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Estrogen and selective estrogen receptor modulators

Neuroprotection in the women’s health initiative era

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Abstract

Estrogen has been comprehensively studied as a neuroprotective agent in women, animals, and a variety of in vitro models of neural injury and degeneration. Most data suggest that estrogen can benefit the ischemic brain and reduce cell death. However, recent data from the Women’s Health Initiative have raised concerns about the utility and safety of chronic estrogen use in women. While estrogen is a potent and reproducible neuroprotectant in animals and in vitro, its current administration in women has had unanticipated and paradoxical effects. Nonetheless, estrogen’s diverse actions make it an ideal prototype for developing new neuroprotectants such as selective estrogen receptor modulators (SERMs). SERMs represent a class of drugs with mixed estrogen agonistic and antagonistic activity. Experimental and clinical data suggest a neuroprotective role for SERMs in normal and injured brain. The discrepancy among observational studies, preclinical data, and clinical trials emphasizes the need for further study of the mechanisms leading to the increased incidence of stroke observed in postmenopausal women. Research is still needed to optimize combined or estrogen alone hormone replacement therapy options as well as the prevention/management of cerebrovascular/central nervous system disorders. This review critiques estrogen and SERMs’ neuroprotective potential in experimental and clinical studies of stroke and cerebrovascular disease.

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References

  1. Writing Group for the Women’s Health Initiative Investigators. (2002). JAMA 288(3), 321–333.

    Google Scholar 

  2. Langer, R. D. (2002). Am. J. Cardiol. 89(Suppl. 12), 36E-46E.

    PubMed  CAS  Google Scholar 

  3. Paganini-Hill, A. (2001). Maturitas 38, 243–261.

    PubMed  CAS  Google Scholar 

  4. Hulley, S., Grady, D., Bush, T., et al. (1998). JAMA 280(7), 605–613.

    PubMed  CAS  Google Scholar 

  5. Grady, D., Herrington, D. Bittner, V., et al. (2002). JAMA 288(1), 49–57.

    PubMed  Google Scholar 

  6. Viscoli, C. M., Brass, L. M., Kernan, W. N., Sarrel, P. M., Suissa, S., and Horowitz, R. I. (2001). N. Engl. J. Med. 345, 1243–1249.

    PubMed  CAS  Google Scholar 

  7. Murphy, S. J., Traystman, R. J., and Hurn, P. D. (2000). Stroke 31, 1173–1178.

    PubMed  CAS  Google Scholar 

  8. Adams, M. R., Register, T. C., Golden, D. L., Wagner, J. D., and Williams, J. K. (1997). Arterioscler. Thromb. Vasc. Biol. 17, 217–221.

    PubMed  CAS  Google Scholar 

  9. Williams, J. K., Honore, E. K., Washburn, S. A., and Clarkson, T. B. (1994). J. Am. Col.. Cardiol. 24, 1757–1761.

    Article  CAS  Google Scholar 

  10. Herrington, D. M., Reboussin, D. M., and Brosnihan, B. (2000). N. Engl. J. Med. 343, 522–529.

    PubMed  CAS  Google Scholar 

  11. Cherry, N., Gilmour, K., Hannaford, P., et al. (2002). Lancet 360(9350), 2001–2008.

    PubMed  CAS  Google Scholar 

  12. Nelson, H. D., Humphrey, L. L., Nygren, P., Teutsch, S. M., and Allan, J. D. (2002). JAMA 288, 872–881.

    PubMed  CAS  Google Scholar 

  13. Alkayed, N. J., Harukuni, I., Kimes, A. S., London, E. D., Traystman, R. J., and Hurn, P. D. (1998). Stroke 29, 159–166.

