Pharmacology of conjugated equine estrogens: Efficacy, safety and mechanism of action

Journal of Steroid Biochemistry and Molecular Biology

Volumn 142, Issue , 2014, Pages 16-29

  Bhavnani, Bhagu R ^a   Stanczyk, Frank Z ^b  

^a ST MICHAEL'S HOSPITAL   (Canada)

^b UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

Author keywords

Alzheimer's disease; Apoptosis; Cardiovascular disease; Conjugated equine estrogens; Excitotoxicity; LDL oxidation

Indexed keywords

ANTIOXIDANT; CHOLESTEROL; CONJUGATED ESTROGEN; EQUILENIN; EQUILIN; ESTRADIOL; ESTROGEN; ESTROGEN RECEPTOR ALPHA; ESTROGEN RECEPTOR BETA; ESTRONE; GESTAGEN; GLUTAMIC ACID; HIGH DENSITY LIPOPROTEIN; LIPOPROTEIN; NEUROTOXIN; OXIDIZED LOW DENSITY LIPOPROTEIN; PROTEINASE;

ALZHEIMER DISEASE; ANTIOXIDANT ACTIVITY; APOPTOSIS; CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; DRUG ABSORPTION; DRUG EFFICACY; DRUG FORMULATION; DRUG MECHANISM; DRUG SAFETY; HEART PROTECTION; HORMONAL THERAPY; HOT FLUSH; HUMAN; IN VITRO STUDY; INSOMNIA; MARE; MENOPAUSAL SYNDROME; METABOLIC CLEARANCE RATE; MOOD DISORDER; NERVE CELL NECROSIS; NEUROPROTECTION; NONHUMAN; OSTEOPOROSIS; OXIDATION; REVIEW; STEADY STATE; STEROIDOGENESIS; VAGINITIS;

EQUIDAE;

ALZHEIMER'S DISEASE; APOPTOSIS; CARDIOVASCULAR DISEASE; CONJUGATED EQUINE ESTROGENS; EXCITOTOXICITY; LDL OXIDATION;

ALZHEIMER DISEASE; ANTIOXIDANTS; CARDIOVASCULAR DISEASES; ESTROGENS, CONJUGATED (USP); FEMALE; HUMANS; MALE; OSTEOPOROSIS, POSTMENOPAUSAL;

EID: 84899899349     PISSN: 09600760     EISSN: 18791220     Source Type: Journal    
DOI: 10.1016/j.jsbmb.2013.10.011     Document Type: Review

References (174)

