The clinical impact of estrogen loss on cardiovascular disease in menopausal females

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Marissa A. Lopez-Pier Yulia Lipovka Matthew P. Koppinger Preston R. Harris John P. Konhilas


According to the CDC (2017), more women than men have died from heart disease over the last 20-25 years. On the contrary, premenopausal women are protected against heart and cardiovascular disease (CVD) compared to men. Following menopause, there is sharp rise in CVD mortality and morbidity in women compared to men indicating that women lose protection against CVD during menopause. This loss of CVD protection in women drives the CDC statistics. Life expectancy of women has now reached 82 (almost 35 years longer than at the turn of the 20th century). Yet, women typically undergo menopause at 50-60 years of age, which means that women spend over 40% of their life in menopause. Therefore, menopausal women, and associated CVD risk, must be considered as distinct from an aging or senescent woman. Despite longstanding knowledge that premenopausal women are protected from CVD, our fundamental understanding regarding the shift in CVD risk with menopause remains inadequate and impedes our ability to develop sex-specific therapeutic strategies to combat menopausal susceptibility to CVD. This review provides a critical overview of clinical trials attempting to address CVD susceptibility postmenopausal using hormone replacement therapy. Next, we outline key deficiencies in pre-clinical menopause models and introduce an alternative to overcome these deficiencies. Finally, we discuss a novel connection between AMPK and estrogen-dependent pathways that may serve as a potential solution to increased CVD susceptibility in menopausal women. 

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LOPEZ-PIER, Marissa A. et al. The clinical impact of estrogen loss on cardiovascular disease in menopausal females. Medical Research Archives, [S.l.], v. 6, n. 2, feb. 2018. ISSN 2375-1924. Available at: <>. Date accessed: 28 nov. 2021. doi:
Research Articles


1. Association AH. Heart and Stroke Statistical Update. 2000 [Available from:
2. Lindenfeld J, Krause-Steinrauf H, Salerno J. Where are all the women with heart failure? J Am Coll Cardiol. 1997;30(6):1417-9.
3. Writing Group M, Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, et al. Executive Summary: Heart Disease and Stroke Statistics--2016 Update: A Report From the American Heart Association. Circulation. 2016;133(4):447-54.
4. Mosca L, Mochari-Greenberger H, Dolor RJ, Newby LK, Robb KJ. Twelve-year follow-up of American women's awareness of cardiovascular disease risk and barriers to heart health. Circ Cardiovasc Qual Outcomes. 2010;3(2):120-7.
5. Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB, Flegal K, et al. Heart disease and stroke statistics--2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2009;119(3):480-6.
6. Schocken DD, Arrieta MI, Leaverton PE, Ross EA. Prevalence and mortality rate of congestive heart failure in the United States. J Am Coll Cardiol. 1992;20(2):301-6.
7. Dubey RK, Oparil S, Imthurn B, Jackson EK. Sex hormones and hypertension. Cardiovasc Res. 2002;53(3):688-708.
8. Lima R, Wofford M, Reckelhoff JF. Hypertension in postmenopausal women. Curr Hypertens Rep. 2012;14(3):254-60.
9. Rosano GM, Vitale C, Marazzi G, Volterrani M. Menopause and cardiovascular disease: the evidence. Climacteric. 2007;10 Suppl 1:19-24.
10. Yang XP, Reckelhoff JF. Estrogen, hormonal replacement therapy and cardiovascular disease. Curr Opin Nephrol Hypertens. 2011;20(2):133-8.
11. Konhilas JP, Leinwand LA. The effects of biological sex and diet on the development of heart failure. Circulation. 2007;116(23):2747-59.
12. Diamond-Stanic MK, Romero-Aleshire MJ, Hoyer PB, Greer K, Hoying JB, Brooks HL. Midkine, a heparin-binding protein, is increased in the diabetic mouse kidney postmenopause. Am J Physiol Renal Physiol. 2011;300(1):F139-46.
13. Riazi S, Maric C, Ecelbarger CA. 17-beta Estradiol attenuates streptozotocin-induced diabetes and regulates the expression of renal sodium transporters. Kidney Int. 2006;69(3):471-80.
14. Romero-Aleshire MJ, Diamond-Stanic MK, Hasty AH, Hoyer PB, Brooks HL. Loss of ovarian function in the VCD mouse-model of menopause leads to insulin resistance and a rapid progression into the metabolic syndrome. Am J Physiol Regul Integr Comp Physiol. 2009;297(3):R587-92.
15. Mankhey RW, Bhatti F, Maric C. 17beta-Estradiol replacement improves renal function and pathology associated with diabetic nephropathy. Am J Physiol Renal Physiol. 2005;288(2):F399-405.
