Estrogens, progestins, menopause and neurodegeneration: basic and clinical studies.
Two classes of ovarian steroids, estrogens and progestins, are potent in protecting neurons against acute toxic events as well as chronic neurodegeneration. Herein we review the evidence for neuroprotection by both classes of steroids, provide plausible mechanisms for these potent neuroprotective activities and indicate the need for further clinical trials of both estrogens and progestins in protection against acute and chronic conditions that cause neuronal death. Estrogens at concentrations ranging from physiological to pharmacological are neuroprotective in a variety of in vitro and in vivo models of cerebral ischemia and brain trauma as well as in reducing key neuropathologies of Alzheimer's disease. While the mechanisms of this potent neuroprotection are currently unresolved, a mitochondrial mechanism is involved. Progestins have been recently shown to activate many of the signaling pathways used by estrogens to neuroprotect, and progestins have been shown to protect against neuronal loss in vitro and in vivo in a variety of models of acute insult. Collectively, results of these animal and tissue culture models suggest that the loss of both estrogens and progestins at the menopause makes the brain more vulnerable to acute insults and chronic neurodegenerative diseases. Further clinical assessment of appropriate regimens of estrogens, progestins and their combination are supported by these data.
Simpkins
J W
JW
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas 76107, USA. jsimpkin@hsc.unt.edu
Yang
S-H
SH
Wen
Y
Y
Singh
M
M
D000818:Animals; D002986:Clinical Trials as Topic; D019610:Cytoprotection / Q000187:drug effects; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008593:Menopause / Q000502:physiology*; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D011372:Progestins / Q000378:metabolism / Q000494:pharmacology*
D004967:Estrogens; D018696:Neuroprotective Agents; D011372:Progestins
EuroIntervention. 2013 May 20;9(1):84-90
23579108
EuroIntervention. 2015 Mar;10(11):1354-60
25798568
J Am Coll Cardiol. 2015 Jul 21;66(3):278-307
26184622
Eur J Heart Fail. 2014 Nov;16(11):1223-9
25314900
J Am Coll Cardiol. 2014 Mar 11;63(9):914-9
24076529
JACC Cardiovasc Interv. 2014 Apr;7(4):394-402
24630887
J Am Coll Cardiol. 2005 Feb 1;45(3):381-7
15680716
N Engl J Med. 2014 Jan 2;370(1):23-32
24245543
Ann Cardiothorac Surg. 2015 May;4(3):220-9
26309823
Eur Heart J. 2015 Oct 21;36(40):2733-41
26233850
Circulation. 2013 May 7;127(18):1870-6
23569153
J Am Coll Cardiol. 2013 Jul 23;62(4):317-28
23665364
Curr Cardiol Rep. 2014 Aug;16(8):517
24957516
JACC Cardiovasc Interv. 2012 Jan;5(1):105-11
22230156
Clin Res Cardiol. 2014 Feb;103(2):85-96
24022331
J Am Coll Cardiol. 2013 Oct 15;62(16):e147-239
23747642
J Am Coll Cardiol. 2015 Jul 21;66(3):308-21
26184623
Circulation. 2013 Apr 9;127(14 ):1485-92
23459614
J Am Coll Cardiol. 2014 Jul 15;64(2):182-92
24184254
J Am Coll Cardiol. 2009 Nov 17;54(21):1961-8
19909877
J Thorac Cardiovasc Surg. 2009 Dec;138(6):1339-48
19660385
Eur Heart J. 2007 Jun;28(11):1358-65
17350971
Eur Heart J. 2016 Jan 7;37(2):133-9
26152116
N Engl J Med. 2014 Dec 4;371(23):2178-88
25405390
Eur J Heart Fail. 2013 Jul;15(7):786-95
23325017
N Engl J Med. 2011 Apr 14;364(15):1395-406
21463154
J Am Coll Cardiol. 2010 Aug 10;56(7):570-8
20688212
Eur J Cardiothorac Surg. 2012 Sep;42(3):524-9
22491659
J Am Coll Cardiol. 2014 Jul 15;64(2):172-81
25011722
J Am Coll Cardiol. 2014 Sep 2;64(9):875-84
25169171
Eur Heart J. 2012 Oct;33(19):2451-96
22922415
J Am Coll Cardiol. 2014 Jun 10;63(22):e57-185
24603191
Catheter Cardiovasc Interv. 2015 Oct;86(4):728-35
25601532
N Engl J Med. 2011 Apr 28;364(17):1607-16
21463150
Circulation. 2012 May 29;125(21):2639-48
22553307
Eur Heart J. 2015 Jul 7;36(26):1651-9
25870204
Eur Heart J. 2010 Aug;31(16):1958-66
20624767
Circulation. 2012 Nov 20;126(21):2502-10
23136163
Lancet. 2006 Sep 16;368(9540):1005-11
16980116
J Am Coll Cardiol. 2013 Sep 17;62(12):1052-61
23747789
Eur Heart J. 2015 Oct 21;36(40):2742-4
26261289
Nat Rev Cardiol. 2011 Mar;8(3):162-72
21263455