title: Estrogen neuroprotection and the critical period hypothesis.
abstract: 17β-Estradiol (estradiol or E2) is implicated as a neuroprotective factor in a variety of neurodegenerative disorders. This review focuses on the mechanisms underlying E2 neuroprotection in cerebral ischemia, as well as emerging evidence from basic science and clinical studies, which suggests that there is a "critical period" for estradiol's beneficial effect in the brain. Potential mechanisms underlying the critical period are discussed, as are the neurological consequences of long-term E2 deprivation (LTED) in animals and in humans after natural menopause or surgical menopause. We also summarize the major clinical trials concerning postmenopausal hormone therapy (HT), comparing their outcomes with respect to cardiovascular and neurological disease and discussing their relevance to the critical period hypothesis. Finally, potential caveats, controversies and future directions for the field are highlighted and discussed throughout the review.
authors.affiliation: Institute of Molecular Medicine and Genetics, Georgia Health Sciences University, Augusta, GA 30912, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Scott
authors.forename: Quan-guang
authors.initials: QG
authors.lastname: Zhang
authors.forename: Ruimin
authors.initials: R
authors.lastname: Wang
authors.forename: Ratna
authors.initials: R
authors.lastname: Vadlamudi
authors.forename: Darrell
authors.initials: D
authors.lastname: Brann
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000517:prevention & control*; D003423:Critical Period, Psychological; D004958:Estradiol / Q000627:therapeutic use*; D047628:Estrogen Receptor alpha / Q000502:physiology; D015914:Estrogen Replacement Therapy; D005260:Female; D006801:Humans; D008593:Menopause; D051379:Mice; D019636:Neurodegenerative Diseases / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled / Q000502:physiology
chemical_list: D047628:Estrogen Receptor alpha; C532507:GPER1 protein, mouse; D018696:Neuroprotective Agents; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D004958:Estradiol
references.citation: J Neurosci. 1999 Aug 1;19(15):6385-93
references.pmid: 10414967
references.citation: Brain Res. 1998 Nov 9;810(1-2):87-92
references.pmid: 9813255
references.citation: J Neurosci. 2006 Oct 11;26(41):10332-48
references.pmid: 17035515
references.citation: Endocrinology. 2007 Mar;148(3):1131-43
references.pmid: 17138646
references.citation: Neuroepidemiology. 2005;24(3):123-8
references.pmid: 15637449
references.citation: Prog Brain Res. 2010;182:77-96
references.pmid: 20541661
references.citation: Clin Exp Pharmacol Physiol. 2011 Sep;38(9):577-85
references.pmid: 21645039
references.citation: Neuroscientist. 2008 Apr;14(2):147-56
references.pmid: 17911219
references.citation: Brain Res. 2005 Aug 30;1054(2):192-9
references.pmid: 16125684
references.citation: Stroke. 1999 Aug;30(8):1665-70
references.pmid: 10436119
references.citation: Ther Adv Neurol Disord. 2009 Jan;2(1):31-49
references.pmid: 19890493
references.citation: J Cereb Blood Flow Metab. 2010 May;30(5):935-42
references.pmid: 20010956
references.citation: J Neurosci Res. 2008 Jun;86(8):1659-69
references.pmid: 18189318
references.citation: J Neurosci. 2009 Nov 4;29(44):13823-36
references.pmid: 19889994
