1997; 95: 1378-1385
Protection of LDL by Physiological Concentrations of 17β-Estradiol
Background: Exposure to estrogens reduces the risk for
artery disease and associated clinical events; however, the
mechanisms responsible for these
observations are not clear. Supraphysiological levels of estrogens act as
antioxidants in vitro, limiting oxidation of low-density lipoprotein (LDL), an
event implicated in atherogenesis. We investigated the conditions under which
physiological concentrations of 17β-estradiol (E2) inhibit oxidative modification of LDL.
Conclusions: Exposure of LDL to
physiological levels of E2 in a plasma milieu is associated with enhanced
resistance to Cu2+-mediated oxidation and incorporation of E2 derivatives into LDL. This antioxidant
capacity may be another means by which E2 limits coronary
artery disease in women.
Antioxidant protection of LDL by physiologic
concentrations of estrogens is specific for 17-beta-estradiol
Atherosclerosis Volume 138, Issue 2 , Pages 255-262, June 1998
Risk for coronary artery disease is reduced by exposure to
estrogens, although the mechanisms of protection are not fully defined. Recent
observations have shown that physiologic concentrations of 17-beta-estradiol (E2) exhibit antioxidant activity in vitro, slowing the formation
of atherogenic, oxidized low-density lipoprotein (LDL). Using concentrations physiologically relevant for premenopausal
women, we compared the antioxidant potency of estrone (E1), E2, and estriol
(E3) as measured
by their ability to inhibit LDL oxidation. Plasma
was incubated with 10 nmol/l
estrogens for 4 h at 37°C, followed by LDL isolation and Cu2+-mediated
oxidation in conjugated diene assays. Only E2 demonstrated antioxidant activity at these physiologic
concentrations. Resistance to oxidation
was not associated with sparing of endogenous α-tocopherol
during plasma incubations. Incubation of plasma with radiolabeled estrogens
yielded similar association of E1 and E2 with LDL which was
5–8-fold greater than the association of E3. Chromatographic analysis revealed the association of authenic E1with LDL, while plasma-derived E2 esters were the major form of E2 associated with LDL which was resistant to oxidation. Thus, conjugation in plasma and association of E2 esters with LDL appear to be specific for E2 among these estrogens and render this LDL resistant to oxidation by
Cu2+. This antioxidant activity may be
another means whereby E2 protects against coronary artery disease in women.
The inhibition of low-density lipoprotein oxidation by 17-βestradiol
Metabolism Volume 41, Issue 10, October 1992, Pages 1110–1114
The antioxidant activities of 17-β-estradiol (E2) and other steroid
studied by determining their effect on copper-catalyzed (cell-free) and
mononuclear cell-mediated oxidation of low-density lipoproteins (LDL), as measured by the
production of thiobarbituric acid-reactive substances (TBARS). The oxidation of LDL increased linearly with
concentrations ranging from 0 to 10 μmol/L. E2 at a concentration of
1 μmol/L inhibited LDL oxidation by 37% to 62%
at the various
concentrations of copper. In a time-course study, E2 at 1 μmol/L delayed the onset of LDL oxidation in the presence
of 5 μmol/L
copper. E2 (1 μmol/L) inhibited TBARS production catalyzed by 5 μmol/L copper
by 54%, compared with 60% inhibition by 1 μmol/L butylated hydroxytoluene
(BHT), a known inhibitor of lipid peroxidation. Estriol at 5 μmol/L
decreased LDL oxidation by 49%.
(DHEA), testosterone, and estrone had no significant effects.
E2 was also an effective inhibitor of mononuclear cell (MNC)-mediated oxidation
of LDL, but had
no effect on superoxide production by these cells. The onset of TBARS formation
from cell-mediated LDL oxidation was also delayed
incubation with 1 μmol/L E2. The results indicate that estrogen may protect
against atherosclerosis by inhibiting lipoprotein oxidation.
This study shows that MPA blocks the anti-oxidation
effect of estrogen upon LDL.