1. J.M. Grodin, P.K. Siiteri, and P.C. MacDonald Source of estrogen production in postmenopausal women J. Clin. Endocrinol. Metab. 36 1973 207 214
2. C. Longcope Metabolic clearance and blood production rates of estrogens in postmenopausal women Am. J. Obstet. Gynecol. 111 1971 778 781
3. B.R. Bhavnani The saga of the ring B unsaturated equine estrogens Endocr. Rev. 9 1988 396 416
4. B.R. Bhavnani Pharmacokinetics and pharmacodynamics of conjugated equine estrogens: chemistry and metabolism Proc. Soc. Exp. Biol. Med. 217 1998 6 16
5. 3H-equilin in the pregnant mare Endocrinology 108 1981 232 238
6. R.P. Howard, and K.C. Keaty Evaluation of equilin-3-monosulfate and other estrogens Arch. Intern. Med. 128 1971 229 233
7. R.L. Lobo, H.N. Nguyen, P. Eggena, and P.F. Brenner Biologic effects of equilin sulfate in postmenopausal women Fertil. Steril. 49 1988 234 238
8. C.A. Mashchak, R.A. Lobo, R. Dozono-Takono, P. Eggena, R.M. Nakamura, P.F. Brenner, and D.R. Mishell Jr. Comparison of pharmacodynamic properties of various estrogen formations Am. J. Obstet. Gynecol. 144 1982 511 518
9. B.R. Bhavnani, A. Cecutti, and M.S. Dey Biologic effects of delta-8-estrone sulfate in postmenopausal women J. Soc. Gynecol. Investig. 5 1998 156 160
10. 3H]equilin sulfate after oral and intravenous administration in normal posmenopausal women and men J. Clin. Endocrinol. Metab. 68 1989 757 765
11. H.J. Ruder, D.L. Loriaux, and M.B. Lipsett Estrone sulfate: Production rate and metabolism in man J. Clin. Invest. 51 1972 1020 1033
12. C. Longcope The metabolism of estrone sulfate in normal males J. Clin. Endocrinol. Metab. 68 1989 757 765
13. B.R. Bhavnani, I.R. Sarda, and C.A. Woolever Radioimmunoassay of plasma equilin and estrone in postmenopausal women after administration of Premarin J. Clin. Endocrinol. Metab. 52 1981 741 747
14. D.E. Englund, and E.D.B. Johansson Plasma levels of oestrone-oestradiol and gonadotrophins in postmenopausal women after oral and vaginal administration of conjugated equine oestrogens (Premarin) Br. J. Obstet. Gynaecol. 85 1978 957 964
15. A.B.M. Anderson, E. Sklovsky, L. Sayers, P. Steele, and A.C. Turbull Comparison of serum oestrogen concentrations in postmenopausal women taking estrone sulfate and oestradiol Br. Med. J. 1 1978 140 142
16. S. Deutsch, R. Ossowski, and I. Benjamin Comparison of estrogens from vaginal and oral administered estrogens at different dose levels in postmenopausal women Am. J. Obstet. Gynecol. 139 1981 967 968
17. F.P. Mandel, F.L. Geola, D.R. Meldrum, J.H. Lu, P. Eggena, M.P. Sambhi, J.M. Hershman, and H.L. Judd Biological effects of various doses of vaginally administered conjugated equine estrogens in postmenopausal women J. Clin. Endocrinol. Metab. 57 1983 133 139
18. R.A. Lobo Absorption and metabolic effects of different types of estrogens and progestogens Obstet. Gynecol. Clin. North Am. 14 1987 143 167
19. J.F. Tait, and S. Burstein In vivo studies of steroid dynamics in man G. Pincus, K.V. Thimann, E.B. Astwood, The Hormones, Vol. 4, 1964 Acad. Press New York 451 457
20. B.R. Bhavnani, C.A. Woolever, H. Benoit, and T. Wong Pharmacokinetics of equilin and equilin sulfate in normal postmenopausal women and men J. Clin. Endocrinol. Metab. 56 1983 1048 1056
21. B.R. Bhavnani, and A. Cecutti Pharmacokinetics of 17β-dihydroequilin sulfate and 17β-dihydroequilenin in normal postmenopausal women J. Clin. Endocrinol. Metab. 78 1994 197 204
22. B.R. Bhavnani, and A. Cecutti Metabolic clearance rate of equilin sulfate, and its conversion to plasma equilin, conjugated and unconjugated equilenin, 17β-dihydroequilin, and 17β-dihydroequilenin in normal and postmenopausal women and men under steady state conditions, J Clin. Endocrinol. Metab. 77 1993 1269 1274
23. B.R. Bhavnani, A. Cecutti, and A.H. Gerulath Pharmacokinetics of 17β-dihydroequilin sulfate in normal postmenopausal women under steady state conditions J. Soc. Gynecol. Investig. 9 2002 102 112
24. C. Longcope, D.S. Layne, and J.F. Tait Metabolic clearance rates and interconversions of estrone and 17β-estradiol in normal males and females J. Clin. Invest. 47 1968 93 106
25. D.T. Baird, R. Horton, C. Longcope, and J.F. Tait Steroid dynamics under steady state conditions Recent Prog. Horm. Res. 25 1969 611 644
26. 8-estrone in postmenopausal women and men J. Steroid Biochem. Mol. Biol. 67 1998 119 131
27. C.C. Pan, C.A. Woolever, and B.R. Bhavnani Transport of equine estrogens: Binding of conjugated equine estrogens with human serum proteins J. Clin. Endocrinol. Metab. 61 1985 499 517
28. 3H]-equilin and malignant human endometrium and endometrial adenocarcinoma transplanted into nude mice J. Steroid Biochem. Mol. Biol. 38 1991 433 439