references.citation: J Neurochem. 2009 Jul;110(1):1-11
references.pmid: 19457121
references.citation: J Cereb Blood Flow Metab. 2009 Aug;29(8):1359-72
references.pmid: 19458604
references.citation: Endocrinology. 2004 Aug;145(8):3788-95
references.pmid: 15131017
references.citation: Am J Physiol Heart Circ Physiol. 2004 Oct;287(4):H1501-4
references.pmid: 15155257
references.citation: Brain Res. 2011 Mar 16;1379:34-43
references.pmid: 21241678
references.citation: Endocrinology. 2006 Jan;147(1):607-14
references.pmid: 16239296
references.citation: Prog Brain Res. 2010;181:251-72
references.pmid: 20478442
references.citation: Neurobiol Aging. 2012 Aug;33(8):1507-21
references.pmid: 21514693
references.citation: Brain Res. 1998 Feb 16;784(1-2):321-4
references.pmid: 9518671
references.citation: Stroke. 1992 Sep;23(9):1225-9
references.pmid: 1519275
references.citation: J Clin Endocrinol Metab. 2010 Jul;95(7 Suppl 1):s1-s66
references.pmid: 20566620
references.citation: Climacteric. 2010 Oct;13(5):429-32
references.pmid: 20670199
references.citation: J Clin Endocrinol Metab. 2011 Feb;96(2):255-64
references.pmid: 21296989
references.citation: J Neurosci Res. 2000 May 1;60(3):321-7
references.pmid: 10797534
references.citation: Treat Endocrinol. 2006;5(1):37-51
references.pmid: 16396517
references.citation: Fundam Clin Pharmacol. 2004 Oct;18(5):547-57
references.pmid: 15482376
references.citation: PLoS One. 2010 May 07;5(5):e9851
references.pmid: 20479872
references.citation: Ann N Y Acad Sci. 2005 Jun;1052:57-74
references.pmid: 16024751
references.citation: J Cereb Blood Flow Metab. 2011 Feb;31(2):413-25
references.pmid: 20940729
references.citation: J Neurosci. 2002 Mar 15;22(6):2115-24
references.pmid: 11896151
references.citation: Antioxid Redox Signal. 2009 Oct;11(10):2481-504
references.pmid: 19309263
references.citation: Neuroepidemiology. 2009;33(1):32-40
references.pmid: 19365140
references.citation: Climacteric. 2007 Oct;10 Suppl 2:92-6
references.pmid: 17882682
references.citation: Trends Neurosci. 2008 Oct;31(10):529-37
references.pmid: 18774188
references.citation: Hum Reprod Update. 2007 Mar-Apr;13(2):175-87
references.pmid: 17135285
references.citation: JAMA. 2002 Jul 3;288(1):49-57
references.pmid: 12090862
references.citation: Am J Med. 2002 Nov;113(7):543-8
references.pmid: 12459399
references.citation: Mol Endocrinol. 2006 Mar;20(3):491-502
references.pmid: 16306086
references.citation: J Neurosurg. 1997 Nov;87(5):724-30
references.pmid: 9347981
references.citation: J Cereb Blood Flow Metab. 2011 Mar;31(3):868-80
references.pmid: 20859296
references.citation: Biochim Biophys Acta. 2010 Oct;1800(10):1121-6
references.pmid: 20538040
references.citation: Brain Res. 2011 Mar 16;1379:11-22
references.pmid: 21241683
references.citation: J Cereb Blood Flow Metab. 1998 Nov;18(11):1253-8
references.pmid: 9809515
references.citation: Front Biosci (Landmark Ed). 2011 Jan 01;16(4):1560-73
references.pmid: 21196248
references.citation: J Neurosci Res. 2001 Jun 1;64(5):466-75
references.pmid: 11391701
references.citation: Climacteric. 2005 Mar;8(1):3-12
references.pmid: 15804727
references.citation: Hippocampus. 2005;15(3):404-12
references.pmid: 15669092
references.citation: J Neurochem. 2009 May;109 Suppl 1:133-8
references.pmid: 19393019
references.citation: Ann Intern Med. 2000 May 2;132(9):689-96
