIRAGE study Group. Postmenopausal hormone therapy and Alzheimer’s disease risk: interaction with age. J Neurol Neurosurg Psychiatry. 2005;76:103–5.  https://doi.org/10.1136/jnnp.2003.024927.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Currie LJ, Harrison MB, Trugman JM, Bennett JP, Wooten JF. Postmenopausal estrogen use affects risk for Parkinson disease. Arch Neurol. 2004;61:886–8.  https://doi.org/10.1001/archneur.61.6.886.CrossRefPubMedGoogle Scholar
  35. 35.
    Gardiner SA, Morrison MF, Mozley PD, Mozley LH, Brensinger C, Bilker W. Pilot study on the effect of estrogen replacement therapy on brain dopamine transporter availability in healthy, postmenopausal women. Am J Geriatr Psychiatry. 2004;12:621–30.  https://doi.org/10.1176/appi.ajgp.12.6.621.CrossRefPubMedGoogle Scholar
  36. 36.
    Li R, Shen Y, Yang LB, Lue LF, Finch C, Rogers J. Estrogen enhances uptake of amyloid beta-protein by microglia derived from the human cortex. J Neurochem. 2000;75:1447–54.  https://doi.org/10.1046/j.1471-4159.2000.0751447.x.CrossRefPubMedGoogle Scholar
  37. 37.
    Xu H, Gouras GK, Greenfield JP, Vincent B, Naslund J, Mazzarelli L, et al. Estrogen reduces neuronal generation of Alzheimer beta-amyloid peptides. Nat Med. 1998;4:447–51.CrossRefGoogle Scholar
  38. 38.
    Kenchappa RS, Diwakar L, Annepu J, Ravindranath V. Estrogen and neuroprotection: higher constitutive expression of glutaredoxin in female mice offers protection against MPTP-mediated neurodegeneration. FASEB J. 2004;18:1102–4.  https://doi.org/10.1096/fj.03-1075fje.CrossRefPubMedGoogle Scholar
  39. 39.
    Ramirez AD, Liu X, Menniti FS. Repeated estradiol treatment prevents MPTP-induced dopamine depletion in male mice. Neuroendocrinology. 2003;77:223–31.  https://doi.org/10.1159/000070277.CrossRefPubMedGoogle Scholar
  40. 40.
    Nilsen J. Estradiol and neurodegenerative oxidative stress. Front Neuroendocrinol. 2008;9(4):463–75.  https://doi.org/10.1016/j.yfrne.2007.12.005.CrossRefGoogle Scholar
  41. 41.
    Zhang QG, Wang RM, Scott E, Han D, Dong Y, Tu JY, et al. C terminus of Hsc70-interacting protein (CHIP)-mediated degradation of hippocampal estrogen receptor-alpha and the critical period hypothesis of estrogen neuroprotection. Proc Natl Acad Sci U S A. 2011;108:E617–E24.  https://doi.org/10.1093/brain/awt046.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Arevalo MA, Santos-Galindo M, Bellini M, Azcoitia I, Garcia-Segura LM. Actions of estrogens on glial cells: implications for neuroprotection. Biochim Biophys Acta. 2010;1800:1106–12.  https://doi.org/10.1016/j.bbagen.2009.10.002.CrossRefGoogle Scholar
  43. 43.
    Dhandapani KM, Brann DW. Role of astrocytes in estrogen-mediated neuroprotection. Exp Gerontol. 2007;42(1–2):70–5.  https://doi.org/10.1016/j.exger.2006.06.032.CrossRefPubMedGoogle Scholar
  44. 44.
    Brinton RD. The healthy cell bias of estrogen action: mitochondrial bioenergetics and neurological implications. Trends Neurosci. 2008;31(10):529–37.  https://doi.org/10.1016/j.tins.2008.07.003.CrossRefGoogle Scholar
  45. 45.
    Irwin RW, Yao J, Hamilton RT, Cadenas E, Brinton RD, Nilsen J. Progesterone and estrogen regulate oxidative metabolism in brain mitochondria. Endocrinology. 2008;149(6):3167–75.  https://doi.org/10.1210/en.2007-1227.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Nilsen J, Brinton RD. Mitochondria as therapeutic targets of estrogen action in the central nervous system. Curr Drug Targets CNS Neurol Disord. 2004;3(4):297–13.CrossRefGoogle Scholar
  47. 47.
    Nilsen J, Chen S, Irwin RW, Iwamoto S, Brinton RD. Estrogen protects neuronal cells from amyloid beta-induced apoptosis via regulation of mitochondrial proteins and function. BMC Neurosci. 2006;7:74.  https://doi.org/10.1186/1471-2202-7-74.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Nilsen J, Irwin RW, Gallaher TK, Brinton RD. Estradiol in vivo regulation of brain mitochondrial proteome. J Neurosci. 2007;27:14069–77.  https://doi.org/10.1523/JNEUROSCI.4391-07.2007.CrossRefGoogle Scholar
  49. 49.
