ABSTRACT
The discrepancy between estrogen's beneficial cardiovascular effects found in animal
studies and observational studies in women compared with the recently published randomized
clinical trials have stimulated a great deal of controversy. Possibilities for the
discrepancy include the age of the women, number of years postmenopausal, and amount
of atherosclerotic complication (necrosis and inflammation) present when hormone therapy
is initiated. Many of the previous benefits of estrogens noted in both animal studies
and observational studies were found in primary prevention studies that experimentally
refer to a decrease in the progression of atherosclerosis extent rather than prevention
of clinical events, which often occur in women with undiagnosed atherosclerotic plaques.
In support of this notion, animal studies in which artery damage was present prior
to hormone treatment, due to either consumption of an atherogenic diet or balloon
injury of the endothelium, found no benefit with estrogen treatment. These animal
studies are consistent with the lack of protection found in secondary prevention studies
in women. Other areas of concern deal with the route of hormone delivery or dose of
hormones used. Higher doses of oral estrogens may result in increased risk of inflammation
and thrombosis. Future studies should be directed at studying hormone therapy in relevant
ages of women (perimenopausal women) using the lowest effective doses of hormones
and comparing oral and parenteral forms of delivery.
KEYWORDS
Atherosclerosis - coronary heart disease - hormones - estrogen - women - monkeys
REFERENCES
- 1
Grodstein F, Manson J E, Colditz G A, Willett W C, Speizer F E, Stampfer M J.
A prospective, observational study of postmenopausal hormone therapy and primary prevention
of cardiovascular disease.
Ann Intern Med.
2000;
133
933-941
- 2
Hulley S, Grady D, Bush T et al..
Randomized trial of estrogen plus progestin for secondary prevention of coronary heart
disease in postmenopausal women.
JAMA.
1998;
280
605-613
- 3
Herrington D M, Reboussin D M, Brosnihan K B et al..
Effects of estrogen replacement on the progression of coronary-artery atherosclerosis.
N Engl J Med.
2000;
343
522-529
- 4
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.
2002;
288
321-333
- 5
The 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.
2004;
291
1701-1712
- 6
Bairey Merz C N, Johnson B D, Sharaf B L et al..
Hypoestrogenemia of hypothalamic origin and coronary artery disease in premenopausal
women: a report from the NHLBI-sponsored WISE study.
J Am Coll Cardiol.
2003;
41
413-419
- 7
Grady D, Rubin S M, Petitti D B et al..
Hormone therapy to prevent disease and prolong life in postmenopausal women.
Ann Intern Med.
1992;
117
1016-1037
- 8
Barrett-Connor E, Grady D.
Hormone replacement therapy, heart disease, and other considerations.
Annu Rev Public Health.
1998;
19
55-72
- 9
Stampfer M J, Colditz G A, Willett W C et al..
Postmenopausal estrogen therapy and cardiovascular disease. Ten-year follow-up from
the Nurses' Health Study.
N Engl J Med.
1991;
325
756-762
- 10
Grodstein F, Stampfer M J, Colditz G A et al..
Postmenopausal hormone therapy and mortality.
N Engl J Med.
1997;
336
1769-1775
- 11
Clarkson T B.
The new conundrum: do estrogens have any cardiovascular benefits?.
Int J Fertil.
2002;
47
61-68
- 12
Strong J P, Malcom G T, McMahan C A et al..
Prevalence and extent of atherosclerosis in adolescents and young adults.
JAMA.
1999;
281
727-735
- 13
McGill Jr H C, Stern M P.
Sex and atherosclerosis.
Atheroscler Rev.
1979;
4
157-242
- 14
Haines C J, Yim S F, Sanderson J E.
The effect of continuous combined hormone replacement therapy on arterial reactivity
in postmenopausal women with established angina pectoris.
Atherosclerosis.
2001;
159
467-470
- 15
Herrington D M, Espeland M A, Crouse J R et al..
Estrogen replacement and brachial artery flow-mediated vasodilation in older women.
Arterioscler Thromb Vasc Biol.
2001;
21
1955-1961
- 16
Herrington D M, Braden G A, Williams J K, Morgan T M.
Endothelial-dependent coronary vasomotor responsiveness in postmenopausal women with
and without estrogen replacement therapy.
Am J Cardiol.
1994;
73
951-952
- 17
Koh K K, Jin D K, Yang S H et al..
Vascular effects of synthetic or natural progestogen combined with conjugated equine
estrogen in healthy postmenopausal women.
Circulation.
2001;
103
1961-1966
- 18
Williams J K, Anthony M S, Honore E K et al..