    PubMed  CAS  Google Scholar 

  14. Carswell, H. V. O., Anderson, N. H., Clark, J. S., et al. (1999). Hypertension 33, 681–685.

    PubMed  CAS  Google Scholar 

  15. Hall, E. D., Pazara, K. E., and Linseman, K. L. (1991). J. Cereb. Blood Flow Metab. 11, 292–298.

    PubMed  CAS  Google Scholar 

  16. Hurn, P. D., Aardelt, A. A., Alkayed, N. J., et al. (2002). In: Pharmacology of cerebral ischemia 2002. Krieglstein, J. (ed.). Medpharm Scientific: Stuttgart, Germany.

    Google Scholar 

  17. Hurn, P. D. and Macrae, I. M. (2000). J. Cereb. Blood Flow Metab. 20, 631–652.

    Article  PubMed  CAS  Google Scholar 

  18. Li, K., Futrell, N., Tovar, J. S., Wang, L. C., Wang, D. Z., and Schultz, L. R. (1996). Stroke 27, 498–503.

    PubMed  CAS  Google Scholar 

  19. Payan, H. M. and Conard, J. R. (1977). Stroke 8, 194–196.

    PubMed  CAS  Google Scholar 

  20. Wise, P. M., Dubal, D. B., Wilson, M. E., Rau, S. W., Bottner, M., and Rosewell, K. L. (2001). Brain Res. Rev. 37, 313–319.

    PubMed  CAS  Google Scholar 

  21. Yamori, Y., Horie, R., Sato, M., and Ohta, K. (1976). Jpn. Heart J. 17(3), 404–406.

    PubMed  CAS  Google Scholar 

  22. Zhang, Y. Q., Shi, J., Rajakumar, G., Day, A. L., and Simpkins, J. W. (1998). Brain Res. 784, 321–324.

    PubMed  CAS  Google Scholar 

  23. Liao, S. L., Chen, W. Y., Kuo, J. S., and Chen, C. J. (2001). Neurosci. Lett. 297, 159–162.

    PubMed  CAS  Google Scholar 

  24. Carswell, H. V. O., Dominiczak, A. F., and Macrae, I. M. (2000). Am. J. Physiol. Heart Circ. Physiol. 278, H290-H294.

    PubMed  CAS  Google Scholar 

  25. Dubal, D. B., Kashon, M. L., Pettigrew, L. C., et al. (1998). J. Cereb. Blood Flow Metab. 18, 1253–1258.

    PubMed  CAS  Google Scholar 

  26. Fukuda, K., Yao, H., Ibayashi, S., Nakahara, T., Uchimura, H., and Fujishima, M. (2000). Stroke 31, 155–160.

    PubMed  CAS  Google Scholar 

  27. Rusa, R., Alkayed, N. J., Crain, B. J., et al. (1999). Stroke 30, 1665–1670.

    PubMed  CAS  Google Scholar 

  28. Simpkins, J. W., Rajakumar, G., Zhang, Y. Q., et al. (1997). J. Neurosurg. 87(5), 724–730.

    Article  PubMed  CAS  Google Scholar 

  29. Wang, Q., Santizo, R., Baughman, V. L., and Pelligrino, D. A. (1999). Stroke 30, 630–637.

    PubMed  CAS  Google Scholar 

  30. Alkayed, N. J., Murphy, S. J., Traystman, R. J., and Hurn, P. D. (2000). Stroke 31, 161–168.

    PubMed  CAS  Google Scholar 

  31. Dhandapani, K. M. and Brann, D. W. (2002). Biol. Reprod. 67, 1379–1385.

    PubMed  CAS  Google Scholar 

  32. Green, P. S. and Simpkins, J. W. (2000). Int. J. Dev. Neurosci. 18, 347–358.

    PubMed  CAS  Google Scholar 

  33. Wise, P. M. and Dubal, D. B. (2000). Biol. Reprod. 63, 982–985.

    PubMed  CAS  Google Scholar 

  34. Harukuni, I., Hurn, P. D., and Crain, B. J. (2001). Brain Res. 900, 137–142.

    PubMed  CAS  Google Scholar 

  35. Hurn, P. D., Littleton-Kearney, M. T., Kirsch, J. R., Dharmaragan, A. M., and Traystman, R. J. (1995). J. Cereb. Blood Flow Metab. 15(4), 666–672.