    Brinton RD. Estrogen regulation of glucose metabolism and mitochondrial function: therapeutic implications for prevention of Alzheimer’s disease. Adv Drug Deliv Rev. 2008;60(13–14):1504–11.  https://doi.org/10.1016/j.addr.2008.06.003.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Sakamoto H, Matsuda K, Hosokawa K, Nishi M, Morris JF, Prossnitz ER, et al. Expression of G protein-coupled receptor-30, a G protein-coupled membrane estrogen receptor, in oxytocin neurons of the rat paraventricular and supraoptic nuclei. Endocrinology. 2007;148(12):5842–50.  https://doi.org/10.1210/en.2007-0436.CrossRefPubMedGoogle Scholar
  51. 51.
    Revankar CM, Cimino DF, Sklar LA, Arterburn JB, Prossnitz ER. A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science. 2005;307(5715):1625–30.  https://doi.org/10.1126/science.1106943.CrossRefPubMedGoogle Scholar
  52. 52.
    Funakoshi T, Yanai A, Shinoda K, Kawano MM, Mizukami Y. G protein-coupled receptor 30 is an estrogen receptor in the plasma membrane. Biochem Biophys Res Commun. 2006;46(3):904–10.  https://doi.org/10.1016/j.bbrc.2006.05.191.CrossRefGoogle Scholar
  53. 53.
    Xu H, Qin S, Carrasco GA, Dai Y, Filardo EJ, Prossnitz ER, et al. Extra-nuclear estrogen receptor GPR30 regulates serotonin function in rat hypothalamus. Neuroscience. 2009;158(4):1599–607.  https://doi.org/10.1016/j.neuroscience.2008.11.028.CrossRefPubMedGoogle Scholar
  54. 54.
    Alyea RA, Laurence SE, Kim SH, Katzenellenbogen BS, Katzenellenbogen JA, Watson CS. The roles of membrane estrogen receptor subtypes in modulating dopamine transporters in PC-12 cells. J Neurochem. 2008;106(4):1525–33.  https://doi.org/10.1111/j.1471-4159.2008.05491.x.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Kuhn J, Dina OA, Goswami C, Suckow V, Levine JD, Hucho T. GPR30 estrogen receptor agonists induce mechanical hyperalgesia in the rat. Eur J Neurosci. 2008;27(7):1700–9.  https://doi.org/10.1111/j.1460-9568.2008.06131.x.CrossRefPubMedGoogle Scholar
  56. 56.
    Qiu J, Bosch MA, Tobias SC, Krust A, Graham SM, Murphy SJ, et al. A G-protein-coupled estrogen receptor is involved in hypothalamic control of energy homeostasis. J Neurosci. 2006;26(21):5649–55.  https://doi.org/10.1523/JNEUROSCI.0327-06.2006.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Delaunay F, Pettersson K, Tujague M, Gustafsson JA. Functional differences between the amino-terminal domains of estrogen receptors alpha and beta. Mol Pharmacol. 2000;58(3):584–90.  https://doi.org/10.1124/mol.58.3.584.CrossRefPubMedGoogle Scholar
  58. 58.
    He S, Nelson ER. 27-Hydroxycholesterol, an endogenous selective estrogen receptor modulator. Maturitas. 2017;104:29–35.  https://doi.org/10.1016/j.maturitas.2017.07.014.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Li X, Schwartz PE, Rissman EF. Distribution of estrogen receptor β-like immunoreactivity in rat forebrain. Neuroendocrinology. 1997;66:63–7.CrossRefGoogle Scholar
  60. 60.
    Shughrue PJ, Lane MV, Merchenthaler I. Comparative distribution of estrogen receptor-α and -β mRNA in the rat central nervous system. J Comp Neurol. 1997;388:507–25.  https://doi.org/10.1002/(SICI)1096-9861(19971201)388:4<507::AID-CNE1>3.0.CO;2-6.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Zhang JQ, Cai WQ, Zhou de S, Su BY. Distribution and differences of estrogen receptor beta immunoreactivity in the brain of adult male and female rats. Brain Res. 2002;935(1–2):73–80.  https://doi.org/10.1016/S0006-8993(02)02460-5.CrossRefPubMedGoogle Scholar
  62. 62.
    Mitra SW, Hoskin E, Yudkovitz J, Pear L, Wilkinson HA, Hayashi S, et al. Immunolocalization of estrogen receptor-α in the mouse brain: comparison with estrogen receptor β. Endocrinology. 2003;144(5):2055–67.  https://doi.org/10.1210/en.2002-221069.CrossRefPubMedGoogle Scholar
  63. 63.
    Brinton RD. Estrogen-induced plasticity from cells to circuits: predictions for cognitive function. Trends Pharmacol Sci. 2009;30(4):212–22.  https://doi.org/10.1016/j.tips.2008.12.006.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Hajszan T, Milner TA, Leranth C. Sex steroids and the dentate gyrus. Prog Brain Res. 2007;163:399–416.  https://doi.org/10.1016/S0079-6123(07)63023-4.CrossRefPubMedGoogle Scholar
  65. 65.