16. Xue B, Zhao Y, Johnson AK, Hay M. Central estrogen inhibition of angiotensin II-induced hypertension in male mice and the role of reactive oxygen species. Am J Physiol Heart Circ Physiol. 2008;295(3):H1025-H32.
17. Widder J, Pelzer T, von Poser-Klein C, Hu K, Jazbutyte V, Fritzemeier KH, et al. Improvement of endothelial dysfunction by selective estrogen receptor-alpha stimulation in ovariectomized SHR. Hypertension. 2003;42(5):991-6.
18. Cavasin MA, Sankey SS, Yu AL, Menon S, Yang XP. Estrogen and testosterone have opposing effects on chronic cardiac remodeling and function in mice with myocardial infarction. Am J Physiol Heart Circ Physiol. 2003;284(5):H1560-9.
19. van Eickels M, Grohe C, Cleutjens JP, Janssen BJ, Wellens HJ, Doevendans PA. 17beta-estradiol attenuates the development of pressure-overload hypertrophy. Circulation. 2001;104(12):1419-23.
20. Sharkey LC, Holycross BJ, Park S, Shiry LJ, Hoepf TM, McCune SA, et al. Effect of ovariectomy and estrogen replacement on cardiovascular disease in heart failure-prone SHHF/Mcc- fa cp rats. J Mol Cell Cardiol. 1999;31(8):1527-37.
21. de Jager T, Pelzer T, Muller-Botz S, Imam A, Muck J, Neyses L. Mechanisms of estrogen receptor action in the myocardium. Rapid gene activation via the ERK1/2 pathway and serum response elements. The Journal of biological chemistry. 2001;276(30):27873-80.
22. Grady D, Applegate W, Bush T, Furberg C, Riggs B, Hulley SB. Heart and Estrogen/progestin Replacement Study (HERS): design, methods, and baseline characteristics. Control Clin Trials. 1998;19(4):314-35.
23. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-33.
24. Vickers MR, MacLennan AH, Lawton B, Ford D, Martin J, Meredith SK, et al. Main morbidities recorded in the women's international study of long duration oestrogen after menopause (WISDOM): a randomised controlled trial of hormone replacement therapy in postmenopausal women. BMJ. 2007;335(7613):239.
25. Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA. 2004;291(14):1701-12.
26. Manson JE, Aragaki AK, Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, et al. Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women's Health Initiative Randomized Trials. JAMA. 2017;318(10):927-38.
27. Reis SE, Holubkov R, Young JB, White BG, Cohn JN, Feldman AM. Estrogen is associated with improved survival in aging women with congestive heart failure: analysis of the vesnarinone studies. J Am Coll Cardiol. 2000;36(2):529-33.
28. Lindenfeld J, Ghali JK, Krause-Steinrauf HJ, Khan S, Adams K, Goldman S, et al. Hormone replacement therapy is associated with improved survival in women with advanced heart failure. J Am Coll Cardiol. 2003;42(7):1238-45.
29. Bibbins-Domingo K, Lin F, Vittinghoff E, Barrett-Connor E, Hulley SB, Grady D, et al. Effect of hormone therapy on mortality rates among women with heart failure and coronary artery disease. Am J Cardiol. 2005;95(2):289-91.
30. Manson JE. The 'timing hypothesis' for estrogen therapy in menopausal symptom management. Womens Health (Lond). 2015;11(4):437-40.
31. Hodis HN, Mack WJ, Shoupe D, Azen SP, Stanczyk FZ, Hwang-Levine J, et al. Methods and baseline cardiovascular data from the Early versus Late Intervention Trial with Estradiol testing the menopausal hormone timing hypothesis. Menopause. 2015;22(4):391-401.
32. Santoro N, Allshouse A, Neal-Perry G, Pal L, Lobo RA, Naftolin F, et al. Longitudinal changes in menopausal symptoms comparing women randomized to low-dose oral conjugated estrogens or transdermal estradiol plus micronized progesterone versus placebo: the Kronos Early Estrogen Prevention Study. Menopause. 2017;24(3):238-46.
33. Peter I, Kelley-Hedgepeth A, Fox CS, Cupples LA, Huggins GS, Housman DE, et al. Variation in estrogen-related genes associated with cardiovascular phenotypes and circulating estradiol, testosterone, and dehydroepiandrosterone sulfate levels. J Clin Endocrinol Metab. 2008;93(7):2779-85.
34. Fox EM, Andrade J, Shupnik MA. Novel actions of estrogen to promote proliferation: integration of cytoplasmic and nuclear pathways. Steroids. 2009;74(7):622-7.
35. Herrington DM, Reboussin DM, Brosnihan KB, Sharp PC, Shumaker SA, Snyder TE, et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med. 2000;343(8):522-9.
