Epidemiological studies have shown a 50% reduction
in coronary heart disease (CHD) after estrogen replacement therapy (ERT) in postmenopausal women (1-2). This protective effect of estrogen is presumably due to its ability to favorably alter
low/high density lipoprotein (LDL/HDL) ratios and decrease vascular reactivity and oxidative stress (3)…. Brazilian Journal of Medical and Biological Research, Braz J Med Biol Res vol.35 no.3 Ribeirão Preto Mar. 2002 at http://www.scielo.br/scielo.php?pid=S0100-879X2002000300001&script=sci_arttext&tlng=en
Epidemiological
Studies showing MI reduction
1. Barrett-Connor
E & Grady D (1998). Hormone replacement therapy, heart disease and other considerations. Annual Review of Public Health,
19: 35-72.
2. Stampfer
MJ & Colditz GA (1991). Estrogen replacement therapy and coronary heart disease: a quantitative assessment of epidemiological
evidence. Preventive Medicine, 20: 47-63.
Large numbers
of hormone
replacement therapies (HRTs) are available for the treatment of menopausal
symptoms. It is still unclear whether some are more deleterious than others
regarding breast cancer risk. The goal of this study was to assess and compare
the association between different HRTs and breast cancer risk, using data from
the French E3N cohort study. Invasive breast cancer cases were identified
through biennial self-administered questionnaires completed from 1990 to 2002.
During follow-up (mean duration 8.1 postmenopausal years), 2,354 cases of
invasive breast cancer occurred among 80,377 postmenopausal women. Compared
with HRT never-use, use of estrogen alone was associated with a significant
1.29-fold increased risk (95% confidence interval 1.02–1.65). The association
of estrogen-progestagen combinations with breast cancer risk varied
significantly according to the type of progestagen: the relative risk was
1.00 (0.83–1.22) for estrogen–progesterone, 1.16 (0.94–1.43) for
estrogen–dydrogesterone, and 1.69 (1.50–1.91) for estrogen combined with other
progestagens. This latter category involves
progestins with different physiologic activities (androgenic, nonandrogenic,
antiandrogenic), but their associations with breast cancer risk did not differ
significantly from one another. This study found no evidence of an association
with risk according to the route of estrogen administration (oral or
transdermal/percutaneous). These findings suggest that the choice of the
progestagen component in combined HRT is of importance regarding breast cancer
risk; it could be preferable to use progesterone
or dydrogesterone
* estrogen-progesterone group was rated at 1.00, those who never used estrogen at 1.29, thus a 29% reduction
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
Estrogen's protective mechanism
An excellent review paper of HRT with information on methods
of action. There is a vast difference
between Prempro, the worst of HRTs, and the natural alternatives of
estradiol and progesterone. Prempro was
used by the 3 purportedly definitive studies mentioned in the Abstract.
Brazilian Journal of
Medical and Biological Research
On-line version ISSN 1414-431X
Braz J
Med Biol Res vol.35 no.3 Ribeirão Preto Mar. 2002
http://dx.doi.org/10.1590/S0100-879X2002000300001
Braz J Med Biol Res, March
2002, Volume 35(3) 271-276 (Mini-Review)
Estrogen
replacement therapy and cardio-protection: mechanisms and controversies
M.T.R. Subbiah
Division of Endocrinology, Department of
Internal Medicine, University of Cincinnati Medical Center, Cincinnati, OH, USA
Abstract
Text
References
Acknowledgments
Correspondence and
Footnotes
Abstract 
Epidemiological and case-controlled studies
suggest that estrogen replacement therapy might be beneficial in terms of
primary prevention of coronary heart disease (CHD). This beneficial effect of
estrogens was initially considered to be due to the reduction of low density
lipoproteins (LDL) and to increases in high density lipoproteins (HDL). Recent
studies have shown that estrogens protect against oxidative stress and decrease
LDL oxidation. Estrogens have direct effects on the arterial tissue and
modulate vascular reactivity through nitric oxide and prostaglandin synthesis.
While many of the effects of estrogen on vascular tissue are believed to be
mediated by estrogen receptors a and ß, there is
evidence for `immediate non-genomic' effects. The role of HDL in interacting
with 17ß-estradiol including its esterification and transfer of esterified
estrogens to LDL is beginning to be elucidated. Despite the suggested positive
effects of estrogens, two recent placebo-controlled clinical trials in women
with CHD did not detect any beneficial effects on overall coronary events with
estrogen therapy. In fact, there was an increase in CHD events in some women.