    Dan P, Cheung JC, Scriven DR, Moore ED. Epitope-dependent localization of estrogen receptor-alpha, but not -beta, in en face arterial endothelium. Am J Physiol Heart Circ Physiol. 2003;284:H1295–306.  https://doi.org/10.1152/ajpheart.00781.2002.CrossRefPubMedGoogle Scholar
  66. 66.
    Mazzucco CA, Lieblich SE, Bingham BI, Williamson MA, Viau V, Galea LAM. Both estrogen receptor alpha and estrogen receptor beta agonists enhance cell proliferation in the dentate gyrus of adult female rats. Neuroscience. 2006;141(4):1793–800.  https://doi.org/10.1016/j.neuroscience.2006.05.032.CrossRefPubMedGoogle Scholar
  67. 67.
    Alkayed NJ, Murphy SJ, Traystman RJ, Hurn PD, Miller VM. Neuroprotective effects of female gonadal steroids in reproductively senescent female rats. Stroke. 2000;31(1):161–8.  https://doi.org/10.1161/01.STR.31.1.161.CrossRefPubMedGoogle Scholar
  68. 68.
    Kuan CY, Roth KA, Flavell RA, Rakic P. Mechanisms of programmed cell death in the developing brain. Trends Neurosci. 2000;23(7):291–7.  https://doi.org/10.1016/S0166-2236(00)01581-2.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Singh M. Ovarian hormones elicit phosphorylation of Akt and extracellular-signal regulated kinase in explants of the cerebral cortex. Endocrine. 2001;14(3):407–15.  https://doi.org/10.1385/ENDO:14:3:407.CrossRefPubMedGoogle Scholar
  70. 70.
    Zaidi AU, D’Sa-Eipper C, Brenner J, Kuida K, Zheng TS, Flavell RA, et al. Bcl-X(L)-caspase-9 interactions in the developing nervous system: evidence for multiple death pathways. J Neurosci. 2001;21(1):169–75.CrossRefGoogle Scholar
  71. 71.
    Wade CB, Dorsa DM. Estrogen activation of cyclic adenosine 5′-monophosphate response element-mediated transcription requires the extracellularly regulated kinase/mitogen-activated protein kinase pathway. Endocrinology. 2003;144:832–8.  https://doi.org/10.1210/en.2002-220899.CrossRefPubMedGoogle Scholar
  72. 72.
    Quesada A, Micevych PE. Estrogen interacts with the IGF-1 system to protect nigrostriatal dopamine and maintain motoric behavior after 6-hydroxydopamine lesions. J Neurosci Res. 2004;75(1):107–16.  https://doi.org/10.1002/jnr.10833.CrossRefPubMedGoogle Scholar
  73. 73.
    Hagen AA, Barr M, Diczfalusy E. Metabolism of 17β-oestradiol-4-14C in early infancy. Acta Endocrinol. 1965;49:207–20.  https://doi.org/10.1530/acta.0.0490207.CrossRefPubMedGoogle Scholar
  74. 74.
    Warmerdam EG, Visser M, Coeling Bennink HJ, Groen M. A new route of synthesis of estetrol. Climacteric. 2008;11(Suppl 1):59–63.  https://doi.org/10.1080/13697130802054078.CrossRefPubMedGoogle Scholar
  75. 75.
    Holinka CF, Diczfalusy E, Coeling Bennink HJTC. Estetrol: a unique steroid in human pregnancy. J Steroid Biochem Mol Biol. 2008;110(1–2):138–43.  https://doi.org/10.1016/j.jsbmb.2008.03.027.CrossRefPubMedGoogle Scholar
  76. 76.
    Visser M, Foidart J-M, Coelingh Bennink HJT. In vitro effects of estetrol on receptor binding, drug targets and human liver cell metabolism. Climacteric. 2008;11(Suppl 1):64–8.  https://doi.org/10.1080/13697130802050340.CrossRefPubMedGoogle Scholar
  77. 77.
    Coeling Bennink HJTC, Skouby S, Bouchard P, Holinka CF. Ovulation inhibition by estetrol in an in vivo model. Contraception. 2008;77(3):186–90.  https://doi.org/10.1016/j.contraception.2007.11.014.CrossRefGoogle Scholar
  78. 78.
    Coelingh Bennink HJTC, Holinka CF, Diczfalusy E. Estetrol review: profile and potential clinical applications. Climacteric. 2008;11(Suppl 1):47–58.  https://doi.org/10.1080/13697130802040077.CrossRefPubMedGoogle Scholar
  79. 79.
    Hirano S, Furutama D, Hanafusa T. Physiologically high concentrations of 17beta-estradiol enhance NF-kappaB activity in human T cells. Am J Physiol Regul Integr Comp Physiol. 2007;292(4):R1465–71.  https://doi.org/10.1152/ajpregu.00778.2006.CrossRefPubMedGoogle Scholar
  80. 80.