29. B.R. Bhavnani, S.P. Tam, and L.U. Xiaofeng Structure activity relationships and differential interactions and functional activity of various equine estrogens mediated via estrogen receptors (ERs) ERα and ERβ Endocrinology 149 2008 4857 4870
30. L. Tseng, and E. Gurpide Estradiol and 20α-dihydroprogesterone dehydrogenase activities in human endometrium during the menstrual cycle Endocrinology 94 1974 419 423
31. W.L. Miller, and R.J. Auchus The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders Endocr. Rev. 32 2011 81 151
32. B.R. Bhavnani, A. Lau, A. Cecutti, and A. Gerulath Demonstration of 2 and 4-hydroxylation of equilin by normal proliferative and secretory human endometrial microsomal preparations 42nd Annual Meeting of the Society of Gynecological Investigations Chicago, USA, March 15-18 1995 424 (Abstract #415)
33. V.V. Reddy, P. Hanjani, and R. Rajan Synthesis of catechol estrogens by human uterus and leiomyoma Steroids 37 1981 195 203
34. J.A. Katzenllenbogen, B.W. O'Malley, and B.S. Katzenellenbogen Tripartite steroid hormone receptor pharmacology; interaction with multiple effector sites as a basis for the cell and promoter-specific action of these hormones Mol. Endocrinol. 10 1996 119 131
35. G.G. Kuiper, E. Enmark, M. Petto-Huikko, S. Nilsson, and J.A. Gustafsson Cloning of a novel receptor expressed in rat prostate and ovary Proc. Natl. Acad. Sci. U.S.A. 93 1996 5925 5930
36. S. Nilsson, and J.A. Gustafsson Biological role of estrogen and estrogen receptors Crit. Rev. Biochem. Mol. Biol. 37 2002 1 28
37. D.P. McDonnell The molecular determinants of estrogen receptor pharmacology Maturitas 48 2004 S7 S12
38. K. Dahlman-Wright, V. Cavailles, S.A. Fuqua, V.C. Jordan, J.A. Katzenellenbogen, K.S. Korach, A. Maggi, M. Muramatsu, M.G. Parker, and J.A. Gustafsson International Union of Pharmacology. LXIV. Estrogen receptors Pharmacol. Rev. 58 2006 773 781
39. B.R. Bhavnani, and C.A. Woolever Interaction of ring B unsaturated estrogens with estrogen receptors of human endometrium and rat uterus Steroids 56 1991 201 210
40. R.W. Hsich, S.R. Rajan, S.K. Sharma, and G.L. Greene Molecular characterization of a B-ring unsaturated estrogens: implications for conjugated equine estrogen components of Premarin Steroids 73 2008 59 68
41. L. Novensa, J. Selent, M. Pastor, K. Sandberg, M. Heras, and A.P. Dantas Equine estrogens impair nitric oxide production and endothelial nitric oxide synthase transcription in human endothelial cells compared with natural 17β-estradiol Hypertension 56 2010 405 411
42. J.M. Hall, and D.P. McDonnell The estrogen receptor β isoform (ERβ) of the human estrogen receptor modulates ERα transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens Endocrinology 140 1999 5566 5578
43. S.M. Aronica, W.L. Kraus, and B.S. Katzenellenbogen Estrogen action via cAMP signaling pathway: Stimulation of adenylate cyclase and cAMP-regulated gene transcription Proc. Natl. Acad. Sci. U.S.A. 91 1994 8517 8521
44. J. Tesarik, and L. Mendoza Nongenomic effects of 17β-estradiol on maturing human oocytes: relationship to oocyte developmental potential J. Clin. Endocrinol. Metab. 80 1995 1438 1443
45. M. Ranzandi, A. Pedram, G.L. Greene, and E.R. Levin Cell membrane and nuclear estrogen receptors (ERs) originate from a single transcript: studies of ERα and ERβ expressed in Chinese hamster ovary cells Mol. Endocrinol. 13 1999 307 319
46. R.G. Anderson The caveolae membrane system Annu. Rev. Biochem 67 1998 199 225
47. M.E. Mendelsohn, and R.H. Karas The protective effects of estrogen on the cardiovascular system N. Engl. J. Med. 340 1999 1801 1811
48. S.R. Hammes, and E.R. Levin Extranuclear steroid receptors: nature and actions Endocr. Rev. 28 2007 726 741
49. A.W. Norman, M.T. Mizwicki, and D.P. Norman Steroid hormone rapid actions, membrane receptors and a conformational ensemble model Nat. Rev. Drugs 3 2004 27 41
50. L. Bjornstrom, and M. Sjoberg Mechanisms of estrogen receptor signaling: Convergence of genomic and non-genomic actions on target genes Mol. Endocrinol. 19 2005 833 842
51. M.E. Mendelsohn Estrogen actions in the cardiovascular system Climacteric 12 Suppl. 1 2009 18 21
52. K.L. Chambliss, Q. Wu, S. Oltmann, E.S. Konaniah, M. Umetani, K.S. Korach, G.D. Thomas, C. Mineo, I.S. Yuhanna, S.H. Kim, Z. Madak-Erdogan, A. Maggi, S.P. Dineen, C.L. Roland, D.Y. Hui, R.A. Brekken, J.A. Katzenellenbogen, B.S. Katzenellenbogen, and P.W. Shaul Non-nuclear estrogen receptor α-signaling promotes cardiovascular protection but not uterine or breast growth in mice J. Clin. Invest. 120 2010 2319 2330
53. K. Ueda, and R.H. Karas Emerging evidence of the importance of rapid, non-nuclear estrogen receptor signaling in the cardiovascular system Steroids 78 2013 589 596