Mutations in thrombogenic genes (factor V Leiden, prothrombin mutation, etc.)
in a subset of women may play a role in this unexpected finding. Thus, the
cardioprotective effect of estrogens appears to be more complicated than
originally thought and requires more research.
Key words: Estrogen
therapy, Postmenopausal women, Cardiovascular disease, Plasma lipoproteins,
Lipoprotein oxidation, Estrogen receptors, Thrombosis, Nitric oxide synthesis
Introduction
Epidemiological studies have shown a 50% reduction
in coronary heart disease (CHD) after estrogen replacement therapy (ERT) in postmenopausal
women (1-2). This protective effect of estrogen is presumably due to its
ability to favorably alter low/high density lipoprotein (LDL/HDL) ratios and
decrease vascular reactivity and oxidative stress (3). Three major
placebo-controlled trials designed to study whether ERT reduces CHD have
questioned this protective effect of estrogen. The Heart and Estrogen/Progestin
Replacement Study (HERS) was the first placebo-controlled trial. HERS noted that
ERT not only failed to reduce the overall rate of coronary events, but actually
increased CHD in the first year with a 89% increase in thromboembolic events [used
Prempro, the worst of HRTs]. (4). In the
Estrogen and Atherosclerosis (ERA) Trial (5) there was no decrease in coronary
artery disease progression with ERT in postmenopausal women with at least one
coronary artery stenosis. In the Women's Health Initiative Hormone Replacement
Trial (WHI-HRT) which includes postmenopausal women with an intact uterus
taking ERT plus progestin and those without a uterus taking only ERT (6,7), a
small increase in the number of myocardial infarctions, strokes and
thromboembolism was noted in women taking active hormones compared to the
placebo group. Along with HERS and ERA, WHI-HRT was the third trial to suggest
that ERT is not cardioprotective in postmenopausal women with CHD and may
actually increase thromboembolism and CHD events [all used Prempro, the worst
of HRTs, which consists of Premarin and MPA]. Several hypotheses have been
advanced to explain these unexpected findings. The most widely accepted notion
is that thrombosis may be limited to a subset of women on estrogen who may be
increasingly susceptible to thrombosis because of confounding risk factors,
i.e., genetic mutations (8-11) in thrombogenic factors (factor V Leiden,
prothrombin and plasminogen activator inhibitor gene mutations). Premarin (a
brand of conjugated equine estrogen mixture marketed by Wyeth/Ayerst Labs,
Radnor, PA, USA) is the estrogen used in all major clinical trials. To date,
the exact composition of Premarin is not known. Recently, another brand of
conjugated estrogen called Cenestin (containing 10 estrogens in a known composition
marketed by Duramed Pharmaceuticals) has received approval for the treatment of
menopausal symptoms (12). Despite these concerns about thrombosis, a
significant portion of postmenopausal women in the United States continue to
take ERT for relief of menopausal symptoms and potential benefits in terms of
osteoporosis and cardiovascular diseases. In terms of cardioprotection, studies
continue to document improvements in risk factors related to heart disease
(2,3,13). Some of these studies are discussed below.
Estrogen and plasma lipids
Considerable data are available that document an
increase in HDL and a reduction of LDL cholesterol following estrogen therapy
(14). Studies have clearly established that estrogen decreases total plasma
cholesterol (15) and increases or maintains plasma triglyceride levels (15-17).
With the addition of progestin, plasma total cholesterol, LDL cholesterol and
triglyceride levels decrease (16-18). The addition of progestin, however,
slightly blunts the increase in HDL levels (16-18). HDL2 levels are increased
with estrogen, but changes in HDL3 have been inconsistent (17,18). Estrogen
with or without progestin significantly lowered plasma lipoprotein(a) levels
(19).
Estrogens as antioxidants
Recent studies have documented that estrogens
are potent antioxidants and decrease LDL oxidation in
vitro andin vivo (3,20). Although earlier studies have
used pharmacological concentrations of estrogens to document antioxidant
activity, recently it has been shown that 17ß-estradiol is active even at
physiological concentrations (21). Furthermore, the potency of catechol
estrogens is far greater than that of parent estrogens (22). Studies on the
mechanism of estrogen antioxidant effects have shown that estrogens strongly
inhibit superoxide formation with minor effects on hydrogen peroxide and
hydroxyl radical formation (23). While estrogens decrease lipid peroxidation
and formation of reactive oxygen species (23), androgens and progestins
increase oxidative stress parameters (24). Clinical studies on humans using
E2-based preparations have clearly shown decreased LDL oxidation (25,26), while
other studies using conjugated estrogens have yielded conflicting results
(27,28). Whether these differences are due to different estrogen preparations
or time frames is not clear at this time.