    Koh KK, Yoon BK. Controversies regarding hormone therapy: insights from inflammation and hemostasis. Cardiovasc Res. 2006;70(1):22–30.  https://doi.org/10.1016/j.cardiores.2005.12.004.CrossRefPubMedGoogle Scholar
  81. 81.
    Herrington DM, Klein KP. Invited review: Pharmacogenetics of estrogen replacement therapy. J Appl Physiol (1985). 2001;91(6):2776–84.  https://doi.org/10.1152/jappl.2001.91.6.2776.CrossRefGoogle Scholar
  82. 82.
    Arnal JF, Valéra MC, Payrastre B, Lenfant F, Gourdy P. Structure-function relationship of estrogen receptors in cardiovascular pathophysiological models. Thromb Res. 2012;130(Suppl 1):S7–11.  https://doi.org/10.1016/j.thromres.2012.08.261.CrossRefPubMedGoogle Scholar
  83. 83.
    Deroo BJ, Korach KS. Estrogen receptors and human disease: an update. Arch Toxicol. 2012;86(10):1491–504.  https://doi.org/10.1007/s00204-012-0868-5.CrossRefGoogle Scholar
  84. 84.
    ACOG. Executive summary: Neonatal encephalopathy and neurologic outcome, second edition. Report of the American College of Obstetricians and Gynecologists’ Task Force on Neonatal Encephalopathy. Obstet Gynecol. 2014;123(4):896–901.CrossRefGoogle Scholar
  85. 85.
    Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicenter randomised trial. Lancet. 2005;65(9460):663–70.  https://doi.org/10.1016/S0140-6736(05)17946-X.CrossRefGoogle Scholar
  86. 86.
    Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005;353(15):1574–84.  https://doi.org/10.1056/NEJMcps050929.CrossRefGoogle Scholar
  87. 87.
    Robertson CM, Perlman M. Follow-up of the term infant after hypoxic-ischemic encephalopathy. Paediatr Child Health. 2006;11(5):278–82.PubMedPubMedCentralGoogle Scholar
  88. 88.
  89. 89.
    Bryce J, Boschi-Pinto C, Shibuya K, Black RE, WHO Child Health Epidemiology Reference Group. WHO estimates of the causes of death in children. Lancet. 2005;365(9465):1147–52.CrossRefGoogle Scholar
  90. 90.
    Badawi N, Kurinczuk JJ, Keogh JM, Alessandri LM, O’Sullivan F, Burton PR, et al. Antepartum risk factors for newborn encephalopathy: the Western Australian case-control study. BMJ. 1998;317(7172):1549–53.  https://doi.org/10.1136/bmj.317.7172.1549.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Badawi N, Kurinczuk JJ, Keogh JM, Alessandri LM, O’Sullivan F, Burton PR, et al. Intrapartum risk factors for newborn encephalopathy: the Western Australian case-control study. BMJ. 1998;317(7172):1554–8.  https://doi.org/10.1136/bmj.317.7172.1554.CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Graham EM, Ruis KA, Hartman AL, Northington FJ, Fox HE. A systematic review of the role of intrapartum hypoxia-ischemia in the causation of neonatal encephalopathy. Am J Obstet Gynecol. 2008;199(6):587–95.  https://doi.org/10.1016/j.ajog.2008.06.094.CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Ankarcrona M, Dypbukt JM, Bonfoco E, Zhivotovsky B, Orrenius S, Lipton SA, et al. Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function. Neuron. 1995;15(4):961–73.  https://doi.org/10.1016/0896-6273(95)90186-8.CrossRefPubMedGoogle Scholar
  94. 94.
    Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. 2007;87(1):315–424.  https://doi.org/10.1152/physrev.00029.2006.CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Chang YC, Huang CC. Perinatal brain injury and regulation of transcription. Curr Opin Neurol. 2006;19(2):141–7.  https://doi.org/10.1097/01.wco.0000218229.73678.a8.CrossRefPubMedGoogle Scholar
  96. 96.
    Domoki F, Kis B, Nagy K, Farkas E, Busija DW, Bari F. Diazoxide preserves hypercapnia-induced arteriolar vasodilation after global cerebral ischemia in piglets. Am J Physiol Heart Circ Physiol. 2005;289:H368–73.  https://doi.org/10.1152/ajpheart.00887.2004.CrossRefPubMedGoogle Scholar
  97. 97.
    Gerosa C, Fanni D, Puddu M, Locci G, Obinu E, Fanos V, et al. Histological markers of neonatal asphyxia: the relevant role of vascular changes. J Pediatr Neonat Individual Med. 2014;3(2):e030275.Google Scholar
  98. 98.
    Olah O, Toth-Szuki V, Temesvari P, Bari F, Domoki F. Delayed neurovascular dysfunction is alleviated by hydrogen in asphyxiated newborn pigs. Neonatology. 2013;104:79–86.  https://doi.org/10.1159/000348445.CrossRefPubMedGoogle Scholar
  99. 99.