Estradiol 17β inhibition of LDL oxidation and endothelial cell
cytotoxicity is opposed by progestins to different degrees
Atherosclerosis Volume 148, Issue 1,
January 2000, Pages 31–41
oppose the effects of estrogens in many biological systems, but it is not known
if progestins oppose the antioxidant
effects of estrogen and to differing degrees. To test these questions, the
effects of various sex steroids on LDL oxidation and cytotoxicity
studied in the absence or presence of endothelial cells [in large blood vessels].
Freshly isolated LDL was incubated in the presence
of Cu++ in the absence or presence of
cultured bovine aortic endothelial cells in phenol red-free medium and without
or with hormones in 0.5% ethanol. The hormones included 17β-estradiol (E2),
progesterone (Pg), norgestimate (NGM), levonorgestrel (LNG), and
medroxyprogesterone acetate (MPA). LDL oxidation was measured as
conjugated dienes, lipid peroxides, and TBARS, and cyotoxicity by tetrazolium
salt reduction (MTT reduction). Progestins diminished conjugated diene lag
phase, accelerated lipid peroxide and TBARS production in the absence and
presence of cells and accelerated cytotoxicity. When E2 and progestin were incubated
with cells at a molar ratio of 1:5, lipid peroxides were reduced from baseline
by E2 alone
31%, E2/Pg 29%, E2/NGM
16%, E2/LNG 9% (all P<0.05 or more)
and E2/MPA 8% (ns) (E2 or E2/Pg>E2/NGM,
E2/LNG and E2/MPA
or E2/MPA [P<0.05]).
MTT reduction followed a similar gradient, greatest with E2 alone, least with E2/MPA.
Conclusions: Progestins promote LDL oxidation and, conjointly,
cell cytotoxicity. Progestins oppose the antioxidant and cytoprotective effects
of estrogen when given in combination. MPA and LNG have the strongest prooxidant and cytotoxic effects,
which may limit the cardiovascular benefit of estrogen during combined
administration in vivo.
article because when considering CVD and morality
rates this article confirms that it isn’t the level of cholesterol and bad
cholesterol LDL that causes CVD and death, but rather oxidative damage (the
articles above). MPA which doesn’t
affect cholesterol levels, but rather blocks estradiol’s anti-oxidative
property, and as a consequence very significant increase CVD and death
Fertility and Sterility
and Metabolic Medicine, Division of Medicine, Imperial College School of
Medicine, London, United Kingdom. firstname.lastname@example.org
Effects of postmenopausal hormone replacement therapy on lipid,
lipoprotein, and apolipoprotein (a) concentrations: analysis of studies
published from 1974-2000.
Objective: To establish reference estimates of the effects of different
hormone replacement therapy (HRT) regimens on lipid and lipoprotein levels.
Design: Review and pooled analysis of prospective studies published up until
the year 2000.
Setting: Clinical trials centers, hospitals, menopause clinics.
Patient(s): Healthy postmenopausal women.
Intervention(s): Estrogen alone, estrogen plus progestogen, tibolone, or
raloxifene in the treatment of menopausal symptoms.
Main Outcome Measure(s): Serum high- and low-density lipoprotein (HDL and LDL)
cholesterol, total cholesterol, triglycerides, and lipoprotein (a).
Result(s): Two-hundred forty-eight studies provided information on the
effects of 42 different HRT regimens. All estrogen alone regimens raised HDL
cholesterol and lowered LDL and total cholesterol. Oral estrogens raised
triglycerides. Transdermal estradiol 17-beta lowered triglycerides.
Progestogens had little effect on estrogen-induced reductions in LDL and total
cholesterol. Estrogen-induced increases in HDL and triglycerides were opposed
according to type of progestogen, in the order from least to greatest effect:
dydrogesterone and medrogestone, progesterone, cyproterone acetate,
medroxyprogesterone acetate, transdermal norethindrone acetate, norgestrel, and
oral norethindrone acetate. Tibolone decreased HDL cholesterol and triglyceride
levels. Raloxifene reduced LDL cholesterol levels. In 41 studies of 20
different formulations, HRT generally lowered lipoprotein (a).
Conclusion(s): Route of estrogen administration and
type of progestogen determined differential effects of HRT on lipid and
lipoprotein levels. Future work will focus on the interpretation of the
clinical significance of these changes.