Estrogen and vascular tone
Currently, there is a strong interest in the
role of estrogens in mediating vascular tone and response to vasoactive agents.
Studies have documented that E2 can induce relaxation
of coronary arteries, reverse
acetylcholine-induced vasoconstriction and improve exercise-induced myocardial
ischemia in women with coronary artery disease (29-32). Collins et al. (33)
showed that E2 decreases acetylcholine-induced coronary artery responses only
in women, but not in men. These vasodilatory effects of estrogen are largely
believed to be mediated by increased synthesis and release of nitric oxide, a
potent relaxant of vascular smooth muscle (34). Short-term E2 treatment
significantly increased plasma nitric oxide levels in postmenopausal women
(35). Synthesis and release of nitric oxide in cultured endothelial cells are
increased significantly by estrogens (36,37) and inhibited by androgens (37).
Some investigators have been able to demonstrate (38) increased expression of
endothelial nitric oxide synthase in women treated with estrogens. The effects
of estrogens on nitric oxide synthesis is believed to be manifested by rapid
non-genomic (without changes in gene expression) effects (38,39). Elucidation of
this phenomenon has indicated that the non-genomic effects may still be
modulated by estrogen receptors and the readers are referred to an excellent
review of this topic by Mendelsohn and Karas (39).
Other mechanisms of
estrogen action
Some of the other mechanisms responsible for
estrogen-mediated cardioprotection include increases
in vascular
prostacyclin synthesis (40), inhibition of aortic smooth muscle cell
proliferation (41) and decreases in hemostatic factors (42,43) like fibrinogen
and plasminogen activator inhibitor-1. The expression of vascular
cell adhesion molecule, a chemotactic factor produced by endothelial cells that
attracts monocytes (44), is also inhibited by estrogens (45) and stimulated by
androgens and progestins (46). The readers are referred to a critical review by
Farhat et al. (47) on some of these mechanisms.
Role of estrogen receptors
Recent research has provided a great deal of
information on the mechanisms involved in the intracellular binding of
estrogens to estrogen receptors (a and ß), translocation
to the nucleus and the occurrence of genomic effects upon binding to estrogen
response elements (48-50). However, the significance of these two receptors in
the manifestation of the cardio-protective effect of estrogen is still open to
question since mice lacking both of these receptors continue to demonstrate
inhibition of intimal proliferation after vascular injury (51). The
distribution of these receptors in vascular and other tissues and their
interactions with estrogens and anti-estrogens are beyond the scope of this
article and have been covered in some excellent recent reviews (52). The
carcinogenic effect of exogenous estrogens either by estrogen receptor
activation and cell proliferation (53) or by DNA adduct formation by metabolites
of catechol estrogens (54) in breast tissues has been of much concern in
postmenopausal women. There is strong evidence suggesting that long-term
estrogen use increases the risk for endometrial and breast cancer in women on
estrogen therapy (55,56). Consequently there is a lot of interest in developing
"designer estrogens" that do not have adverse effects on breast and
endometrium, yet retain their beneficial effects on the bone and cardiovascular
system. [Other studies fail to find this see Breast Cancer Res Treat. 2008
January; 107(1): 103–111]
Recently discovered selective estrogen receptor
modulators seem to have no estrogen agonistic effects on breast and endometrial
tissue (57), but their long-term cardiovascular benefits are still being assessed.
Significance of
differential delivery of estrogens
Therefore, considerable attention has been
focused on targeting estrogens to desired tissues (ex: vascular tissue or site
of atherosclerosis, bone, etc.). Our laboratory has been interested in achieving
differential effects of estrogens by differential delivery to cells. During
studies exploring this possibility, we have shown (58) that a significant
fraction of 17ß-estradiol (<10%) is associated with lipoproteins
(predominantly with HDL), where it can be subsequently esterified and
transferred to LDL (59,60). These steps also appear
to be important in the
manifestation of the antioxidant effect of estrogens (61).