    PubMed  CAS  Google Scholar 

  36. McCullough, L. D., Alkayed, N. J., Traystman, R. J., Williams, M. J., and Hurn, P. D. (2001). Stroke 32, 796–802.

    PubMed  CAS  Google Scholar 

  37. Watanabe, Y., Littleton-Kearney, M. T., Traystman, R. J., and Hurn, P. D. (2001). Am. J. Physiol. Heart Circ. Physiol. 281(1), H155-H160.

    PubMed  CAS  Google Scholar 

  38. Dubal, D. B., Zhu, H., Yu, J., et al. (2001). Proc. Natl. Acad. Sci. USA 98(4), 1952–1957.

    PubMed  CAS  Google Scholar 

  39. Sampei, K., Goto, S., Alkayed, N. J., et al. (2000). Stroke 31 (3), 738–743.

    PubMed  CAS  Google Scholar 

  40. Sawada, M., Alkayed, N. J., Goto, S., et al. (2000). J. Cereb. Blood Flow Metab. 20(1), 112–118.

    PubMed  CAS  Google Scholar 

  41. Falkenstein, E., Tillman, H. C., Christ, M., Feuring, M., and Wehling, M. (2000). Pharmacol. Rev. 52(4), 513–556.

    PubMed  CAS  Google Scholar 

  42. Linford, N., Wade, C., and Dorsa, D. (2000). J. Neurocytol. 29, 367–374.

    PubMed  CAS  Google Scholar 

  43. Kume-Kick, J. and Rice, M. E. (1998). Brain Res. 803, 105–113.

    PubMed  CAS  Google Scholar 

  44. Mooradian, A. D. (1993). J. Steroid Biochem. Mol. Biol. 45, 509–511.

    PubMed  CAS  Google Scholar 

  45. Ernst, T., Chang, L., Cooray, D., et al. (2002). J. Natl. Cancer Inst. 94(8), 592–597.

    PubMed  CAS  Google Scholar 

  46. Chang, L., Ernst, T., Poland, R. E., and Jenden, D. J. (1996). Life Sci. 58, 2049–2056.

    PubMed  CAS  Google Scholar 

  47. Ganz, P. A., Castellon, S. A., and Silverman, D. H. S. (2002). J. Natl. Cancer Inst. 94(8), 547–549.

    PubMed  Google Scholar 

  48. Resnick, S. M. and Maki, P. M. (2001). Ann. NY Acad. Sci. 949, 203–214.

    Article  PubMed  CAS  Google Scholar 

  49. Yaffe, K., Krueger, K., Sarkar, S., et al. (2001). N. Engl. J. Med. 344(16), 1207–1213.

    PubMed  CAS  Google Scholar 

  50. Schagen, S. B., van Dam, F. S., Muller, M. J., Boogerd, W., Lindeboom, J., and Bruning, P. F. (1999). Cancer 85, 640–650.

    PubMed  CAS  Google Scholar 

  51. Paganini-Hill, A. and Clark, L. J. (2000). Breast Cancer Res. Treat. 64, 165–176.

    PubMed  CAS  Google Scholar 

  52. Breuer, B. and Anderson, R. (2000). Women Health 31(1), 71–85.

    PubMed  CAS  Google Scholar 

  53. Day, R., Ganz, P. A., Costantino, J. P., Cronin, W. M., Wickerham, D. L., and Fisher, B. (1999). J. Clin. Oncol. 17(9), 2659–2669.

    PubMed  CAS  Google Scholar 

  54. Day, R., Ganz, P. A., and Costantino, J. P. (2001). J. Natl. Cancer Inst. 93, 1615–1623.

    Article  PubMed  CAS  Google Scholar 

  55. Nickelsen, T., Lufkin, E. G., Riggs, B. L., Cox, D. A., and Crook, T. H. (1999). Psychoneuroendocrinology 24, 115–128.