    Ireland Z, Castillo-Melendez M, Dickinson H, Snow R, Walker DW. A maternal diet supplemented with creatine from mid-pregnancy protects the newborn spiny mouse brain from birth hypoxia. Neuroscience. 2011;194:372–9.  https://doi.org/10.1016/j.neuroscience.2011.05.012.CrossRefPubMedGoogle Scholar
  100. 100.
    Fleiss B, Coleman HA, Castillo-Melendez M, Ireland Z, Walker DW, Parkington HC. Effects of birth asphyxia on neonatal hippocampal structure and function in the spiny mouse. Int J Dev Neurosci. 2011;29:757–66.  https://doi.org/10.1016/j.ijdevneu.2011.05.006.CrossRefPubMedGoogle Scholar
  101. 101.
    Schiering IA, de Haan TR, Niermeijer JM, Koelman JH, Majoie CB, Reneman L, et al. Correlation between clinical and histologic findings in the human neonatal hippocampus after perinatal asphyxia. J Neuropathol Exp Neurol. 2014;73:324–34.  https://doi.org/10.1097/NEN.0000000000000056.CrossRefPubMedGoogle Scholar
  102. 102.
    Okereafor A, Allsop J, Counsell SJ, Fitzpatrick J, Azzopardi D, Rutherford MA, et al. Patterns of brain injury in neonates exposed to perinatal sentinel events. Pediatrics. 2008;121(5):906–14.  https://doi.org/10.1542/peds.2007-0770.CrossRefPubMedGoogle Scholar
  103. 103.
    Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress: a clinical and electroencephalographic study. Arch Neurol. 1976;33(10):696–705.  https://doi.org/10.1001/archneur.1976.00500100030012.CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Douglas-Escobar M, Weiss MD. Hypoxic-ischemic encephalopathy: a review for the clinician. JAMA Pediatr. 2015;169(4):397–403.  https://doi.org/10.1001/jamapediatrics.2014.3269.CrossRefPubMedGoogle Scholar
  105. 105.
    Thoresen M, Hellstrom-Westas L, Liu X, de Vries LS. Effect of hypothermia on amplitude-integrated electroencephalogram in infants with asphyxia. Pediatrics. 2010;126(1):e131–9.  https://doi.org/10.1542/peds.2009-2938.CrossRefPubMedGoogle Scholar
  106. 106.
    Rothermundt M, Peters M, Prehn JH, Arolt V. S100B in brain damage and neurodegeneration. Microsc Res Tech. 2003;60(6):614–32.  https://doi.org/10.1002/jemt.10303.CrossRefPubMedGoogle Scholar
  107. 107.
    Ennen CS, Huisman TA, Savage WJ, Northington FJ, Jennings JM, Everett AD, et al. Glial fibrillary acidic protein as a biomarker for neonatal hypoxic-ischemic encephalopathy treated with whole-body cooling. Am J Obstet Gynecol. 2005;205(3):251.e1–7.  https://doi.org/10.1016/j.ajog.2011.06.025.CrossRefGoogle Scholar
  108. 108.
    Shankaran S. The postnatal management of the asphyxiated term infant. Clin Perinatol. 2002;29(4):675–92.CrossRefGoogle Scholar
  109. 109.
    Stola A, Perlman J. Post-resuscitation strategies to avoid ongoing injury following intrapartum hypoxia-ischemia. Semin Fetal Neonatal Med. 2008;13(6):424–31.  https://doi.org/10.1016/j.siny.2008.04.011.CrossRefPubMedGoogle Scholar
  110. 110.
    Hoehn T, Hansmann G, Bührer C, Simbruner G, Gunn AJ, Yager J, et al. Therapeutic hypothermia in neonates. Review of current clinical data, ILCOR recommendations and suggestions for implementation in neonatal intensive care units. Resuscitation. 2008;78:7–12.  https://doi.org/10.1016/j.resuscitation.2008.04.027.CrossRefPubMedGoogle Scholar
  111. 111.
    Thoresen M, Tooley J, Liu X, Jary S, Fleming P, Luyt K, et al. Time is brain: starting therapeutic hypothermia within three hours after birth improves motor outcome in asphyxiated newborns. Neonatology. 2013;104(3):228–33.  https://doi.org/10.1159/000353948.CrossRefPubMedGoogle Scholar
  112. 112.
    Edwards DA, Azzopardi DV, Gunn AJ. Neonatal neural rescue: a clinical guide. Cambridge, UK: Cambridge University Press; 2013.CrossRefGoogle Scholar
  113. 113.
    Ballot DE. Cooling for newborns with hypoxic ischaemic encephalopathy: RHL commentary (last revised: 1 October 2010). The WHO Reproductive Health Library. Geneva: World Health Organization (WHO).Google Scholar
  114. 114.