Interestingly, increasing hydrophobicity of the estrogen molecule (by
esterification) increases its association with LDL (61,62), providing an
opportunity to target estrogen derivatives complexed with native or modified
LDL to vascular tissues. Future research should be directed at targeting
estrogens to specific tissues without undesirable side effects.
References
1. Barrett-Connor E & Grady D (1998).
Hormone replacement therapy, heart disease and other considerations.Annual
Review of Public Health, 19:
35-72. [ Links ]
2. Stampfer MJ & Colditz GA (1991). Estrogen
replacement therapy and coronary heart disease: a quantitative assessment of
epidemiological evidence. Preventive Medicine, 20:
47-63. [ Links ]
3. Subbiah MTR (1998). Mechanisms of cardioprotection
by estrogens. Proceedings of the Society for Experimental Biology and
Medicine, 217:
23-29. [ Links ]
4. Hulley S, Grady D & Bush T (1998). Heart
and Estrogen/Progestin Replacement Study (HERS). Randomized trial of estrogen
plus progestin for secondary prevention of coronary heart disease in
postmenopausal women. Journal of the American Medical Association,
280: 605-612. [ Links ]
5. Herrington DM, Reboussin DM, Brosnihan KB,
Sharp PC, Schumaker SA, Snyder TE, Furberg CD, Kowalchuk CJ, Stuckey TJ, Rogers
W, Givens DH & Waters D (2000). Effects of estrogen replacement on the
progression of coronary artery atherosclerosis. New England Journal of
Medicine, 343: 522-529. [ Links ]
6. McGowan JA & Pottern L (2000). Commentary
on the Women's Health Initiative. Maturitas, 34:
109-112. [ Links ]
7. The Women's Health Initiative Study Group
(1998). Design of the Women's Health Initiative clinical trial and
observational study. Controlled Clinical Trials, 19:
61-109. [ Links ]
8. Glueck CJ, Wang P, Fontaine RN, Tracy T,
Sieve-Smith L & Lang JE (1999). Effect of exogenous estrogen on
atherothrombotic vascular disease risk related to the presence or absence of
the factor V Leiden mutation (resistance to activated protein C). American
Journal of Cardiology, 84:
549-554. [ Links ]
9. Glueck CJ, Wang P, Fontaine RN, Sieve-Smith L
& Lang JE (2001). Interaction of estrogen replacement therapy with the
thrombophilic 20210 G/A prothrombin gene mutation for atherothrombotic vascular
disease: a cross-sectional study of 275 hyperlipidemic women. Metabolism,
50: 360-365. [ Links ]
10. Psaty BM, Smith NL, Lemaitre RN, Vos HL,
Heckbert SR, LaCoix E & Rosendaal FR (2001). Hormone replacement therapy,
prothrombotic mutations and the risk of incident non-fatal myocardial
infarction in postmenopausal women. Journal of the American Medical
Association, 285:
906-913. [ Links ]
11. Gardemann A, Lohre J, Katz N, Tillmans H,
Hehrlein FW & Haberbosch W (1999). The 4G/4G genotype of the plasminogen
activator inhibitor 4G/5G gene polymorphism is associated with coronary
atherosclerosis in patients at high risk for the disease. Thrombosis
and Haemostasis, 82:
1121-1126. [ Links ]
12. Stevens RE, Hanford C, Wasan S, Cusack SL
& Phelps KV (2000). A 12 week clinical trial determining the efficacy of
synthetic conjugated estrogen A (SCE) in the treatment of vasomotor symptoms in
African American and Caucasian postmenopausal women. International
Journal of Fertility and Women's Medicine, 45:
264-272. [ Links ]
13. Gerhard M & Ganz P (1995). How do we
explain the clinical benefits of estrogen? Circulation, 92:
5-8. [ Links ]
14. Paganini-Hill A, Dworsky R & Krauss RM
(1996). Hormone replacement therapy, hormone levels and lipoprotein cholesterol
concentration in elderly women. American Journal of Obstetrics and
Gynecology, 174:
897-902. [ Links ]
15. Farish E, Spowart K, Barnes JF, Fletcher CD,
Hart PM & Degen MM (1996). Effects of postmenopausal hormone replacement
therapy on lipoproteins including Lp(a) and LDL subfractions. Atherosclerosis,
126: 77-84. [ Links ]
16. Landenpara S, Puolakka J, Pyorola T, Luotola
H & Taskinen MR (1996). Effects of postmenopausal estrogen/progestin
replacement therapy on LDL particles: comparison of transdermal and oral
treatment regimens.Atherosclerosis, 122:
153-162. [ Links ]
17. Miller VT, Muessing RA, Larosa JC, Phillips
EA & Stilman RJ (1991). Effects of conjugated estrogen with and without
three different progestins on lipoproteins, high density lipoprotein
sub-fractions and apolipoprotein A1.Obstetrics and Gynecology, 77:
235-240. [ Links ]
18. Ottoson U, Johansson B & Von Schoultz B
(1985). Subfractions of high density cholesterol during estrogen replacement
therapy: a comparison between progestogens and natural progesterone. American
Journal of Obstetrics and Gynecology, 151:
746-750. [ Links ]
19. Soma MR, Oswago I, Paoletti R, Fumagalli R,
Morriset JD, Moschia M & Crosignani P (1993). The lowering of lipoprotein
(a) induced by estrogen plus progesterone therapy in postmenopausal
women. Archives of Internal Medicine, 153:
1402-1408. [ Links ]