    PubMed  CAS  Google Scholar 

  56. Strickler, R., Stovall, D. W., Merritt, D., Shen, W., Wong, M., and Silfen, S. L. (2000). Obstet. Gynecol. 96(3), 359–365.

    PubMed  CAS  Google Scholar 

  57. Neele, S. J. M., Rombouts, S., Bierlaagh, M. A., Barkhof, F., Scheltens, P., and Netelenbos, J. C. (2001). J. Clin. Endocrinol. Metab. 86(3), 1422–1424.

    PubMed  CAS  Google Scholar 

  58. Barrett-Connor, E., Grady, D., Sashegyi, A., et al. (2002). JAMA 287, 847–857.

    PubMed  CAS  Google Scholar 

  59. Barrett-Connor, E., Grady, D., Sashegyi, A., et al. (2002). American Heart Scientific Sessions, abstract ID 100292.

  60. Littleton-Kearney, M. T., Ostrowski, N. L., Cox, D. A., Rossberg, M. I., and Hurn, P. D. (2002). CNS Drug Rev. 8(3), 309–330.

    Article  PubMed  CAS  Google Scholar 

  61. Zhou, W., Koldzic-Zivanovic, N., Clarke, C. H., et al. (2002). Neuroendocrinology 75, 24–33.

    PubMed  CAS  Google Scholar 

  62. Nilsen, J., Mor, G., and Naftolin, F. (1998). Menopause 5, 211–216.

    PubMed  CAS  Google Scholar 

  63. Silva, I., Mello, L. E., Freymuller, E., Haidar, M. A., and Baracat, E. C. (2000). Neurosci. Lett. 291, 183–186.

    PubMed  CAS  Google Scholar 

  64. McEwen, B. (2002). Recent Prog. Horm. Res. 57, 357–384.

    PubMed  CAS  Google Scholar 

  65. McEwen, B. S., Alves, S. E., Bullock, K., and Weiland, N. G. (1997). Neurology 48, S8-S15.

    PubMed  CAS  Google Scholar 

  66. Cyr, M., Ghribi, O., Thibault, C., Morissette, M., Landry, M., and Di Paolo, T. (2001). Brain Res. Rev. 37, 153–161.

    PubMed  CAS  Google Scholar 

  67. Cyr, M., Morissette, M., Landry, M., and Di Paolo, T. (2001). Neuroreport 12, 535–539.

    PubMed  CAS  Google Scholar 

  68. Cyr, M., Thibault, C., Morissette, M., Landry, M., and Di Paolo, T. (2001). Neuropyschopharmacology 25, 242–257.

    CAS  Google Scholar 

  69. Cyr, M., Bosse, R., and Di Paolo, T. (1998). Neuroscience 83, 826–836.

    Google Scholar 

  70. Cyr, M., Landry, M., and Di Paolo, T. (2000). Neuropyschopharmacology 23, 69–78.

    CAS  Google Scholar 

  71. Sumner, B. E., Grant, K. E., Rosie, R., Hegele-Hartung, C. H., Fritzemeier, K. H., and Fink, G. (1999). Mol. Brain Res. 73, 119–128.

    PubMed  CAS  Google Scholar 

  72. Ferretti, C., Blengio, M., Ghi, P., Racca, S., Genazzani, E., and Portaleone, P. (1988). Life Sci. 42(24), 2457–2465.