54. R. Lindsay, J.C. Gallagher, R. Kagan, J.H. Pickar, and G. Constantine Efficacy of tissue-selective estrogen complex of bazedoxifene/conjugated estrogens for osteoporosis prevention in at-risk postmenopausal women Fertil. Steril. 92 2009 1045 1052
55. D.F. Archer, J.V. Pinkerton, W.H. Utian, J.C. Menegoci, T.J. de Villiers, C.K. Yuen, A.B. Levine, A.A. Chines, and G.D. Constantine Bazedoxifene, a selective estrogen receptor modulator: effects on the endometrium, ovaries and on breast from a randomized controlled trial in osteoporotic postmenopausal women Menopause 16 2009 1109 1115
56. R. Kagan The tissue selective estrogen complex: a novel approach to the treatment of menopausal symptoms J. Womens Health 9 2012 975 981
57. V. Rossi, G. Bellastella, C. De Rosa, C. Abbondanza, D. Visconti, L. Maione, P. Chieffi, F. Della Ragione, D. Prezioso, A. De Bellis, A. Bellastella, and A.A. Sinisi Raloxifene induces cell death and inhibits proliferation through multiple signaling pathways in prostate cancer cells expressing different levels of estrogen receptor α and β J. Cell. Physiol. 226 2011 1334 1339
58. W.R. Kannel, M.C. Hjortland, P.M. McNamara, and T. Gordon Menopause and risk of cardiovascular disease. The Framingham Study Ann. Intern. Med. 85 1976 447 452
59. T.L. Bush, E. Barrett-Conner, and L.D. Cowan Cardiovascular mortality and non-contraceptive use of estrogens in women. Results from Lipid Research Clinics Programs Follow up Study Circulation 75 1987 1102 1109
60. G.A. Colditz, W.C. Willett, M.J. Stampfer, B. Rosner, F.E. Speizer, and C.H. Hennekens Menopause and the risk of coronary heart disease in women N. Engl. J. Med. 316 1987 1105 1110
61. M.J. Stampfer, G.A. Colditz, and W.C. Willett Postmenopausal estrogen therapy and cardiovascular disease N. Engl. J. Med. 325 1991 756 762
62. F. Grodstein, M.J. Stampfer, J.E. Manson, G.A. Colditz, W.C. Willett, B. Rosner, F.E. Speizer, and C.H. Hennekens Postmenopausal estrogen and progestin use and the risk of cardiovascular disease N. Engl. J. Med. 335 1996 453 461
63. D. Grady, S.M. Rubin, D.B. Petitti, C.S. Fox, D. Black, B. Ettinger, V.L. Ernster, and S.R. Cummings Hormone therapy to prevent disease and prolong life in postmenopausal women Ann. Intern. Med. 117 1992 1016 1037
64. S. Hulley, D. Grady, T. Bush, C. Furberg, D. Herrington, B. Riggs, and E. Vittinghoff 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 280 1998 605 613
65. D. Grady, D. Herrington, V. Bittner, R. Blumenthal, M. Davidson, M. Hlatky, J. Hsia, S. Hulley, A. Herd, S. Khan, L.K. Newby, D. Waters, E. Vittinghoff, and N. Wenger HERS Research Group, Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II) JAMA 288 2002 49 57
66. S. Hulley, C. Furberg, E. Barrett-Connor, J. Cauley, D. Grady, W. Haskell, R. Knopp, M. Lowery, S. Satterfield, H. Schrott, E. Vittinghoff, and D. Hunninghake HERS Research Group, Noncardiovascular disease outcomes during 6.8 years of hormone therapy, Heart and Estrogen/Progestin Replacement Study Follow-up (HERSII) JAMA 288 2002 58 66
67. J.E. Rossouw, G.L. Anderson, R.L. Prentice, A.Z. LaCroix, C. Kooperberg, M.L. Stefanick, R.D. Jackson, S.A. Beresford, B.V. Howard, K.C. Johnson, J.M. Kotchen, J. Ockene, and 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 288 2002 321 333
68. G.L. Anderson, M. Limacher, A.R. Assaf, T. Bassford, S.A. Beresford, H. Black, D. Bonds, R. Brunner, R. Brzyski, B. Caan, R. Chlebowski, D. Curb, M. Gass, J. Hays, G. Heiss, S. Hendrix, B.V. Howard, J. Hsia, A. Hubbell, R. Jackson, K.C. Johnson, H. Judd, J.M. Kotchen, L. Kuller, A.Z. LaCroix, D. Lane, R.D. Langer, N. Lasser, C.E. Lewis, J. Manson, K. Margolis, J. Ockene, M.J. O'Sullivan, L. Phillips, R.L. Prentice, C. Ritenbaugh, J. Robbins, J.E. Rossouw, G. Sarto, M.L. Stefanick, L. Van Horn, J. Wactawski-Wende, R. Wallace, S. Wassertheil-Smoller, and Women's Health Initiative Steering Committee Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial JAMA 291 2004 1701 1712
69. K. Machens, and K. Schmidt-Gollwitzer Issues to debate on the Women's Health Initiative (WHI) Study Hormone Replacement Therapy: an epidemiological dilemma? Hum. Reprod. 18 2003 1992 1999
70. S. Shapiro Risks of estrogen plus progestin therapy: a sensitivity analysis of findings in the Women's Health Initiative Randomized Controlled Trial Climacteric 6 2003 302 310
71. B.R. Bhavnani, and R.C. Strickler Menopausal hormone therapy J. Obstet. Gynaecol. Can. 27 2005 137 162
72. S. Shapiro Recent epidemiological evidence relevant to the clinical management of the menopause Climacteric 10 Suppl. 2 2007 2 15
73. W.H. Utian A decade past WHI, menopausal hormone therapy comes full circle - need for independent commission Climacteric 15 2012 320 325
