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University of Washington Northwest Lipid Research Clinic Seattle, Washington 98104
Address correspondence and requests for reprints to: Robert H. Knopp, M.D., University of Washington, Northwest Lipid Research Clinic, 326 Ninth Avenue, #359720, Seattle, Washington 98104.
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Introduction |
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The results of Campos et al. (2), show that the hypertriglyceridemia associated with estrogen therapy, in this case 2 mg estradiol 17ß daily, given in the micronized form for 6 weeks is associated with an increase in light, or buoyant, very low density lipoprotein (VLDL). Smaller, more dense, and less buoyant forms of lipoproteins, including dense VLDL and intermediate density lipoproteins, did not increase in their concentrations. The reduction in LDL was associated primarily with the reduction in light LDL with no change in the smaller, more dense LDL.
As a generalization, the rates of formation of all lipoprotein
fractions are increased under the influence of estrogen (Fig. 1
), but their removal rates are variably
increased, so that most of the fractions except the light VLDL fraction
do not increase, or as in the case of light LDL, actually decrease.
Particularly notable is the fact that the intermediate density
lipoprotein, a very atherogenic species in its own right, does not
increase with estrogen therapy, again because the rate of removal keeps
pace with the rate of production.
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Much more likely to be atherogenic are those conditions associated with increases in the less buoyant or dense VLDL, typically in individuals who have familial combined hyperlipidemia (5). Dense VLDL is more likely to be retained in the arterial wall, causing atherogenesis (6). According to Campos et al. (2), concentrations of this subfraction are not increased at all with estrogen therapy, neither in cholesterol, triglyceride, or apo B moieties. In addition, the more rapid rate of transport in the bloodstream or flux of dense VLDL might render it less atherogenic than would be expected, as discussed above.
The intermediate density lipoprotein (IDL), which approximates the
remnant lipoprotein (Fig. 1
), deserves special mention in the
consideration of the effects of estrogen on lipoprotein metabolism. In
these normal subjects studied by Campos et al. (2), there
was no change in pool size and no change in production or removal
rates, but estrogen nonetheless had an effect on the origin and fate of
IDL, a lesser proportion formed directly, a greater portion formed from
dense VLDL, a lesser amount directly removed and a greater amount
converted to light and dense LDL. These alterations may have no
significance for atherogenesis. Nonetheless, one of the earliest
described beneficial effects of estrogen was to lower plasma
triglyceride levels and to lower the IDL fraction in individuals with
Type III hyperlipidemia, or remnant removal disease (7, 8). Presumably
the reason for the decrease in IDL, or remnant levels in Type III with
estrogen therapy is the upregulation of the LDL receptor, rather than
any direct effect on hepatic lipase, which is reduced by estrogen (3)
and would be expected to impede remnant clearance. The lack of change
in IDL concentrations in the normal subjects of Campos et
al. (2) may be a consequence of the interplay between an increase
in LDL receptor activity and a decrease in hepatic lipase activity.
From the standpoint of atherogenesis, it is very important to keep in
mind that the intermediate density particle is highly atherogenic, as
shown by Tatami et al. as early as 1981 (9) and others since
(see reference 10 for review). It would be interesting to know the
effect of estrogen on IDL and dense VLDL in the hyperlipidemic
populations of women at higher risk for cardiovascular disease.
Regarding low density lipoprotein (LDL), the study of Campos et al. (2) resolves what has until now been a perplexing question—how can a beneficial effect of estrogen be derived from a change in LDL composition toward a smaller, more dense particle, which is associated with greater atherogenicity (11)? Campos et al. conclusively show that the estrogen-induced reduction in LDL is in the light form, while the level of the dense form remains unchanged. Such a reduction is associated with diminished coronary artery disease. For instance, in the original Coronary Primary Prevention Trial of 1984 (12) the bile-acid binding drug cholestyramine attained a reduction in LDL and coronary artery disease. The LDL reduction associated with this treatment occurs in the more buoyant LDL form (13). Similarly, reductase inhibitor therapy lowers cholesterol without actually changing the LDL subclass pattern from buoyant (pattern A) to more dense (pattern B) (14), yet is highly successful in preventing coronary disease (14). Estrogen therapy appears to be not unlike these more classical treatments, where the reduction in the more buoyant LDL form allows the more dense LDL to remain, but a reduction in coronary disease risk still results. Again, as in the other lipoprotein fractions, the more rapid rate of turnover of LDL remaining in the circulation should allow for less lipoprotein remodeling, less acquisition of cholesterol from HDL, and less exposure to oxidative stress.
What are some of the practical implications of these observations
for general health? First of all, an estrogen-induced triglyceride rise
is not without clinical importance when the patient has an elevated
triglyceride level before treatment or develops very elevated
triglyceride levels with treatment. Thus, in individuals with elevated
triglyceride levels at baseline of 300 mg/dL (
3.4 mmol/L), estrogen
administration in the form of oral contraceptives or postmenopausal
oral replacement therapy can raise the plasma triglyceride to the
danger level for pancreatitis, which is above 1,000 mg/dL (8.86
mmol/L). In this instance we routinely suggest that women taking oral
postmenopausal hormone replacement switch to patch estrogen, which
avoids the plasma triglyceride increase by circumventing the hepatic
first pass effect and avoids stopping the estrogen. Unfortunately, most
of the lipoprotein effects of oral estrogen therapy are also lost, but
it should be kept in mind that the systemic circulation is the
physiological route of entry of estrogen into the body.