    PubMed  CAS  Google Scholar 

  73. Ferretti, C., Ghi, P., Blengio, M., Gaietta, G., and Genazzani, E. (1989). Pharmacol. Res. 21(1), 93–94.

    PubMed  CAS  Google Scholar 

  74. Bethea, C. L., Mirkes, S. J., Su, A., and Michelson, D. (2002). PNEC 27, 431–445.

    CAS  Google Scholar 

  75. McMillan, P. J., LeMaster, A. M., and Dorsa, D. M. (2002). Mol. Brain Res. 103, 140–145.

    PubMed  CAS  Google Scholar 

  76. Wu, X., Glinn, M. A., Ostrawski, N. L., et al. (1999). Brain Res. 847, 98–104.

    PubMed  CAS  Google Scholar 

  77. Baksi, S. N., Redington, T. E., and Hughes, M. J. (1981). Neuropharmacology 20, 1163–1167.

    PubMed  CAS  Google Scholar 

  78. McDermott, J. L., Liu, B., and Dluzen, D. E. (1995). Brain Res. 698, 248–252.

    PubMed  CAS  Google Scholar 

  79. Baksi, S. N., Hughes, M. J., and Lights, K. E. (1985). Neuroscience 14(4), 1053–1059.

    PubMed  CAS  Google Scholar 

  80. Etgen, A. M. and Shamamian, P. (1986). Horm. Behav. 20, 166–180.

    PubMed  CAS  Google Scholar 

  81. McKenna, S. E., Simon, N. G., and Cologer-Clifford, A. (1992). Horm. Behav. 26, 536–544.

    PubMed  CAS  Google Scholar 

  82. Bryant, H. U., Glasebrook, A. L., Yang, N. N., and Sato, M. (1996). J. Bone Miner. Metab. 14, 1–9.

    CAS  Google Scholar 

  83. Rossberg, M. I., Murphy, S. J., Traystman, R. J., and Hurn, P. D. (2000). Stroke 31, 3041–3046.

    PubMed  CAS  Google Scholar 

  84. Kimelberg, H. K., Feustel, P. J., Jin, Y., et al. (2000). Neuroreport 11, 2675–2679.

    PubMed  CAS  Google Scholar 

  85. Mehta, S. J., Dhandapani, K. M., Webb, R. C., Mahesh, V. B., and Brann, D. W. (2001). Soc. Neurosci. Abstr. 27, 437.11.