20. Ayers S, Tang M & Subbiah MTR (1996).
Estradiol-17ß as an antioxidant: distinct features when compared to other fat
soluble antioxidants. Journal of Laboratory and Clinical Medicine,
128: 367-375. [ Links ]
21. Shwaery GT, Vita GA & Keaney Jr JF
(1997). Antioxidant protection of LDL by physiological concentrations of
17ß-estradiol. Requirement for estradiol modification. Circulation,
95: 1378-1385. [ Links ]
22. Tang M, Abplanalp W & Subbiah MTR
(1996). Superior and distinct antioxidant effect of selected estrogen
metabolites on lipid peroxidation. Metabolism, 45:
411-414. [ Links ]
23. Ayers S, Abplanalp W, Liu JH & Subbiah
MTR (1998). Mechanisms involved in the protective effects of estradiol-17ß on
lipid peroxidation and DNA damage. American Journal of Physiology,
274: E1002-E1008. [ Links ]
24. Zhu X, Bonet B & Knopp RH (1997).
17ß-Estradiol, progesterone and testosterone inversely modulate low density
lipoprotein oxidation and cytotoxicity in cultured placental trophoblast and
macrophages. American Journal of Obstetrics and Gynecology, 177:
196-209. [ Links ]
25. Sack MN, Rader DJ & Cannon Jr RO (1994).
Oestrogen and inhibition of oxidation of low density lipoproteins in
postmenopausal women. Lancet, 343:
269-270. [ Links ]
26. Wilcox JG, Hwang J, Hodis HN, Sevanian A,
Stanczyk FZ & Lobo RA (1997). Cardioprotective effects of individual
conjugated equine estrogens through their possible modulation of insulin
resistance and LDL oxidation in postmenopausal women. Fertility and
Sterility, 67: 57-62. [ Links ]
27. Guetta V, Lush RM, Figg WD, Waclawiw MA
& Cannon Jr RO (1995). Effects of antiestrogen tamoxifen and conjugated
estrogens on low density lipoprotein concentration and oxidation in
postmenopausal women. Journal of the American College of Cardiology,
76: 1072-1073. [ Links ]
28. McManus J, McEnany J, Thompson W & Young
IS (1997). The effect of hormone replacement therapy on the oxidation of low
density lipoprotein in postmenopausal women. Atherosclerosis, 135:
73-81. [ Links ]
29. Jiang C, Sarrel PM, Poole-Wilson PA &
Collins P (1992). Acute effect of 17 beta estradiol on rabbit coronary artery
contractile response to endothelin-1. American Journal of Physiology,
263: H271-H275. [ Links ]
30. Williams JK, Adams MR, Herrington DM &
Clarkson TB (1992). Short term administration of estrogens and vascular
response of atherosclerotic coronary arteries. Journal of the American
College of Cardiology, 20:
452-457. [ Links ]
31. Reis SE, Gloth ST, Blumenthal RS, Resar JR,
Zacur HA, Gersenblith G & Brinker JA (1994). Ethinyl estradiol acutely
attenuates abnormal coronary vasomotor response to acetylcholine in
postmenopausal women.Circulation, 89:
52-60. [ Links ]
32. Rosano GMC, Sarrell RM, Poole-Wilson PA
& Collins D (1993). Beneficial effect of estrogen on exercise induced
myocardial ischemia in women with coronary artery disease. Lancet,
362: 133-136. [ Links ]
33. Collins P, Giuseppe MC, Rosano MC, Sarrell
PM, Ulrich L, Adamopoulos S, Beale CM, McNeill JG & Poole-Wilson A (1995).