references.pmid: 10787361
references.citation: Neuroscience. 2000;101(3):485-512
references.pmid: 11113299
references.citation: Neurology. 2000 Jan 25;54(2):295-301
references.pmid: 10668686
references.citation: J Cereb Blood Flow Metab. 2005 Mar;25(3):414-20
references.pmid: 15647739
references.citation: Brain Res Brain Res Rev. 2001 Nov;37(1-3):320-34
references.pmid: 11744097
references.citation: Horm Behav. 2009 Jun;56(1):73-83
references.pmid: 19303882
references.citation: Neurosci Lett. 2001 Jan 19;297(3):159-62
references.pmid: 11137752
references.citation: Brain Res. 2011 Mar 16;1379:188-98
references.pmid: 20965156
references.citation: Exp Gerontol. 2007 Jan-Feb;42(1-2):70-5
references.pmid: 16872778
references.citation: J Neurosci. 2002 Jan 1;22(1):209-17
references.pmid: 11756504
references.citation: Exp Brain Res. 2007 Apr;178(4):470-6
references.pmid: 17091294
references.citation: Brain Res. 2001 May 4;900(1):137-42
references.pmid: 11325356
references.citation: Int J Biochem Cell Biol. 2008;40(12):2707-19
references.pmid: 18562239
references.citation: Menopause. 2007 May-Jun;14(3 Pt 2):572-9
references.pmid: 17476147
references.citation: J Immunol. 2010 Apr 15;184(8):4087-94
references.pmid: 20304826
references.citation: J Bone Miner Res. 2010 Apr;25(4):769-81
references.pmid: 19821774
references.citation: J Toxicol. 2011;2011:683728
references.pmid: 21785590
references.citation: Neuroscience. 2003;116(3):851-61
references.pmid: 12573724
references.citation: Endocr Rev. 2007 Feb;28(1):1-19
references.pmid: 17018839
references.citation: J Neurosci. 2003 Sep 24;23(25):8701-5
references.pmid: 14507969
references.citation: Ann N Y Acad Sci. 2003 Dec;1007:89-100
references.pmid: 14993043
references.citation: JAMA. 1998 Aug 19;280(7):605-13
references.pmid: 9718051
references.citation: Semin Reprod Med. 2009 May;27(3):283-93
references.pmid: 19401959
references.citation: Proc Natl Acad Sci U S A. 2011 Aug 30;108(35):E617-24
references.pmid: 21808025
references.citation: Brain Res. 2011 Feb 4;1372:92-102
references.pmid: 21138737
references.citation: J Pharmacol Exp Ther. 2003 Jan;304(1):172-8
references.pmid: 12490588
references.citation: Neuroscience. 2005;133(1):343-52
references.pmid: 15893655
references.citation: Endocrinology. 2005 Jun;146(6):2749-59
references.pmid: 15746252
references.citation: Eur J Neurosci. 2010 Dec;32(12):1995-2002
references.pmid: 21143654
references.citation: Lancet. 1996 Aug 17;348(9025):429-32
references.pmid: 8709781
references.citation: J Womens Health (Larchmt). 2010 Jan;19(1):47-55
references.pmid: 20088658
references.citation: Proc Natl Acad Sci U S A. 2011 May 24;108(21):8867-72
references.pmid: 21555578
references.citation: Fertil Steril. 2005 Dec;84(6):1589-601
references.pmid: 16359951
references.citation: Curr Top Behav Neurosci. 2012;10:165-84
references.pmid: 21533680
references.citation: Biochim Biophys Acta. 2010 Oct;1800(10):1113-20
references.pmid: 19931595
references.citation: J Cereb Blood Flow Metab. 2000 Jan;20(1):112-8
references.pmid: 10616799
references.citation: Psychoneuroendocrinology. 2010 Jun;35(5):694-705
references.pmid: 19926225
references.citation: Br J Obstet Gynaecol. 1996 May;103 Suppl 13:80-6
references.pmid: 8624348
references.citation: Nucl Recept Signal. 2006 Oct 30;4:e023