Regression of atherosclerosis in female monkeys.
Arterioscler Thromb Vasc Biol.
1995;
15
827-836
- 19
Angerer P, Störk S, Kothny W, Schmitt P, von Schacky C.
Effect of oral postmenopausal hormone replacement on progression of atherosclerosis.
A randomized, controlled trial.
Arterioscler Thromb Vasc Biol.
2001;
21
262-268
- 20
Espeland M A, Applegate W, Furberg C D, Lefkowitz D, Rice L, Hunninghake D.
Estrogen replacement therapy and progression of intimal-medial thickness in the carotid
arteries of postmenopausal women.
Am J Epidemiol.
1995;
142
1011-1019
- 21
Westendorp I CD, Veld I, Bots M L et al..
Hormone replacement therapy and intima-media thickness of the common carotid artery.
The Rotterdam study.
Stroke.
1999;
30
2562-2567
- 22
Hodis H N, Mack W J, Lobo R A et al..
Estrogen in the prevention of atherosclerosis.
Ann Intern Med.
2001;
135
939-953
- 23
Hodis H N, Mack W J, Azen S P et al..
for the Women's Estrogen-Progestin Lipid-Lowering Hormone Atherosclerosis Regression
Trial Research Group. Hormone therapy and the progression of coronary-artery atherosclerosis
in postmenopausal women.
N Engl J Med.
2003;
349
535-545
- 24 Wagner J D. Effects of sex steroid treatment on the cardiovascular system. In:
Blacker C Infertility and Reproductive Medicine Clinics of North America. Endocrinologic
Issues in the Care of the Mature Woman Vol. 12(3) Philadelphia; W.B. Saunders 2001:
511-533
- 25
Haarbo J.
Hormone replacement therapy and cardiovascular disease: the rabbit model.
Br J Obstet Gynaecol.
1996;
103(suppl 13)
49-52
- 26
Adams M R, Kaplan J R, Manuck S B et al..
Inhibition of coronary artery atherosclerosis by 17-beta estradiol in ovariectomized
monkeys: lack of an effect of added progesterone.
Arteriosclerosis.
1990;
10
1051-1057
- 27
Adams M R.
Register TC, Golden DL, Wagner JD, Williams JK. Medroxyprogesterone acetate antagonizes
inhibitory effects of conjugated equine estrogens on coronary artery atherosclerosis.
Arterioscler Thromb Vasc Biol.
1997;
17
217-221
- 28
Clarkson T B, Anthony M S, Wagner J D.
A comparison of tibolone and conjugated equine estrogens effects on coronary artery
atherosclerosis and bone density of postmenopausal monkeys.
J Clin Endocrinol Metab.
2001;
86
5396-5404
- 29
Cline J M.
Surgically postmenopausal monkeys for assessing risk and benefits to the breast and
endometrium.
Menopausal Med.
2001;
10
2-5
- 30
Hanke H, Hanke S, Bruck B et al..
Inhibition of the protective effect of estrogen by progesterone in experimental atherosclerosis.
Atherosclerosis.
1996;
121
129-138
- 31
Hanke H, Kamenz J, Hanke S et al..
Effect of 17-β estradiol on pre-existing atherosclerotic lesions: role of the endothelium.
Atherosclerosis.
1999;
147
123-132
- 32
Rosenfeld M E, Kauser K, Martin-McNulty B, Polinsky P, Schwartz S M, Rubanyi G M.
Estrogen inhibits the initiation of fatty streaks throughout the vasculature but does
not inhibit intra-plaque hemorrhage and the progression of established lesions in
apolipoprotein E deficient mice.
Atherosclerosis.
2002;
164
251-159
- 33
Anthony M S, Clarkson T B.
Does extent of pretreatment atherosclerosis influence the effects of conjugated equine
estrogens on atherosclerosis progression?.
J Am Coll Cardiol.
2002;
39
248 (abst)
- 34
Holm P, Andersen H L, Andersen M L, Erhardtsen E, Stender S.
The direct antiatherogenic effect of estrogen is present, absent, or reversed, depending
on the state of the arterial endothelium. A time course study in cholesterol-clamped
rabbits.
Circulation.
1999;
100
1727-1733
- 35
Losordo D W, Kearney M, Kim E A.
Variable expression of the estrogen receptor in normal and atherosclerotic coronary
arteries of premenopausal women.
Circulation.
1994;
89
1501-1510
- 36
Mäkelä S, Savolainen H, Aavik E et al..
Differentiation between vasculoprotective and uterotrophic effects of ligands with
different binding affinities to estrogen receptors α and β.