    Zanelli S, Buck M, Fairchild K. Physiologic and pharmacologic considerations for hypothermia therapy in neonates. J Perinatol. 2011;31(6):377–86.  https://doi.org/10.1038/jp.2010.146.CrossRefGoogle Scholar
  115. 115.
    Thoresen M, Whitelaw A. Therapeutic hypothermia for hypoxic-ischaemic encephalopathy in the newborn infant. Curr Opin Neurol. 2005;18(2):111–6.  https://doi.org/10.1097/01.wco.0000162850.44897.c6.CrossRefPubMedGoogle Scholar
  116. 116.
    Tskitishvili E, Nisolle M, Munaut C, Pequeux C, Gerard C, Noel A, et al. Neonatal estetrol attenuates neonatal hypoxic-ischemic brain injury. Exp Neurol. 2014;261:298–307.  https://doi.org/10.1016/j.expneurol.2014.07.015.CrossRefPubMedGoogle Scholar
  117. 117.
    Tskitishvili E, Pequeux C, Munaut C, Viellevoye R, Nisolle M, Noël A, et al. Use of estetrol with other steroids for attenuation of neonatal hypoxic-ischemic brain injury: to combine or not to combine? Oncotarget. 2016;7(23):33722–43.  https://doi.org/10.18632/oncotarget.9591.CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Tskitishvili E, Pequeux C, Munaut C, Viellevoye R, Nisolle M, Noël A, et al. Estrogen receptors and estetrol-dependent neuroprotective actions: a pilot study. J Endocrinol. 2017;232(1):85–95.  https://doi.org/10.1530/JOE-16-0434.CrossRefPubMedGoogle Scholar
  119. 119.
    Johnson GV, Jope RS. The role of microtubule-associated protein 2 (MAP-2) in neuronal growth, plasticity, and degeneration. J Neurosci Res. 1992;33(4):505–12.  https://doi.org/10.1002/jnr.490330402.CrossRefPubMedGoogle Scholar
  120. 120.
    Bartosik-Psujek H, Stelmasiak Z. Biochemical markers of damage of the central nervous system in multiple sclerosis. Ann Univ Mariae Curie Sklodowska Med. 2001;56:389–92.PubMedGoogle Scholar
  121. 121.
    Roof RL, Duvdevani R, Braswell L, Stein DG. Progesterone facilitates cognitive recovery and reduces secondary neuronal loss caused by cortical contusion injury in male rats. Exp Neurol. 1994;129:64–9.  https://doi.org/10.1006/exnr.1994.1147.CrossRefPubMedGoogle Scholar
  122. 122.
    Roof RL, Hoffman SW, Stein DG. Progesterone protects against lipid peroxidation following traumatic brain injury in rats. Mol Chem Neuropathol. 1997;31(1):1–11.CrossRefGoogle Scholar
  123. 123.
    Roof RL, Hall E. Gender differences in acute CNS trauma and stroke: neuroprotective effects of estrogen and progesterone. J Neurotrauma. 2000;17(5):367–88.  https://doi.org/10.1089/neu.2000.17.367.CrossRefPubMedGoogle Scholar
  124. 124.
    Stein D. Brain damage, sex hormones and recovery: a new role for progesterone and estrogen? Trends Neurosci. 2001;24(7):386–91.  https://doi.org/10.1016/S0166-2236(00)01821-X.CrossRefPubMedPubMedCentralGoogle Scholar
  125. 125.
    Gold SM, Voskuhl RR. Estrogen and testosterone therapies in multiple sclerosis. Prog Brain Res. 2009;175:239–51.  https://doi.org/10.1016/S0079-6123(09)17516-7.CrossRefPubMedPubMedCentralGoogle Scholar
  126. 126.
    Kaur P, Jodhka PK, Underwood WA, Bowles CA, de Fiebre NC, de Fiebre CM, et al. Progesterone increases brain-derived neurotrophic factor expression and protects against glutamate toxicity in a mitogen-activated protein kinase- and phosphoinositide-3 kinase-dependent manner in cerebral cortical explants. J Neurosci Res. 2007;85(11):2441–9.  https://doi.org/10.1002/jnr.21370.CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    Nilsen J, Brinton RD. Impact of progestins on estradiol potentiation of the glutamate calcium response. Neuroreport. 2002;13(6):825–30.CrossRefGoogle Scholar
  128. 128.
    Nilsen J, Brinton RD. Impact of progestins on estrogen induced neuroprotection: synergy by progesterone and 19-norprogesterone and antagonism by medroxyprogesterone acetate. Endocrinology. 2002;143(1):205–12.  https://doi.org/10.1210/endo.143.1.8582.CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Nilsen J, Brinton RD. Divergent impact of progesterone and medroxyprogesterone acetate (Provera) on nuclear mitogen activated protein kinase signaling. Proc Natl Acad Sci U S A. 2003;100(18):10506–11.  https://doi.org/10.1073/pnas.1334098100.CrossRefPubMedPubMedCentralGoogle Scholar
  130. 130.