17ß-Estradiol attenuates acetyl choline induced coronary arterial constriction
in women but not men with coronary heart disease. Circulation, 92:
24-30. [ Links ]
34. Collins P, Shay J, Jiang C & Moss J
(1994). Nitric oxide accounts for dose dependent estrogen mediated coronary
relaxations after acute estrogen withdrawal. Circulation, 90:
1964-1968. [ Links ]
35. Cicinelli EC, Ignarro LJ, Schonauer LM,
Matteo MG, Galantino P & Balzano G (1998). Effects of short term
transdermal estradiol administration on plasma levels of nitric oxide in
postmenopausal women. Fertility and Sterility, 69:
58-61. [ Links ]
36. Hishikawa K, Nakaki T & Marumo T (1995).
Upregulation of nitric oxide synthase by estradiol in human endothelial
cells. FEBS Letters, 360:
291-293. [ Links ]
37. Singh R, Pervin S, Shryne J, Gorski R &
Chaudhari G (2000). Castration increases and androgens decrease nitric oxide
synthase activity in the brain: physiological implications. Proceedings
of the National Academy of Sciences, USA, 97:
3672-3677. [ Links ]
38. Chen Z, Yuhanna IS, Galcheva-Gargova Z,
Karas RH, Mendelsohn ME & Shaul PW (1999). Estrogen receptor amediates
the non-genomic activation of endothelial nitric oxide synthase by
estrogen. Journal of Clinical Investigation, 103: 401-406. [ Links ]
39. Mendelsohn ME & Karas RH (1999). The
protective effects of estrogen on the cardiovascular system. New
England Journal of Medicine, 340:
1801-1811. [ Links ]
40. Fogelberg M, Vesterquist O, Diezfalusky U
& Henriksson P (1990). Experimental atherosclerosis: effect of estrogen and
atherosclerosis on thromboxane and prostacyclin formation. European
Journal of Clinical Investigation, 20:
105-110. [ Links ]
41. Bhalla RC, Toth KF, Bhatty RA, Thompson LP
& Sharma RS (1997). Estrogen reduces proliferation and agonist induced
calcium increase in coronary artery smooth muscle cells. American
Journal of Physiology, 272: H1996-H2003. [ Links ]
42. Saloma V, Rasi V & Pekkanen J (1997).
Association of hormone replacement therapy with hemostatic and other
cardiovascular risk factors. The FINRISK Hemostasis Study. Arteriosclerosis,
Thrombosis, and Vascular Biology, 15:
1549-1555. [ Links ]
43. Koh KK, Mincemoyer R & Bui MN (1997).
Effect of hormone replacement therapy on fibrinolysis in postmenopausal
women. New England Journal of Medicine, 336: 683-690. [ Links ]
44. Kume N, Cybulsky MI & Gimbrone MA
(1992). Lysophosphatidylcholine, a component of atherogenic lipoproteins,
induces mononuclear leukocyte adhesion molecules in cultured human and rabbit
arterial endothelial cells. Journal of Clinical Investigation, 90:
1138-1144. [ Links ]
45. Caulin-Glazer T, Watson TA, Pardi R &
Bender JR (1996). Effects of estradiol on cytokine-induced endothelial cell
adhesion molecule expression. Journal of Clinical Investigation,
98: 36-42. [ Links ]
46. McCrohon JA, Jessup W, Handelsman DJ &
Celermajer DS (1999). Androgen exposure increases human monocyte adhesion to
vascular endothelium and endothelial cell expression of vascular cell adhesion
molecule.Circulation, 99:
2317-2322. [ Links ]
47. Farhat MY, Levigne MC & Ramwell PW
(1996). The vascular protective effect of estrogen. FASEB Journal,
10: 615-624. [ Links ]
48. Pettersson K, Grandien K, Kuiper GJM &
Gustafsson JA (1997). Mouse estrogen receptor beta forms estrogen response
element-binding heterodimers with estrogen receptor alpha. Molecular Endocrinology,
11: 1486-1496. [ Links ]
49. Enmark E, Pelto-Huikko M, Grandien K, Fried
G, Lagerkrantz S, Lagerkrantz J, Nordenskjold M & Gustafsson JA (1997).