Recently, the focus on mechanisms of the vascular benefit of estrogen
has expanded to direct arterial wall effects, which include diminished
penetration of LDL into the arterial wall (15), diminished retention of
LDL in the arterial wall (16), diminished susceptibility of LDL to
oxidation (17), improved arterial vasomotion (18), and diminished
arterial susceptibility to injury (19) (Table 1). Indeed, women with Prinzmetal or
vasospastic angina may improve with estrogen replacement therapy (20),
further justifying the interest of our cardiologist colleagues in the
hormonal management of coronary artery disease.
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) (1). In this respect
it is important to note that certain progestins cannot only have
antiestrogenic effects based on receptor-mediated mechanisms but can
also potentiate oxidative damage to LDL, as recently shown by Zhu
et al. (17). Indeed, one progestin, medroxyprogesterone
acetate, cancels the antiatherosclerotic and vasodilator effects of
estrogen in a subhuman primate model of atherosclerosis (21, 22). Thus,
the opposition of estrogen effects by progestins, which every
endocrinologist recognizes, needs to be kept in mind by practitioners
in general, to the extent that risk from coronary artery disease cannot
automatically be expected to be reduced to the same degree in combined
therapy as with estrogen therapy alone. Progestin type is also likely
to be important, as shown by the PEPI study (23), where natural
progesterone was less adverse in effects on lipoproteins, clotting, and
carbohydrate metabolism than two doses of medroxyprogesterone acetate
2.5 mg daily, continuously or 10 mg daily, cyclically. In conclusion, estrogen has multiple effects on lipoprotein metabolism, largely to enhance the rate of transport in the blood stream. This adaptation probably serves a reproductive need by enhancing the availability of lipoprotein-born cholesterol and fatty acids to the ovary and placenta for endocrine steroidogenesis and for the growth and development of the fetus. Perhaps not surprisingly, nature has provided an apparent survival benefit with estrogen in respect to cardiovascular disease susceptibility and many other body systems such as osteoporosis, skin, and higher integrative functions. Future research should be directed toward refining our understanding of the interactions between estrogens and antiestrogens on these systems of the body, as well as the effects of selective-estrogen response modulators (SERMs), which may embody estrogen and progestin effects in the same molecule (24) or only selectively affect estrogen receptors in certain systems (25). In the meantime, the elegant study of Campos and associates (2) reminds us that estrogen must be one of nature’s most favored hormones!
Received October 1, 1997.
Accepted October 1, 1997.
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References |
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and ERß at
AP1 sites. Science. 277:1508–1510.This article has been cited by other articles:
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  M. B. Hapon, S. M. Varas, G. A. Jahn, and M. S. Gimenez Effects of hypothyroidism on mammary and liver lipid metabolism in virgin and late-pregnant rats J. Lipid Res., June 1, 2005; 46(6): 1320 - 1330. [Abstract] [Full Text] [PDF]
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 I. Bureau, F. Laporte, M. Favier, H. Faure, M. Fields, A. E. Favier, and A.-M. Roussel No Antioxidant Effect of Combined HRT on LDL Oxidizability and Oxidative Stress Biomarkers in Treated Post-Menopausal Women J. Am. Coll. Nutr., August 1, 2002; 21(4): 333 - 338. [Abstract] [Full Text] [PDF]
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 M. Perera, N. Sattar, J. R. Petrie, C. Hillier, M. Small, J. M. C. Connell, G. D. O. Lowe, and M.-A. Lumsden The Effects of Transdermal Estradiol in Combination with Oral Norethisterone on Lipoproteins, Coagulation, and Endothelial Markers in Postmenopausal Women with Type 2 Diabetes: A Randomized, Placebo-Controlled Study J. Clin. Endocrinol. Metab., March 1, 2001; 86(3): 1140 - 1143. [Abstract] [Full Text]
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 P. Parini, B. Angelin, A. Stavreus-Evers, B. Freyschuss, H. Eriksson, and M. Rudling Biphasic Effects of the Natural Estrogen 17{beta}-Estradiol on Hepatic Cholesterol Metabolism in Intact Female Rats Arterioscler. Thromb. Vasc. Biol., July 1, 2000; 20(7): 1817 - 1823. [Abstract] [Full Text] [PDF]
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 S. E Kasim-Karakas, R. U Almario, W. M Mueller, and J. Peerson Changes in plasma lipoproteins during low-fat, high-carbohydrate diets: effects of energy intake Am. J. Clinical Nutrition, June 1, 2000; 71(6): 1439 - 1447. [Abstract] [Full Text] [PDF]
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 X. Zhu, B. Bonet, H. Gillenwater, and R. H. Knopp Opposing Effects of Estrogen and Progestins on LDL Oxidation and Vascular Wall Cytotoxicity: Implications for Atherogenesis Experimental Biology and Medicine, December 1, 1999; 222(3): 214 - 221. [Abstract] [Full Text]
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K. H. Han, K. O. Han, S. R. Green, and O. Quehenberger Expression of the monocyte chemoattractant protein-1 receptor CCR2 is increased in hypercholesterolemia: differential effects of plasma lipoproteins on monocyte function J. Lipid Res., June 1, 1999; 40(6): 1053 - 1063. [Abstract] [Full Text]
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E. Simpson Why Do the Clinical Sequelae of Estrogen Deficiency Affect Women More than Men?a J. Clin. Endocrinol. Metab., June 1, 1998; 83(6): 2214 - 2215. [Full Text]
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