74. F. Grodstein, J.E. Manson, and M.F. Stampfer Hormone therapy and coronary heart disease: the role of time since menopause and age at hormone initiation J. Womens Health 15 2006 35 44
75. R.A. Lobo Menopause and stroke and the effects of hormonal therapy Climacteric 10 Suppl. 2 2007 27 31
76. J. Hsia, R.D. Langer, J.E. Manson, L. Kuller, K.C. Johnson, S.L. Hendrix, M. Pettinger, S.R. Heckbert, N. Greep, S. Crawford, C.B. Eaton, J.B. Kostis, P. Caralis, and R. Prentice Women's Health Initiative Investigators, Conjugated equine estrogens and coronary heart disease: the Women's Health Initiative Arch. Intern. Med. 166 2006 357 365
77. J.E. Rossouw, R.L. Prentice, J.E. Manson, L. Wu, D. Barad, V.M. Barnabei, M. Ko, A.Z. LaCroix, K.L. Margolis, and M.L. Stefanick Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause JAMA 297 2007 1465 1477 (Erratum in: JAMA 299 (2008) 1426)
78. D.A. Davey Update: estrogen and estrogen plus progestin therapy in the care of women at and after the menopause Womens Health (Lond. Engl.) 8 2012 168 189
79. R. Ross The pathogenesis of atherosclerosis: an update N. Engl. J. Med. 314 1986 488 500
80. M.S. Brown, and J.L. Goldstein Koch's postulates for cholesterol Cell 71 1992 187 188
81. L.H. Kuller, J.P. Gutai, E. Meilahn, K.A. Matthews, and P. Plantinga Relationship of endogenous sex steroid hormones to lipids and apoproteins in postmenopausal women Arteriosclerosis 10 1990 1058 1066
82. J.C. LaRosa Women, lipoproteins and cardiovascular disease risk Can. J. Cardiol. 6 Suppl B 1990 23B 29B
83. A. Paganini-Hill, R. Dworsky, and R.M. Krauss Hormone replacement therapy, hormone levels, and lipoprotein cholesterol concentrations in elderly women Am. J. Obstet. Gynecol. 174 1996 897 902
84. D. Steinberg, S. Parthasarathy, T.E. Carew, J.C. Khoo, and J.L. Witztum Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity N. Engl. J. Med. 320 1989 915 924
85. W. Palinski, M.E. Rosenfield, S. Yla-Herttuola, G.C. Gurtner, S.S. Socher, S.W. Butler, S. Parthasarathy, T.E. Carew, D. Steinberg, and J.L. Witztum Low density lipoprotein undergoes oxidative modifications in vivo Proc. Natl. Acad. Sci. U.S.A. 86 1989 1372 1376
86. U.P. Steinbrecher, S. Parthasarathy, D.S. Leake, J.L. Witztum, and D. Steinberg Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids Proc. Natl. Acad. Sci. U.S.A. 81 1984 3883 3887
87. R. Stocker, and Y. Keaney Role of oxidative modification in atherosclerosis Physiol. Rev. 84 2004 1381 1478
88. M.T.R. Subbiah, B. Kessel, and M. Agrawal Antioxidant potential of specific estrogens on lipid peroxidation J. Clin. Endocrinol. Metab. 77 1993 1095 1097
89. M.N. Sack, D.J. Rader, and R.O. Cannon Oestrogen and inhibition of low density lipoproteins in postmenopausal women Lancet 343 1994 269 270
90. M. Tang, W. Abplanalp, S. Ayres, and M.T.R. Subbiah Superior and distinct antioxidant effects of selected estrogen metabolites on lipid peroxidation Metabolism. 45 1996 411 414
91. J.G. Wilcox, J. Hwang, H.N. Hodis, A. Sevanian, F.Z. Stanczyk, and R.A. Lobo Cardioprotective effects of individual conjugated equine estrogens through their possible modulation of insulin resistance and oxidation of low-density lipoprotein Fertil. Steril. 67 1997 57 62
92. B.R. Bhavnani, A. Cecutti, A. Gerulath, C.A. Woolever, and M. Berco Comparison of the antioxidant effects of equine estrogens, red wine components, vitamin E, and probucol on low-density lipoprotein oxidation in postmenopausal women Menopause 8 2001 408 419
93. B.R. Bhavnani, J.A. Nisker, J. Martin, F. Aletebi, L. Watson, and J.K. Milne Comparison of pharmacokinetics of a conjugated equine estrogen preparation (Premarin) and a synthetic mixture of estrogens (CES) in postmenopausal women J. Soc. Gynecol. Investig. 7 2000 175 183
94. G.T. Shwaery, J.A. Vita, and J.F. Keaney Antioxidant protection of LDL by physiological concentrations of 17β-estradiol Circulation 95 1997 1378 1385
95. H.E. Brussaard, J.A. Gevers Leuven, C. Kluft, H.M. Krans, W. van Duyvenvoorde, R. Buytenhek, A. van der Laarse, and H.M. Princen Effect of 17β-estradiol on plasma lipids and LDL oxidation in postmenopausal women with type II diabetes mellitus Arterioscler. Thromb. Vasc. Biol. 17 1997 324 330
96. J. McManus, J. McEneny, W. Thompson, and I.S. Young The effect of hormone replacement therapy on the oxidation of low density lipoprotein in postmenopausal women Atherosclerosis 135 1997 73 81
97. J.G. Wilcox, J. Hwang, E.K. Gentzschein, H.N. Hodis, A. Sevanian, F.Z. Stanczyk, and R.A. Lobo Effects of combined estrogen and progestin therapy in postmenopausal women on endothelium levels and oxidation of LDL J. Soc. Gynecol. Investig. 3 Suppl 3 1996 69A
98. E. Barrett-Conner, and T.L. Bush Estrogens and coronary heart disease in women JAMA 265 1991 1861 1867