Human estrogen receptor beta: gene structure, chromosomal localization and
expression pattern. Journal of Clinical Endocrinology and Metabolism,
82: 4258-4265. [ Links ]
50. Kuiper GJM, Carlsson B, Grandien K, Enmark
E, Haagblad J & Gustafsson JA (1997). Comparison of the ligand binding
specificities and transcript tissue distribution of estrogen receptors a and
ß. Endocrinology, 138:
863-870. [ Links ]
51. Karas RH, Schulten H, Pare G, Aromovitz MJ,
Ohlsson C, Gustafsson JA & Mendelsohn ME (2001). Effect of estrogen on the
vascular injury response in estrogen receptor alpha, beta (double) knockout
mice. Circulation Research, 89:
534-539. [ Links ]
52. Nilsson S, Makela S, Trueter E, Thomsen J,
Andersson G, Enmark E, Tujague M, Pettersson K, Warner M & Gustafsson J
(2001). Mechanisms of estrogen action. Physiological Reviews, 81:
1536-1565. [ Links ]
53. Reed SE, Murthy MS, Kaufman M & Scanlan
EF (1996). Endocrine and paracrine hormones in the promotion, progression and
reoccurrence of breast cancer. British Journal of Surgery, 83:
1037-1046. [ Links ]
54. Roy D & Liehr JG (1999). Estrogen, DNA
damage and mutations. Mutation Research, 424:
107-115. [ Links ]
55. Colditz GA (1996). Postmenopausal estrogen
and breast cancer. Journal of the Society for Gynecologic Investigation,
3: 50-56. [ Links ]
56. Zumoff B (1993). Biological and
endocrinological insights into the possible breast cancer risk from menopausal
estrogen replacement therapy. Steroids, 58:
196-204. [ Links ]
57. Bryant HU & Dere WH (1998). Selective
estrogen receptor modulators: an alternative to estrogen replacement
therapy. Proceedings of the Society for Experimental Biology and
Medicine, 217:
45-52. [ Links ]
58. Tang M, Abplanalp W & Subbiah MTR
(1997). Association of estrogens with human plasma lipoproteins: studies using
estradiol-17ß and its hydrophobic derivative. Journal of Laboratory and
Clinical Medicine, 129:
447-452. [ Links ]
59. Pahuja SL & Hochberg RB (1994). A
comparison of the esterification of steroids by rat lecithin: cholesterol acyl
transferase and acyl coenzyme A:cholesterol transferase. Endocrinology,
136: 180-186. [ Links ]
60. Provost PR, Lavallee B & Belanger A
(1997). Transfer of dehydroepiandrosterone and pregnenolone-fatty acid esters
between human lipoproteins. Journal of Clinical Endocrinology and
Metabolism, 82:
182-187. [ Links ]
61. Abplanalp W, Ayers S, Scheiber M, Kessel B,
Liu J & Subbiah MTR (2000). Potential role of HDL in the manifestation of
antioxidant effect of estrogens on LDL peroxidation. European Journal
of Endocrinology, 142:
79-83. [ Links ]
62. Abplanalp W & Subbiah MTR (2001). Uptake
and protection against oxidative stress by estrogen esters in THP-1 human
macrophage cell lines. Gynecologic and Obstetric Investigation, 51:
81-84. [ Links ]
Acknowledgments
The author is indebted to many colleagues who
contributed significantly to some of these studies.
Correspondence
and Footnotes
Address for correspondence: M.T.R.
Subbiah, Division of Endocrinology, Department of Internal Medicine, University
of Cincinnati, Medical Center, M.L.547, 234 Bethesda Ave, Cincinnati, OH 45267,
USA. Fax: +1-513-221-1891. E-mail: ravi.subbiah@uc.edu
Presented at the XVI Annual Meeting of the
Federação de Sociedades de Biologia Experimental, Caxambu, MG, Brazil, August
29 - September 1, 2001. Research supported by the National Heart, Lung and
Blood Institute (No. HL-50881). Received December 10, 2001. Accepted January
22, 2002.
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
* Oxidative damage is the key cause
for the development of atherosclerosis http://healthfully.org/heart/id15.html