Proc Natl Acad Sci U S A.
1999;
96
7077-7082
- 37
Post W S, Goldschmidt-Clermont P J, Wilhide C C.
Methylation of the estrogen receptor gene is associated with aging and atherosclerosis
in the cardiovascular system.
Cardiovasc Res.
1999;
43
985-991
- 38
Mendelsohn M E, Karas R H.
The protective effects of estrogen on the cardiovascular system.
N Engl J Med.
1999;
340
1801-1811
- 39
Ridker P M, Hennekens C H, Buring J E, Rifai N.
C-reactive protein and other markers of inflammation in the prediction of cardiovascular
disease in women.
N Engl J Med.
2000;
342
836-843
- 40
Ridker P M, Hennekens C H, Rifai N, Buring J E, Manson J E.
Hormone replacement therapy and increased plasma concentration of C-reactive protein.
Circulation.
1999;
100
713-716
- 41
Cushman M, Legault C, Barrett-Connor E et al..
Effect of postmenopausal hormones on inflammation-sensitive proteins. The postmenopausal
estrogen/progestin interventions (PEPI) study.
Circulation.
1999;
100
717-722
- 42
Desensi A, Omodei U, Robertson C et al..
Effect of transdermal estradiol and oral conjugated equine estrogen on C-reactive
protein in retinoid-placebo trial in healthy women.
Circulation.
2002;
106
1224-1228
- 43
Vongpatanasin W, Tuncel M, Wang Z, Arbique D, Mehrad B, Jialal I.
Differential effects of oral versus transdermal estrogen replacement therapy on C-reactive
protein in postmenopausal women.
J Am Coll Cardiol.
2003;
41
1358-1363
- 44
Heinrich P C, Castell J V, Andus T.
Interleukin-6 and the acute phase response.
Biochem J.
1990;
265
621-636
- 45
Silvestri A, Gebara O, Vitale C et al..
Increased levels of C-reactive protein after oral hormone replacement therapy may
not be related to an increased inflammatory response.
Circulation.
2003;
107
3165-3169
- 46
Naghavi M, Libby P, Falk E et al..
From vulnerable plaque to vulnerable patient: a call for new definitions and risk
assessment strategies: part I.
Circulation.
2003;
108
1664-1672
- 47
Zanger D, Yang B K, Ardans J et al..
Divergent effects of hormone therapy on serum markers of inflammation in postmenopausal
women with coronary artery disease on appropriate medical management.
J Am Coll Cardiol.
2000;
36
1797-1802
- 48
Cano A, Van Baal W M.
The mechanisms of thrombotic risk induced by hormone replacement therapy.
Maturitas.
2001;
40
17-38
- 49
Koh K K, Mincemoyer R, Bui M N et al..
Effects of hormone-replacement therapy on fibrinolysis in postmenopausal wowen.
N Engl J Med.
1997;
336
683-690
- 50
Davidson M H, Maki K C, Marx P et al..
Effects of continuous estrogen and estrogen-progestin replacement regimens on cardiovascular
risk markers in postmenopausal women.
Arch Intern Med.
2000;
160
3315-3325
- 51
Kessler C M, Szymanski L M, Shamsipour Z, Muesing R A, Miller V T, Larosa J C.
Estrogen replacement therapy and coagulation: Relationship to lipid and lipoprotein
changes.
Obstet Gynecol.
1997;
89
326-331
- 52
Grady D, Wenger N K, Herrington D et al..
for the Heart and Estrogen/progestin Replacement Study Research Group. Postmenopausal
hormone therapy increases venous thromboembolic disease.
Ann Intern Med.
2000;
132
689-696
- 53
Grodstein F, Stampfer M J, Goldhaber S Z et al..
Prospective study of exogenous hormones and risk of pulmonary embolism in women.
Lancet.
1996;
348
983-987
- 54
Lobo R A, Bush T, Carr B R, Pickar J H.
Effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate
on plasma lipids and lipoproteins, coagulation factors, and carbohydrate metabolism.
Fertil Steril.
2001;
76
13-24
- 55
Wakatsuki A, Ikenoue N, Shinohara K, Watanabe K, Fukaya T.
Effect of lower dosage of oral conjugated equine estrogen on inflammatory markers
and endothelial function in healthy postmenopausal women.
Arterioscler Thromb Vasc Biol.
2004;
24
571-576
Janice D WagnerD.V.M. Ph.D.
Professor of Pathology, Comparative Medicine Clinical Research Center
Wake Forest University School of Medicine, Winston-Salem
NC 27157-1040
eMail: jwagner@wfubmc.edu