references.pmid: 17088939
references.citation: Brain Res. 2005 Mar 2;1036(1-2):155-62
references.pmid: 15725413
references.citation: Brain Res Mol Brain Res. 2002 Jun 15;102(1-2):48-54
references.pmid: 12191493
references.citation: Physiol Rev. 2007 Jan;87(1):245-313
references.pmid: 17237347
references.citation: JAMA. 2003 May 28;289(20):2673-84
references.pmid: 12771114
references.citation: Neuroscience. 2006;138(3):1027-30
references.pmid: 16488547
references.citation: Clin Trials. 2004;1(5):440-50
references.pmid: 16279282
references.citation: Ann Neurol. 2011 Jan;69(1):163-9
references.pmid: 21280086
references.citation: Peptides. 2005 Nov;26(11):2257-64
references.pmid: 15919133
references.citation: Ann Neurol. 2008 Aug;64(2):168-76
references.pmid: 18496870
references.citation: Med Hypotheses. 2011 Jun;76(6):847-54
references.pmid: 21398043
references.citation: Maturitas. 2010 Feb;65(2):161-6
references.pmid: 19733988
references.citation: Mol Cell Endocrinol. 2006 Feb 26;246(1-2):1-9
references.pmid: 16388890
references.citation: Mol Cell Biol. 2010 Jul;30(13):3249-61
references.pmid: 20439495
references.citation: Curr Cardiol Rep. 2010 Jan;12(1):6-13
references.pmid: 20425178
references.citation: Mol Cell Neurosci. 2011 Nov;48(3):185-94
references.pmid: 21803156
references.citation: J Biol Chem. 2004 May 21;279(21):22684-92
references.pmid: 14982935
references.citation: Womens Health (Lond). 2009 Sep;5(5):565-76
references.pmid: 19702455
references.citation: Neuroscience. 2005;132(3):581-9
references.pmid: 15837120
references.citation: Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1952-7
references.pmid: 11172057
references.citation: JAMA. 2003 May 28;289(20):2651-62
references.pmid: 12771112
references.citation: Menopause. 2010 Mar;17(2):242-55
references.pmid: 20154637
references.citation: Neurodegener Dis. 2010;7(1-3):163-6
references.pmid: 20197698
references.citation: J Neurosci. 2008 Aug 20;28(34):8430-41
references.pmid: 18716201
references.citation: Mol Endocrinol. 2008 Sep;22(9):2116-27
references.pmid: 18617595
references.citation: J Neurosci. 1999 Apr 1;19(7):2455-63
references.pmid: 10087060
references.citation: Biochem Biophys Res Commun. 2006 Aug 4;346(3):904-10
references.pmid: 16780796
references.citation: J Neurosci. 2007 Feb 7;27(6):1422-33
references.pmid: 17287517
references.citation: Endocrinology. 2007 Feb;148(2):627-37
references.pmid: 17082253
references.citation: Circulation. 2009 Jan 27;119(3):e21-181
references.pmid: 19075105
references.citation: Proc Natl Acad Sci U S A. 2006 Dec 5;103(49):18727-32
references.pmid: 17121991
references.citation: Stroke. 2003 Jul;34(7):1581-5
references.pmid: 12805490
references.citation: BMJ. 2010 Jun 03;340:c2519
references.pmid: 20525678
references.citation: Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11569-74
references.pmid: 11504919
references.citation: J Neurosci. 2003 Dec 10;23(36):11420-6
references.pmid: 14673006
references.citation: Horm Behav. 2008 Jan;53(1):159-69
references.pmid: 17964576
references.citation: Proc Natl Acad Sci U S A. 2007 Apr 3;104(14):6013-8
references.pmid: 17389368
references.citation: J Neurosci. 1999 May 1;19(9):3414-22
references.pmid: 10212301
references.citation: J Neurochem. 2007 Apr;101(1):232-40
references.pmid: 17250656