36. Hodis HN, Mack WJ, Azen SP, Lobo RA, Shoupe D, Mahrer PR, et al. Hormone therapy and the progression of coronary-artery atherosclerosis in postmenopausal women. N Engl J Med. 2003;349(6):535-45.
37. Hodis HN, Mack WJ, Lobo RA, Shoupe D, Sevanian A, Mahrer PR, et al. Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2001;135(11):939-53.
38. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, et al. 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. 1998;280(7):605-13.
39. Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA. 2002;288(1):49-57.
40. Mayer LP, Devine PJ, Dyer CA, Hoyer PB. The follicle-deplete mouse ovary produces androgen. Biol Reprod. 2004;71(1):130-8.
41. Hu X, Christian PJ, Thompson KE, Sipes IG, Hoyer PB. Apoptosis induced in rats by 4-vinylcyclohexene diepoxide is associated with activation of the caspase cascades. Biol Reprod. 2001;65(1):87-93.
42. Rivera Z, Christian PJ, Marion SL, Brooks HL, Hoyer PB. Steroidogenic capacity of residual ovarian tissue in 4-vinylcyclohexene diepoxide-treated mice. Biol Reprod. 2009;80(2):328-36.
43. Pollow DP, Jr., Romero-Aleshire MJ, Sanchez JN, Konhilas JP, Brooks HL. ANG II-induced hypertension in the VCD mouse model of menopause is prevented by estrogen replacement during perimenopause. Am J Physiol Regul Integr Comp Physiol. 2015;309(12):R1546-52.
44. Lipovka Y, Chen H, Vagner J, Price TJ, Tsao TS, Konhilas JP. Oestrogen receptors interact with the alpha-catalytic subunit of AMP-activated protein kinase. Biosci Rep. 2015;35(5).
45. Levin ER, Hammes SR. Nuclear receptors outside the nucleus: extranuclear signalling by steroid receptors. Nat Rev Mol Cell Biol. 2016;17(12):783-97.
46. Pedram A, Razandi M, Levin ER. Nature of functional estrogen receptors at the plasma membrane. Mol Endocrinol. 2006;20(9):1996-2009.
47. Razandi M, Pedram A, Greene GL, Levin ER. Cell membrane and nuclear estrogen receptors (ERs) originate from a single transcript: studies of ERalpha and ERbeta expressed in Chinese hamster ovary cells. Mol Endocrinol. 1999;13(2):307-19.
48. Hardie DG, Hawley SA, Scott JW. AMP-activated protein kinase--development of the energy sensor concept. The Journal of physiology. 2006;574(Pt 1):7-15.
49. Hawley SA, Davison M, Woods A, Davies SP, Beri RK, Carling D, et al. Characterization of the AMP-activated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinase. The Journal of biological chemistry. 1996;271(44):27879-87.
50. Nesatyy VJ, Ammann AA, Rutishauser BV, Suter MJ. Effect of cadmium on the interaction of 17beta-estradiol with the rainbow trout estrogen receptor. Environ Sci Technol. 2006;40(4):1358-63.
51. Baron D, Fostier A, Breton B, Guiguen Y. Androgen and estrogen treatments alter steady state messengers RNA (mRNA) levels of testicular steroidogenic enzymes in the rainbow trout, Oncorhynchus mykiss. Mol Reprod Dev. 2005;71(4):471-9.
52. Bungard D, Fuerth BJ, Zeng PY, Faubert B, Maas NL, Viollet B, et al. Signaling kinase AMPK activates stress-promoted transcription via histone H2B phosphorylation. Science. 2010;329(5996):1201-5.
53. Salminen A, Kauppinen A, Kaarniranta K. AMPK/Snf1 signaling regulates histone acetylation: Impact on gene expression and epigenetic functions. Cell Signal. 2016;28(8):887-95.
54. Lipovka Y, Konhilas JP. The complex nature of estrogen signaling in breast cancer: enemy or ally? Biosci Rep. 2016.
55. Mosselman S, Polman J, Dijkema R. ER beta: identification and characterization of a novel human estrogen receptor. FEBS letters. 1996;392(1):49-53.
56. Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA. Cloning of a novel receptor expressed in rat prostate and ovary. Proceedings of the National Academy of Sciences of the United States of America. 1996;93(12):5925-30.
57. Penot G, Le Peron C, Merot Y, Grimaud-Fanouillere E, Ferriere F, Boujrad N, et al. The human estrogen receptor-alpha isoform hERalpha46 antagonizes the proliferative influence of hERalpha66 in MCF7 breast cancer cells. Endocrinology. 2005;146(12):5474-84.