99. M.J. Tikkanen Sex hormones J. Betterridge, R. Illingworth, J. Sheperd, Lipoproteins in health and disease, 1999 Hodder and Stoughton Publishers London, England 967 984
100. M.J. Stampfer, F.M. Sacks, S. Salvini, W.C. Willett, and C.H. Hennekens A prospective study of cholesterol, apolipoproteins and the risk of myocardial infarction N. Engl. J. Med. 325 1991 373 381
101. P.N. Durrington High-density lipoprotein cholesterol: methods and clinical significance Crit. Rev. Clin. Lab. Sci. 18 1982 31 78
102. S. Parthasarthy, J. Barnett, and L.G. Fong High-density lipoprotein inhibits the oxidative modification of low-density lipoprotein Biochim. Biophys. Acta 1044 1990 275 283
103. D. Bonnefont-Rousselot, P. Therond, J.L. Beaudeux, J. Peynet, A. Legrand, and J. Delattre High density lipoproteins (HDL) and the oxidative hypothesis of atherosclerosis Clin. Chem. Lab. Med. 37 1999 939 948
104. M.J. Thomas, Q. Chen, M. Zablawi, R. Anderson, M. Wilson, R. Weinberg, M.G. Sorci-Thomas, and L.L. Rudel Is the oxidation of high-density lipoprotein lipids different than the oxidation of low-density lipoprotein lipids? Biochemistry 40 2001 1719 1724
105. M.I. Mackness, S. Arrol, C. Abbott, and P.N. Durrington Protection of low-density lipoprotein against oxidative modification by high-density lipoprotein associated paraoxonase Atherosclerosis 104 1993 129 135
106. Y. Nagano, H. Arai, and T. Kita High-density lipoproteins loses its effect to stimulate efflux of cholesterol from foam cells after oxidative modification Proc. Natl. Acad. Sci. U.S.A. 88 1991 6457 6461
107. H. Ohmura, Y. Watanabe, C. Hatsumi, H. Sato, H. Daida, H. Mokuno, and H. Yamaguchi Possible role of high susceptibility of high-density lipoprotein to lipid peroxidative modification and oxidized high-density lipoprotein in genesis of coronary artery spasm Atherosclerosis 142 1999 179 184
108. J. Perrella, M. Berco, A. Cecutti, A. Gerulath, and B.R. Bhavnani Potential role of the interaction between equine estrogens, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) in the prevention of coronary heart and neurodegenerative diseases in post-menopausal women Lipids Health Dis. 2 2003 1 10
109. M. Yoshikawa, N. Sakuma, T. Hibino, T. Sato, and T. Fujinami HDL-3 exerts more powerful antioxidative, protective effects against copper-catalyzed LDL oxidation than HDL-2 Clin. Biochem. 30 1997 221 225
110. P. Wahl, C. Walden, R. Knopp, J. Hoover, R. Wallace, G. Heiss, and B. Rifkind Effect of estrogen/progestin potency on lipid/lipoprotein cholesterol N. Engl. J. Med. 308 1983 862 867
111. R.M. Krauss, F.T. Lindgren, J. Wingerd, D.D. Bradley, S.
112. The Writing Group for the PEPI Trial The effect of estrogens or estrogen/progestin on regimens on heart disease risk factors in postmenopausal women: the postmenopausal Estrogen/Progestin Interventions (PEPI) Trial JAMA 273 1995 199 208
113. R. Brookmeyer, S. Gray, and C. Kawas Projections of Alzheimer's disease in the United States and Public Health impact in delaying disease onset Am. J. Public Health 88 1998 1337 1342
114. A. Paganini-Hill, and V.W. Henderson Estrogen deficiency and risk of AD in women Am. J. Epidemiol. 140 1994 156 261
115. M.X. Tang, D. Jacobs, Y. Stern, K. Marder, P. Schofield, B. Gurland, H. Andrews, and R. Mayeux Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease Lancet 348 1996 429 432
116. H.D. Nelson, L.L. Humphrey, P. Nygren, S.M. Teutsch, and J.D. Allan Postmenopausal hormone replacement therapy: scientific review JAMA 288 2002 872 881
117. S.A. Shumaker, C. Legault, S.R. Rapp, L. Thal, R.B. Wallace, J.K. Ockene, S.L. Hendrix, B.N. Jones 3rd, A.R. Assaf, R.D. Jackson, J.M. Kotchen, S. Wassertheil-Smoller, J. Wactawski-Wende, and WHIMS. Investigators Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial JAMA 289 2003 2651 2662
118. S.A. Shumaker, C. Legault, L. Kuller, S.R. Rapp, L. Thal, D.S. Lane, H. Fillit, M.L. Stefanick, S.L. Hendrix, C.E. Lewis, K. Masaki, and L.H. Coker Women's Health Initiative Memory Study, Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study JAMA 291 2004 2947 2958
119. P.M. Maki, and V.W. Henderson Hormone therapy, dementia, and cognition: the women's Health Initiative 10 years on Climacteric 15 2012 256 262
120. P.M. Maki Mini review: effect of different HT formulations on cognition Endocrinology 153 2012 3564 3570
121. C. Behl, M. Widmann, T. Trapp, and F. Holsboer 17β-estradiol protects neurons from oxidative stress-induced cell death in vitro Biochem. Biophys. Res. Commun. 216 1995 473 482
122. P.S. Green, K. Gordon, and J.W. Simpkins Phenolic A ring requirement for the neuroprotective effects of steroids J. Steroid Biochem. Mol. Biol. 63 1997 229 235