    Goodman Y, Bruce AJ, Cheng B, Mattson MP. Estrogens attenuate and corticosterone exacerbates excitotoxicity, oxidative injury, and amyloid beta-peptide toxicity in hippocampal neurons. J Neurochem. 1996;66:1836–44.  https://doi.org/10.1046/j.1471-4159.1996.66051836.x.CrossRefPubMedGoogle Scholar
  131. 131.
    Singh M, Su C. Progesterone and neuroprotection. Horm Behav. 2013;63(2):284–90.  https://doi.org/10.1016/j.yhbeh.2012.06.003.CrossRefPubMedGoogle Scholar
  132. 132.
    Trotter A, Steinmacher J, Kron M, Pohlandt F. Neurodevelopmental follow-up at five years corrected age of extremely low birth weight infants after postnatal replacement of 17-estradiol and progesterone. J Clin Endocrinol Metab. 2012;97(3):1041–7.  https://doi.org/10.1210/jc.2011-2612.CrossRefPubMedGoogle Scholar
  133. 133.
    Lorenz L, Dang J, Misiak M, Tameh Abolfazl A, Beyer C, Kipp M. Combined 17beta-oestradiol and progesterone treatment prevents neuronal cell injury in cortical but not midbrain neurones or neuroblastoma cells. J Neuroendocrinol. 2009;21(10):841–9.  https://doi.org/10.1111/j.1365-2826.2009.01903.x.CrossRefPubMedGoogle Scholar
  134. 134.
    Mannella P, Sanchez AM, Giretti MS, Genazzani AR, Simoncini T. Oestrogen and progestins differently prevent glutamate toxicity in cortical neurons depending on prior hormonal exposure via the induction of neural nitric oxide synthase. Steroids. 2009;74(8):650–6.  https://doi.org/10.1210/me.2008-0408.CrossRefPubMedGoogle Scholar
  135. 135.
    Aguirre CC, Baudry M. Progesterone reverses 17betaestradiol-mediated neuroprotection and BDNF induction in cultured hippocampal slices. Eur J Neurosci. 2009;29(3):447–54.  https://doi.org/10.1111/j.1460-9568.2008.06591.x.CrossRefPubMedPubMedCentralGoogle Scholar
  136. 136.
    Aguirre C, Jayaraman A, Pike C, Baudry M. Progesterone inhibits estrogen-mediated neuroprotection against excitotoxicity by down-regulating estrogen receptor-beta. J Neurochem. 2010;115(5):1277–87.  https://doi.org/10.1111/j.1471-4159.2010.07038.x.CrossRefPubMedPubMedCentralGoogle Scholar
  137. 137.
    Carroll JC, Rosario ER, Pike CJ. Progesterone blocks estrogen neuroprotection from kainate in middle-aged female rats. Neurosci Lett. 2008;445(3):229–32.  https://doi.org/10.1016/j.neulet.2008.09.010.CrossRefPubMedPubMedCentralGoogle Scholar
  138. 138.
    Jayaraman A, Pike CJ. Progesterone attenuates oestrogen neuroprotection via downregulation of oestrogen receptor expression in cultured neurones. J Neuroendocrinol. 2009;21(1):77–81.  https://doi.org/10.1111/j.1365-2826.2008.01801.x.CrossRefPubMedPubMedCentralGoogle Scholar
  139. 139.
    Rosario ER, Ramsden M, Pike CJ. Progestins inhibit the neuroprotective effects of estrogen in rat hippocampus. Brain Res. 2006;1099(1):206–10.  https://doi.org/10.1016/j.brainres.2006.03.127.CrossRefPubMedGoogle Scholar
  140. 140.
    Yao J, Chen S, Cadenas E, Brinton RD. Estrogen protection against mitochondrial toxin-induced cell death in hippocampal neurons: antagonism by progesterone. Brain Res. 2011;1379:2–10.  https://doi.org/10.1016/j.brainres.2010.11.090.CrossRefPubMedGoogle Scholar
  141. 141.
    Gibson C, Constantin D, Prior M, Bath P, Murphy S. Progesterone suppresses the inflammatory response and nitric oxide synthase-2 expression following cerebral ischemia. Exp Neurol. 2005;193(2):522–30.  https://doi.org/10.1016/j.expneurol.2005.01.009.CrossRefPubMedGoogle Scholar
  142. 142.
    Grossman K, Goss C, Stein D. Effects of progesterone on the inflammatory response to brain injury in the rat. Brain Res. 2004;1008(1):29–39.  https://doi.org/10.1016/j.brainres.2004.02.022.CrossRefPubMedGoogle Scholar
  143. 143.
    Labombarda F, Gonzalez S, Gonzalez Deniselle MC, Garay L, Guennoun R, Schumacher M, et al. Progesterone increases the expression of myelin basic protein and the number of cells showing NG2 immunostaining in the lesioned spinal cord. J Neurotrauma. 2006;23(2):181–92.  https://doi.org/10.1089/neu.2006.23.181.CrossRefPubMedGoogle Scholar
  144. 144.