references.citation: J Cereb Blood Flow Metab. 2010 Jul;30(7):1306-17
references.pmid: 20145655
references.citation: Front Neuroendocrinol. 2009 Jul;30(2):142-57
references.pmid: 19410597
references.citation: Steroids. 2009 Jul;74(7):555-61
references.pmid: 19428444
references.citation: Biochim Biophys Acta. 2010 Oct;1800(10):1106-12
references.pmid: 19818384
references.citation: Horm Behav. 2006 Sep;50(3):361-9
references.pmid: 16815389
references.citation: Rev Neurosci. 2010;21(5):363-80
references.pmid: 21280455
references.citation: J Cereb Blood Flow Metab. 1998 Feb;18(2):196-205
references.pmid: 9469163
references.citation: Stroke. 2009 Apr;40(4):1082-90
references.pmid: 19211488
references.citation: J Neuroendocrinol. 2007 Feb;19(2):77-81
references.pmid: 17214869
references.citation: Psychoneuroendocrinology. 2011 Feb;36(2):182-92
references.pmid: 20696528
references.citation: Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11741-6
references.pmid: 14504383
references.citation: Neuroscience. 2005;135(1):59-72
references.pmid: 16084662
references.citation: Neuroscience. 2010 Sep 29;170(1):54-66
references.pmid: 20619320
references.citation: Brain Res Brain Res Rev. 2005 Apr;48(2):273-86
references.pmid: 15850667
references.citation: Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2792-6
references.pmid: 11226319
references.citation: J Neurochem. 2004 Oct;91(1):99-109
references.pmid: 15379891
references.citation: J Clin Epidemiol. 1998 Dec;51(12):1271-6
references.pmid: 10086819
references.citation: Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14670-5
references.pmid: 19667196
references.citation: Eur J Pharmacol. 2000 Jul 21;400(2-3):205-9
references.pmid: 10988335
references.citation: Nat Chem Biol. 2006 Apr;2(4):207-12
references.pmid: 16520733
references.citation: J Neurosci. 2009 Dec 2;29(48):15323-30
references.pmid: 19955385
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2711-6
references.pmid: 18263738
references.citation: Endocrinology. 2005 Jul;146(7):3070-9
references.pmid: 15817665
references.citation: Nat Rev Endocrinol. 2009 Nov;5(11):620-7
references.pmid: 19844249
references.citation: J Neuroendocrinol. 2008 Aug;20(8):1023-7
references.pmid: 18540996
references.citation: J Cereb Blood Flow Metab. 2006 Sep;26(9):1103-13
references.pmid: 16437060
references.citation: Front Neuroendocrinol. 2009 Jul;30(2):239-58
references.pmid: 19427328
references.citation: Menopause. 2011 Sep;18(9):943-50
references.pmid: 21532511
references.citation: Am J Med. 2005 Dec 19;118 Suppl 12B:14-24
references.pmid: 16414323
references.citation: Gene. 2001 May 16;269(1-2):131-40
references.pmid: 11376945
references.citation: JAMA. 1998 Mar 4;279(9):688-95
references.pmid: 9496988
references.citation: Arterioscler Thromb Vasc Biol. 2010 Feb;30(2):340-5
references.pmid: 19834106
references.citation: J Neuroendocrinol. 2001 Jun;13(6):483-9
references.pmid: 11412334
references.citation: Endocr Rev. 2003 Apr;24(2):133-51
references.pmid: 12700177
references.citation: Eur J Neurosci. 2001 Feb;13(3):472-6
references.pmid: 11168553
references.citation: J Neurosci. 2011 Feb 16;31(7):2638-48
references.pmid: 21325532
references.citation: Biochim Biophys Acta. 2010 Oct;1800(10):1068-76
references.pmid: 20100548
references.citation: J Steroid Biochem Mol Biol. 2010 Feb 28;118(4-5):304-10