123. J. Chen, N. Adachi, K. Liu, and T. Arai The effects of 17β-estradiol on ischemia-induced neuronal damage in the gerbil hippocampus Neuroscience 87 1998 817 822
124. R.D. Brinton, J. Tran, P. Proffitt, and M. Montoya 17β-Estradiol enhances the outgrowth and survival of neocortical neurons in culture Neurochem. Res. 22 1997 1339 1351
125. V.W. Henderson Hormone therapy and the Brain: A Clinical Perspective on the Role of Estrogen 2000 Parthenon Publishing New York
126. P.S. Roheim, M. Carey, T. Forte, and G.L. Vega Apolipoproteins in human cerebrospinal fluid Proc. Natl. Acad. Sci. U.S.A. 76 1979 4646 4649
127. R.E. Pitas, J.K. Boyles, S.H. Lee, D. Hui, and K.H. Weisgraber Lipoproteins and their receptors in the central nervous system. Characterization of the lipoproteins in cerebrospinal fluid and identification of apolipoprotein B,E(LDL) receptors in the brain J. Biol. Chem. 262 1987 14352 14360
128. B. Dehouck, L. Fenart, M.P. Dehouck, A. Pierce, G. Torpier, and R. Cecchelli A new function for the LDL receptor: transcytosis of LDL across the blood-brain barrier J. Cell Biol. 138 1997 877 889
129. H. Esterbauer, J. Gebicki, H. Puhl, and G. Jurgens The role of lipid peroxidation and antioxidants in oxidative modification of LDL Free Radic. Biol. Med. 13 1992 341 390
130. B. Draczynska-Lusiak, A. Doung, and A.Y. Sun Oxidized lipoproteins may play a role in neuronal cell death in Alzheimer's disease Mol. Chem. Neuropathol. 33 1998 139 148
131. M. Sugawa, S. Ikeda, Y. Kushima, Y. Takashima, and O. Cynshi Oxidized low-density lipoprotein causes CNS neuron cell death Brain Res. 761 1997 165 172
132. J.N. Keller, K.B. Hanni, and W.R. Markesbery Oxidized low-density lipoproteins induces neuronal death: implications for calcium, reactive oxygen species, and caspases J. Neurochem. 72 1999 2601 2609
133. J.N. Keller, K.B. Hanni, S.P. Gabbita, V. Friebe, M.P. Mattson, and M.S. Kindy Oxidized lipoproteins increase reactive oxygen species formation in microglia and astrocyte cell lines Brain Res. 830 1999 10 15
134. L.A. Greene, and A.S. Tischler Establishment of noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor Proc. Natl. Acad. Sci. U.S.A. 73 1976 2424 2428
135. S. Chanvitayapongs, B. Draczynska-Lusiak, and A.Y. Sun Amelioration of oxidative stress by antioxidants and resveratrol in PC-12 cells Neuroreport 8 1997 1499 1502
136. M. Berco, and B.R. Bhavnani Differential neuroprotective effects of equine estrogens against oxidized low-density lipoprotein-induced neuronal cell death J. Soc. Gynecol. Investig. 8 2001 245 254
137. M.K. Osterlund, J.A. Gustafsson, E. Keller, and Y.L. Hurd Estrogen receptor beta (ERβ) messenger ribonucleic acid (mRNA) expression within the human forebrain: distinct distribution pattern to ERα mRNA J. Clin. Endocrinol. Metab. 85 2000 3840 3846
138. C. Behl, T. Skutella, F. Lezoualc'h, A. Post, M. Widmann, C.J. Newton, and F. Holsboer Neuroprotection against oxidative stress by estrogens: structure-activity relationship Mol. Pharmacol. 51 1997 535 541
139. L. Zhao, and R.D. Brinton Select estrogens within the complex formulation of conjugated equine estrogens (Premarin) are protective against neurodegenerative insults: implications for a composition of estrogen therapy to promote neuronal function and prevent Alzheimer's disease BMC Neurosci. 7 2006 24
140. P.S. Green, K.E. Gridley, and J.W. Simpkins Nuclear estrogen receptor independent neuroprotection by estratrienes: a novel interaction with glutathione Neuroscience 84 1998 7 10
141. L.M. Garcia-Segura, I. Azcoitia, and L.L. DonCarlos Neuroprotection by estradiol Prog. Neurobiol. 63 2001 29 60
142. D.W. Choi Glutamate neurotoxicity and diseases of the nervous system Neuron 1 1988 623 634
143. J.T. Coyle, and K.P. Puttfarcken Oxidative stress, glutamate and neurodegenerative disorders Science 262 1993 689 695
144. S.A. Lipton, and P.A. Rosenberg Excitatory amino acids as a final common pathway for neurologic disorders N. Engl. J. Med. 330 1994 13 22
145. G. Cooper, and R.L. Rodnitzky Dementia and abnormalities of cognition P. Michael Conn, Neuroscience in Medicine 2003 Humana Press, Inc. New Jersey 367 368
146. M. Ankarcrona, J.M. Dypbukt, E. Bonfoco, B. Zhivotovsky, S. Orrenius, S.A. Lipton, and P. Nicotera Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function Neuron 15 1995 961 973
147. D.W. Choi Excitotoxic cell death J. Neurobiol. 23 1992 1261 1276
148. T.H. Murphy, M. Miyamoto, A. Sastre, R.L. Schnaar, and J.T. Coyle Glutamate toxicity in a neuronal cell line involves inhibition of cystine transport leading to oxidative stress Neuron 2 1989 1547 1558
149. P. Albrecht, J. Lewerenz, S. Dittmer, R. Noack, P. Maher, and A. Methner Mechanisms of oxidative glutamate toxicity: the glutamate/cystine antiporter system XC - as a neuroprotective drug target CNS Neurol. Disord. Drug Targets 9 2010 373 382