    Pierson RC, Lyons AM, Greenfield LJ Jr. Gonadal steroids regulate GABAA receptor subunit mRNA expression in NT2-Nneurons. Brain Res Mol Brain Res. 2005;138(2):105–15.  https://doi.org/10.1016/j.molbrainres.2004.10.047.CrossRefPubMedGoogle Scholar
  145. 145.
    Mani SK. Signaling mechanisms in progesterone neurotransmitter interactions. Neuroscience. 2006;138(3):773–81.  https://doi.org/10.1016/j.neuroscience.2005.07.034.CrossRefPubMedGoogle Scholar
  146. 146.
    Pettus EH, Wright DW, Stein DG, Hoffman SW. Progesterone treatment inhibits the inflammatory agents that accompany traumatic brain injury. Brain Res. 2005;1049(1):112–9.  https://doi.org/10.1016/j.brainres.2005.05.004.CrossRefPubMedGoogle Scholar
  147. 147.
    Quadros PS, Pfau JL, Wagner CK. Distribution of progesterone receptor immunoreactivity in the fetal and neonatal rat forebrain. J Comp Neurol. 2007;504(1):42–56.CrossRefGoogle Scholar
  148. 148.
    Jahagirdar V, Wagner CK. Ontogeny of progesterone receptor expression in the subplate of fetal and neonatal rat cortex. Cereb Cortex. 2010;20(5):1046–52.  https://doi.org/10.1002/cne.21427.CrossRefPubMedGoogle Scholar
  149. 149.
    Abot A, Fontaine C, Buscato M, Solinhac R, Flouriot G, Fabre A, et al. The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor modulation, uncoupling nuclear and membrane activation. EMBO Mol Med. 2014;6(10):1328–46.  https://doi.org/10.15252/emmm.201404112.CrossRefPubMedPubMedCentralGoogle Scholar
  150. 150.
    La Rosa P, Pesiri V, Leclerq G, Marino M, Acconcia F. Palmitoylation regulates 17β-estradiol-induced estrogen receptor-α degradation and transcriptional activity. Mol Endocrinol. 2012;26(5):762–74.  https://doi.org/10.1210/me.2011-1208.CrossRefPubMedPubMedCentralGoogle Scholar
  151. 151.
    Acconcia F, Ascenzi P, Fabozzi G, Visca P, Marino M. S-palmitoylation modulates human estrogen receptor-alpha functions. Biochem Biophys Res Commun. 2004;316:878–83.  https://doi.org/10.1016/j.bbrc.2004.02.129.CrossRefPubMedGoogle Scholar
  152. 152.
    Khalaj AJ, Yoon J, Nakai J, Winchester Z, Moore SM, Yoo T, et al. Estrogen receptor (ER) β expression in oligodendrocytes is required for attenuation of clinical disease by an ERβ ligand. Proc Natl Acad Sci U S A. 2013;110(47):19125–30.  https://doi.org/10.1073/pnas.1311763110.CrossRefPubMedPubMedCentralGoogle Scholar
  153. 153.
    Prokai L, Prokai-Tatrai K, Perjesi P, Simpkins JW. Mechanistic insights into the direct antioxidant effects of estrogens. Drug Dev Res. 2005;66(2):118–25.  https://doi.org/10.1002/ddr.20050.CrossRefGoogle Scholar
  154. 154.
    Hammes SR, Levin ER. Extranuclear steroid receptors: nature and actions. Endocr Rev. 2007;28:726–41.  https://doi.org/10.1210/er.2007-0022.CrossRefPubMedGoogle Scholar
  155. 155.
    Suzuki S, Gerhold LM, Bottner M, Rau SW, Dela Cruz C, Yang E, et al. Estradiol enhances neurogenesis following ischemic stroke through estrogen receptors a and b. J Comp Neurol. 2007;500:1064–75.  https://doi.org/10.1002/cne.21240.CrossRefPubMedGoogle Scholar
  156. 156.
    Spence RD, Hamby ME, Umeda E, Itoh N, Du S, Wisdom AJ, et al. Neuroprotection mediated through estrogen receptor-α in astrocytes. Proc Natl Acad Sci U S A. 2011;108:8867–72.  https://doi.org/10.1073/pnas.1103833108.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Gynecological Endocrinology 2019

Authors and Affiliations

  • Ekaterine Tskitishvili
    • 1
  • Jean Michel Foidart
    • 1
    • 2
    • 3
  1. 1.Laboratory of Tumor Biology and Development, GIGA-CancerUniversity of LiegeLiegeBelgium
  2. 2.Department of Obstetrics and Gynecology, Faculty of MedicineUniversity of LiegeLiegeBelgium
  3. 3.Department of Clinical Sciences, Faculty of MedicineUniversity of LiegeLiegeBelgium

Personalised recommendations