58. Wang Z, Zhang X, Shen P, Loggie BW, Chang Y, Deuel TF. Identification, cloning, and expression of human estrogen receptor-alpha36, a novel variant of human estrogen receptor-alpha66. Biochemical and biophysical research communications. 2005;336(4):1023-7.
59. Moore JT, McKee DD, Slentz-Kesler K, Moore LB, Jones SA, Horne EL, et al. Cloning and characterization of human estrogen receptor beta isoforms. Biochemical and biophysical research communications. 1998;247(1):75-8.
60. Simpson ER. Sources of estrogen and their importance. The Journal of steroid biochemistry and molecular biology. 2003;86(3-5):225-30.
61. Anderson KA, Means RL, Huang QH, Kemp BE, Goldstein EG, Selbert MA, et al. Components of a calmodulin-dependent protein kinase cascade. Molecular cloning, functional characterization and cellular localization of Ca2+/calmodulin-dependent protein kinase kinase beta. The Journal of biological chemistry. 1998;273(48):31880-9.
62. Hawley SA, Boudeau J, Reid JL, Mustard KJ, Udd L, Makela TP, et al. Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. Journal of biology. 2003;2(4):28.
63. Woods A, Johnstone SR, Dickerson K, Leiper FC, Fryer LG, Neumann D, et al. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Current biology : CB. 2003;13(22):2004-8.
64. Roepstorff C, Thiele M, Hillig T, Pilegaard H, Richter EA, Wojtaszewski JF, et al. Higher skeletal muscle alpha2AMPK activation and lower energy charge and fat oxidation in men than in women during submaximal exercise. The Journal of physiology. 2006;574(Pt 1):125-38.
65. Briski KP, Ibrahim BA, Tamrakar P. Energy metabolism and hindbrain AMPK: regulation by estradiol. Hormone molecular biology and clinical investigation. 2014;17(3):129-36.
66. D'Eon TM, Rogers NH, Stancheva ZS, Greenberg AS. Estradiol and the estradiol metabolite, 2-hydroxyestradiol, activate AMP-activated protein kinase in C2C12 myotubes. Obesity. 2008;16(6):1284-8.
67. Rogers NH, Witczak CA, Hirshman MF, Goodyear LJ, Greenberg AS. Estradiol stimulates Akt, AMP-activated protein kinase (AMPK) and TBC1D1/4, but not glucose uptake in rat soleus. Biochemical and biophysical research communications. 2009;382(4):646-50.
68. Song X, Pan ZZ. Estrogen receptor-beta agonist diarylpropionitrile counteracts the estrogenic activity of estrogen receptor-alpha agonist propylpyrazole-triol in the mammary gland of ovariectomized Sprague Dawley rats. The Journal of steroid biochemistry and molecular biology. 2012;130(1-2):26-35.
69. Strom A, Hartman J, Foster JS, Kietz S, Wimalasena J, Gustafsson JA. Estrogen receptor beta inhibits 17beta-estradiol-stimulated proliferation of the breast cancer cell line T47D. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(6):1566-71.
70. Irsik DL, Carmines PK, Lane PH. Classical estrogen receptors and ERalpha splice variants in the mouse. PloS one. 2013;8(8):e70926.
71. Skavdahl M, Steenbergen C, Clark J, Myers P, Demianenko T, Mao L, et al. Estrogen receptor-beta mediates male-female differences in the development of pressure overload hypertrophy. Am J Physiol Heart Circ Physiol. 2005;288(2):H469-76.
72. Mohamed MK, Abdel-Rahman AA. Effect of long-term ovariectomy and estrogen replacement on the expression of estrogen receptor gene in female rats. European journal of endocrinology / European Federation of Endocrine Societies. 2000;142(3):307-14.
73. Meng Z, Jing H, Gan L, Li H, Luo B. Resveratrol attenuated estrogen-deficient-induced cardiac dysfunction: role of AMPK, SIRT1, and mitochondrial function. Am J Transl Res. 2016;8(6):2641-9.
74. Perez JN, Chen H, Regan JA, Emert A, Constantopoulos E, Lynn M, et al. Effects of chemically induced ovarian failure on voluntary wheel-running exercise and cardiac adaptation in mice. Comparative medicine. 2013;63(3):233-43.
75. Stehle R, Iorga B. Kinetics of cardiac sarcomeric processes and rate-limiting steps in contraction and relaxation. J Mol Cell Cardiol. 2010;48(5):843-50.
76. Mahmoodzadeh S, Eder S, Nordmeyer J, Ehler E, Huber O, Martus P, et al. Estrogen receptor alpha up-regulation and redistribution in human heart failure. FASEB journal: official publication of the Federation of American Societies for Experimental Biology. 2006;20(7):926-34.
77. Barton M, Meyer MR. Postmenopausal hypertension: mechanisms and therapy. Hypertension. 2009;54(1):11-8.