150. Y. Li, P. Maher, and D. Schubert Phosphatidylcholine-specific phospholipase C regulates glutamate-induced nerve cell death Proc. Natl. Acad. Sci. U.S.A. 95 1998 7748 7753
151. R. Sattler, and M. Tymianski Molecular mechanisms of calcium dependent excitotoxicity J. Mol. Med. 78 2000 3 13
152. M. Yamanchi, K. Omote, and T. Ninomiya Direct evidence for the role of nitric oxide on the glutamate-induced neuronal death in cultured cortical neurons Brain Res. 780 1998 253 259
153. V.L. Dawson, T.M. Dawson, E.D. London, D.S. Bredt, and S.H. Snyder Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures Proc. Natl. Acad. Sci. U.S.A. 88 1991 6368 6371
154. B.R. Bhavnani, M. Berco, and J. Binkley Equine estrogens differentially prevent neuronal cell death induced by glutamate J. Soc. Gynecol. Investig. 10 2003 302 308
155. Y.M. Zhang, X.F. Lu, and B.R. Bhavnani Equine estrogens differentially inhibit DNA fragmentation induced by glutamate in neuronal cells by modulation of regulatory proteins involved in programmed cell death BMC Neurosci. 4 2003 1 15
156. R.D. Brinton, P. Proffit, J. Tran, and R. Luu Equilin, a principal component of the estrogen replacement therapy Premarin, increases the growth of cortical neurons via an NMDA receptor-dependent mechanism Exp. Neurol. 140 1997 211 220
157. J.F.R. Kerr, A. Wyllie, and A. Currie Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics Br. J. Cancer 26 1972 239 257
158. S. Nagata Apoptotic DNA fragmentation Exp. Cell Res. 256 2000 12 18
159. F. Nicotera, M. Ankarcrona, and E. Bonfoco Neuronal necrosis and apoptosis: two distinct events induced by exposure to glutamate or oxidative stress Adv. Neurol. 72 1997 95 101
160. S.J. Martin, and D.R. Green Protease activation during apoptosis: death by a thousand cuts Cell 82 1995 349 352
161. Y.M. Zhang, and B.R. Bhavnani Glutamate-induced apoptosis in primary
162. D.W. Nicholson, A. Ali, N.A. Thornberry, J.P. Vaillancourt, C.K. Ding, M. Gallant, Y. Gareau, P.R. Griffin, M. Labelle, and Y.A. Lazebnik Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis Nature 376 1995 37 43
163. G.M. Cohen Caspases: the executioners of apoptosis Biochem. J. 326 1997 1 16
164. F.G. Gervais, D. Xu, G.S. Robertson, J.P. Vaillancourt, Y. Zhu, J. Huang, A. LeBlanc, D. Smith, M. Rigby, M.S. Shearman, E.E. Clarke, H. Zheng, L.H. Van Der Ploeg, S.C. Ruffolo, N.A. Thornberry, S. Xanthoudakis, R.J. Zamboni, S. Roy, and D.W. Nicholson Involvement of caspases in proteolytic cleavage of Alzheimer's amyloid-beta precursor protein and amyloidogenic A beta peptide formation Cell 97 1999 395 406
165. E. Bossy-Wetzel, D.D. Newmeyer, and D.R. Green Mitochondrial cytochrome C release in apoptosis occurs upstream of DEVD-specific caspase activation and independently of mitochondrial transmembrane depolarization EMBO J. 17 1998 37 49
166. P. Li, D. Nijhawan, I. Budihardjo, S.M. Srinivasula, M. Ahmad, E.S. Alnemri, and X. Wang Cytochrome C and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade Cell 91 1997 479 489
167. Y.M. Zhang, and B.R. Bhavnani Glutamate-induced apoptosis in primary cortical neurons is inhibited by equine estrogens via a down-regulation of caspase-3 and prevention of mitochondrial cytochrome C release BMC Neurosci. 6 13 2005 1 23
168. J. Perrella, and B.R. Bhavnani Protection of cortical cells by equine estrogens against glutamate-induced excitotoxicity is mediated through a calcium independent mechanism BMC Neurosci. 6 34 2005 1 17
169. Y.M. Zhang, and B.R. Bhavnani Glutamate-induced apoptosis in neuronal cells is mediated via caspase-dependent and independent mechanisms involving calpain and caspase-3 proteases as well as apoptosis inducing factor (AIF) and this process is inhibited by equine estrogens BMC Neurosci. 7 49 2006 1 22
170. S. Noguchi, K. Murakami, and N. Yamada Apolipoprotein E genotype and Alzheimer's disease Lancet 342 1993 737
171. A. Hofman, A. Ott, M.M. Breteler, M.L. Bots, A.J. Slooter, F. van Harskamp, C.N. van Duijn, C. Van Broeckhoven, and D.E. Grobbee Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer's disease in the Rotterdam Study Lancet 349 1997 151 154
172. R. Stewart Cardiovascular factors in Alzheimer's disease J. Neurol. Neurosurg. Psychiatry 65 1998 143 147
173. W. Abplanalp, M. Rymaszewski, J. Adamski, and M.T.R. Subbiah Evidence for interference in estradiol-17β inactivation to estrone by oxidized low-density lipoprotein and selected lipid peroxidation products J. Lab. Clin. Med. 134 1999 253 259
174. F.Z. Stanczyk Estrogens used for replacement therapy in postmenopausal women Gynecol. Endocrinol. 15 Suppl. 4 2001 17 25