references.pmid: 19932751
references.citation: Endocrinology. 1997 Sep;138(9):4030-3
references.pmid: 9275096
references.citation: JAMA. 2004 Jun 23;291(24):2959-68
references.pmid: 15213207
references.citation: Psychoneuroendocrinology. 2002 Oct;27(7):835-41
references.pmid: 12183218
references.citation: Neuroscience. 2005;132(2):233-8
references.pmid: 15802177
references.citation: Neuroscience. 2008 Jun 23;154(2):556-62
references.pmid: 18511205
references.citation: J Neurochem. 2006 Dec;99(6):1543-54
references.pmid: 17064355
references.citation: Future Neurol. 2010 Jan 1;5(1):47-59
references.pmid: 20190872
references.citation: Proc Natl Acad Sci U S A. 2004 Aug 17;101(33):12354-7
references.pmid: 15302933
references.citation: J Steroid Biochem Mol Biol. 2007 Aug-Sep;106(1-5):151-6
references.pmid: 17588742
references.citation: Womens Health (Lond). 2009 Jan;5(1):39-48
references.pmid: 19102639
references.citation: Maturitas. 2008 Jul-Aug;60(3-4):185-201
references.pmid: 18775609
references.citation: J Cereb Blood Flow Metab. 2005 Apr;25(4):502-12
references.pmid: 15689952
references.citation: Antioxid Redox Signal. 2011 Apr 15;14(8):1505-17
references.pmid: 20812869
references.citation: J Neurosci. 1999 Feb 15;19(4):1179-88
references.pmid: 9952396
references.citation: Endocrine. 2004 Aug;24(3):195-202
references.pmid: 15542885
references.citation: J Comp Neurol. 2001 Jan 15;429(3):355-71
references.pmid: 11116225
references.citation: Proc Natl Acad Sci U S A. 2010 Nov 9;107(45):19543-8
references.pmid: 20974957
references.citation: Stroke. 1996 Jun;27(6):1124-9
references.pmid: 8650725
references.citation: J Cardiovasc Transl Res. 2009 Sep;2(3):228-39
references.pmid: 19668346
references.citation: Brain Res. 2011 Mar 16;1379:53-60
references.pmid: 21138734
references.citation: JAMA. 2011 Apr 6;305(13):1305-14
references.pmid: 21467283
references.citation: Neurology. 2009 Jan 13;72(2):125-34
references.pmid: 19139363
references.citation: J Neurosci. 2006 Sep 13;26(37):9439-47
references.pmid: 16971528
references.citation: Eur J Biochem. 2001 Aug;268(15):4285-91
references.pmid: 11488923
references.citation: Endocr Rev. 2010 Apr;31(2):224-53
references.pmid: 20019127
references.citation: Ann Neurol. 2008 Dec;64(6):654-63
references.pmid: 19107988
references.citation: J Cereb Blood Flow Metab. 2004 Mar;24(3):298-304
references.pmid: 15091110
references.citation: Int J Alzheimers Dis. 2011 Mar 22;2011:104545
references.pmid: 21547208
references.citation: JAMA. 2000 Feb 23;283(8):1007-15
references.pmid: 10697060
references.citation: Neurosci Lett. 2008 Aug 15;441(1):94-9
references.pmid: 18586395
references.citation: Circulation. 2007 Feb 20;115(7):840-5
references.pmid: 17309934
references.citation: Neurology. 2007 Sep 11;69(11):1074-83
references.pmid: 17761551
references.citation: Neurochem Res. 2005 Jun-Jul;30(6-7):779-90
references.pmid: 16187213
references.citation: ILAR J. 2004;45(2):147-59
references.pmid: 15111734
references.citation: Steroids. 2007 May;72(5):381-405
references.pmid: 17379265
references.citation: Menopause. 2006 Jan-Feb;13(1):28-36
references.pmid: 16607096
references.citation: Neurobiol Aging. 2008 Jan;29(1):95-101
references.pmid: 17030472
references.citation: Adv Drug Deliv Rev. 2008 Oct-Nov;60(13-14):1504-11
references.pmid: 18647624