Multiple Beneficial Effects of Estrogen on Lipoprotein Metabolism

The effects of estrogen on physiological systems have fascinated endocrinologists for generations. Over the past generation, it has become clear that estrogen affects lipoprotein metabolism at many points and in many potentially beneficial ways, to the point where estrogen as a prophylactic for cardiovascular disease prevention has entered general medical practice, well out of the domain of the specialist endocrinologist (1). The report of Campos et al. (2) in this issue of JCEM (see page 3955) adds to our understanding of why the effects of estrogen on lipoprotein metabolism are beneficial and at what points they are beneficial. The results of Campos et al. (2), show that the hypertriglyceridemia associated with estrogen therapy, in this case 2 mg estradiol 17β 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. What are the implications of these changes in both concentration and rate of lipoprotein transport in the bloodstream for arteriosclerotic vascular disease? Regarding the increase in light VLDL concentration and rate of transport, the authors suggest that the rapid rate of transfer through the blood stream reduces the amount of time for oxidation and for the remodeling of the lipoprotein by acquisition of cholesterol from other lipoproteins, such as HDL. The lack of a cholesterol rise in the light VLDL fraction, despite the increase in the triglyceride concentration, is consistent with this effect and has been observed previously (3). Additional reasons for the lack of atherogenicity of light VLDL may be offered. One is that families of hypertriglyceridemic individuals have been observed without heart disease and with this particular kind of buoyant noncholesterol enriched VLDL (4, 5). Another reason is that the larger size of buoyant, light VLDL limits infiltration into the arterial intima and the amount of cholesterol likely to be trapped (6). Thus, there are several metabolic and physical reasons to believe that the hypertriglyceridemia of estrogen therapy is nonatherogenic. 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. Finally, it cannot be assumed that beneficial effects of estrogen on lipoprotein metabolism and arterial wall biology will be preserved or will be equivalent in degree in the presence of concomitant progestin therapy. While the metabolism of lipoproteins is generally enhanced under the influence of estrogen, as elegantly documented by Campos et al. (2), progestins tend to inhibit this rate of metabolism by acting as an antiestrogen (Fig. 1) (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! Effects of sex steroids on lipid metabolism. Width of lines indicate the rate of cholesterol traffic under influence of estrogen (L) or progestin/androgen (R). Question marks indicate effects for which documentation is uncertain or unclear. Modified from Reference 26 with permission. Beneficial effects of estrogen on the arterial wall Beneficial effects of estrogen on the arterial wall