    Google Scholar 

  86. Osuka, K., Feustel, P. J., Mongin, A. A., Tranmer, B. I., and Kimelberg, H. K. (2001). J. Neurochem. 76, 1842–1850.

    PubMed  CAS  Google Scholar 

  87. Phillis, J. W., Song, D., and O’Regan, M. H. (1998). Brain Res. 780, 352–355.

    PubMed  CAS  Google Scholar 

  88. Choi, D. W. (1988). Neuron 1, 623–634.

    PubMed  CAS  Google Scholar 

  89. Shy, H., Malaiyandi, L., and Timiras, P. S. (2000). Int. J. Dev. Neurosci. 18, 289–297.

    PubMed  CAS  Google Scholar 

  90. Hoyt, K. R., McLaughlin, B. A., Higgins, D. S. Jr., and Reynolds, I. J. (2000). J. Pharm. Exp. Ther. 293, 480–486.

    CAS  Google Scholar 

  91. Obata, T. (2002). Neurochem. Res. 27(5), 423–431.

    PubMed  CAS  Google Scholar 

  92. Obata, T. and Kubota, S. (2001). Neurosci. Lett. 308, 87–90.

    PubMed  CAS  Google Scholar 

  93. Callier, S., Morissette, M., Grandbois, M., Pelaprat, D., and Di Paolo, T. (2001). Synapse 41, 131–138.

    PubMed  CAS  Google Scholar 

  94. Grandbois, M., Morissette, M., Callier, S., and DiPaolo, R. (2000). Neuroreport 11, 343–346.

    PubMed  CAS  Google Scholar 

  95. Shi, J., Bui, J. D., Yang, S. H., et al. (2001). Stroke 32, 987–992.

    PubMed  CAS  Google Scholar 

  96. Vergouwen, M. D. I., Anderson, R. E., and Meyer, F. B. (2000). Brain Res. 878, 88–97.

    PubMed  CAS  Google Scholar 

  97. Toung, T. J. K., Traystman, R. J., and Hurn, P. D. (1998). Stroke 29, 1666–1670.

    PubMed  CAS  Google Scholar 

  98. Hawk, T., Zhang, Y. Q., Rajakumar, G., Day, A. L., and Simpkins, J. W. (1998). Brain Res. 796(1–2), 296–298.

    PubMed  CAS  Google Scholar 

  99. Dubal, D. B. and Wise, P. M. (2001). Endocrinology 142(1), 43–48.

    PubMed  CAS  Google Scholar 

  100. Saleh, T. M., Cribb, A. E., and Connell, B. J. (2001). Am. J. Physiol. Regul. Integrative Comp. Physiol. 281, R2088-R2095.

    CAS  Google Scholar 

  101. Saleh, T. M., Cribb, A. E., and Connell, B. J. (2001b). Am. J. Physiol. Regul. Integrative Comp. Physiol. 281, R1531-R1539.

    CAS  Google Scholar 

  102. Culmsee, C., Vedder, H., Ravati, A., et al. (1999). J. Cereb. Blood Flow Metab. 19(11), 1263–1269.

    PubMed  CAS  Google Scholar 

  103. He, Z., He, Y. J., Day, A. L., and Simpkins, J. W. (2002). J. Neurol. Sci. 193, 79–87.

    PubMed  CAS  Google Scholar 

  104. Pelligrino, D. A., Santizo, R., Baughman, V. L., and Want, Q. (1998). Neuroreport 9, 3285–3291.

    PubMed  CAS  Google Scholar 

  105. Horsburgh, K., Macrae, I. M., and Carswell, H. (2002). J. Cereb. Blood Flow Metab. 22, 1189–1195.

    PubMed  CAS  Google Scholar 

  106. Jover, T., Tanaka, H., Calderone, A., et al. (2002). J. Neurosci. 22(6), 2115–2124.

    PubMed  CAS  Google Scholar 

  107. Chen, J., Adachi, N., Liu, K., and Arai, T. (1998). Neuroscience 87(4), 817–822.

    PubMed  CAS  Google Scholar 

  108. Chen, J., Weiren, X., and Jiang, H. (2001). Anesth. Analg. 92, 1520–1523.

    PubMed  CAS  Google Scholar 

  109. Sudo, S., Wen, T. C., Desaki, J., et al. (1997). Neurosci. Res. 29, 345–354.

    PubMed  CAS  Google Scholar 

  110. Davis, S. R. (2002). In: Selective estrogen receptor modulators: research and clinical applications. Manni, A. and Verderame, M. F. (eds.). Humana: Totowa, NJ.

    Google Scholar 

  111. Goldstein, J. S. and Sites, C. K. (2002). Ageing Res. Rev. 1, 17–28.

    PubMed  CAS  Google Scholar 

  112. Labrie, F., Labrie, C., Belanger, A., and Simard, J. (2002). In: Selective estrogen receptor modulators: research and clinical applications. Manni, A. and Verderame, M. F. (eds.). Humana: Totowa, NJ.

    Google Scholar 

  113. Morello, K. C., Wurz, G. T., and DeGregorio, M. W. (2002). Crit. Rev. Oncol./Hematol. 43, 63–76.

    Google Scholar 

  114. Wardley, A. M. (2002). Int. J. Clin. Pract. 56(4), 305–309.

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, MD

    Stephanie J. Murphy, Marguerite T. Littleton-Kearney & Patricia D. Hurn

  2. Department of Neurology, Johns Hopkins Medical Institutions, Baltimore, MD

    Louise D. McCullough

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Murphy, S.J., McCullough, L.D., Littleton-Kearney, M.T. et al. Estrogen and selective estrogen receptor modulators. Endocr 21, 17–26 (2003). https://doi.org/10.1385/ENDO:21:1:17

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