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New Markers for Cardiovascular Disease Risk in Women: Impact of Endogenous Estrogen Status and Exogenous Postmenopausal Hormone Therapy

The Jean Hailes Foundation, Victoria, Australia 3168

Address all correspondence and requests for reprints to: Susan Davis, M.D., The Jean Hailes Foundation, 173 Carinish Road Clayton, Victoria, Australia 3168. E-mail: susan.davis{at}jeanhailes.org.au.

	Abstract

Top Abstract Introduction Inflammatory and other... Inflammatory and other... Effects of exogenous... Oral estrogen Transdermal estrogen Progestin effects Tibolone and selective estrogen... Conclusion References

 
The role of estrogen in altering cardiovascular disease risk in women is contentious. Menopause is associated with increased risk for ischemic heart disease and cerebrovascular disease, which collectively are the main causes of morbidity and mortality in women of developed nations. Observational studies suggest a protective role of estrogen, whereas recent randomized controlled trials report a negative role for oral estrogen in primary and secondary prevention of cardiovascular events. Inflammatory mechanisms underlie the process of arterial thrombus formation following atheromatous plaque rupture, and as such modulation of the inflammatory process may be a potential means of reducing cardiovascular risk. Sex steroids may influence inflammatory processes and hence modify cardiovascular risk. The objective of the study was to review the current understanding of the relationships between C-reactive protein (CRP), homocysteine, IL-6, and lipoprotein (a) [Lp(a)] and endogenous estrogen status, exogenous estrogen treatment, and cardiovascular disease risk. The design was a review of all relevant published, peer- reviewed studies. Raised levels of CRP, homocysteine, Lp(a), IL-6, and CRP are each independently associated with increased risk for cardiovascular events in women. Changes in these parameters across the menopausal transition cannot clearly be attributed to hormonal changes. With respect to the effects of exogenous postmenopausal therapy, oral estrogen use is consistently associated with elevations in CRP, no change or a reduction in homocysteine, varied effects on IL-6, and a consistent reduction in Lp(a). Transdermal estradiol overall has no significant effect on any of these parameters. Progestin use appears to attenuate the effect of oral estrogen on CRP and is associated with a reduction in Lp(a). Like oral estrogen, tibolone use is associated with a rise in CRP, with no change in homocysteine and consistent lowering of Lp(a). Selective estrogen receptor modulators modestly lower homocysteine and Lp(a), have varied effects on CRP, and have no reported effects on IL-6. Despite these varied effects of postmenopausal hormone treatment on inflammatory markers, homocysteine, and Lp(a), there is no evidence that change in these markers results in modification of cardiovascular risk. Further studies are required to specifically investigate whether treatments that increase or decrease these markers in fact modulate the risk of cardiovascular events in women.

	Introduction

Top Abstract Introduction Inflammatory and other... Inflammatory and other... Effects of exogenous... Oral estrogen Transdermal estrogen Progestin effects Tibolone and selective estrogen... Conclusion References

 
CARDIOVASCULAR DISEASE REMAINS the one of leading causes of morbidity and mortality in women of developed countries. For several years emphasis has been on identifying risk factors for cardiovascular disease, with targets being early disease detection and, where possible, disease prevention. Various intervention studies have shown reductions in cardiac events with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in women with low-density lipoprotein cholesterol levels greater than 124 mg/dl (1, 2, 3). Comparable improvements in lipoprotein profiles in women have been reported in studies of oral estrogen therapy (4, 5, 6), particularly in hypercholesterolemic women (7, 8). These findings, along with evidence that estrogen enhances vascular endothelial nitric oxide production and thus improves peripheral and coronary endothelium-dependent vasodilation (9, 10), has supported the hypothesis that postmenopausal estrogen therapy may be cardioprotective. However, most recently the Women’s Health Initiative (WHI) study investigators reported that postmenopausal hormone therapy in the form of continuous combined oral conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA) resulted in increased rates of cardiac events and thromboembolic events, such that the overall impact after an average follow-up of 5.2 yr was an increase in cardiac events in those given hormone therapy vs. placebo (11). This increase in events was greatest in the first year of use, compared with placebo, with a negative trend in events over time. Consistent with this, the same postmenopausal hormonal regimen was associated in the Hormone Estrogen-Progestin Replacement Study (HERS) with an initial increase in cardiovascular events in women with established coronary artery disease and a reduction in events, compared with placebo by the fourth year (5). This was despite significant reductions in low-density lipoprotein cholesterol and increased high-density lipoprotein (HDL) cholesterol (5). Thus, regardless of the favorable effects of oral estrogen-progestin on endothelial function and lipoprotein lipids, this therapy appears to be associated with perturbations in other factors that mediate arterial and venous thrombotic events.

A more recent focus has been on the role of inflammation in the process of atherogenesis and plaque disruption, with a growing body of evidence that circulating inflammatory markers are strongly associated with cardiovascular event risk, even in individuals with normal lipoprotein lipid profiles (12). Measurement of the inflammatory markers C- reactive protein (CRP) and IL-6 has been postulated as a method of determining increased risk of cardiovascular disease in apparently healthy individuals (13). Lipoprotein(a) [Lp(a)] is a known independent risk factor for the development of atherosclerosis (14, 15, 16, 17, 18). The synthesis of Lp(a) is primarily under genetic control and unlike other lipid rich particles, its levels are not altered by conventional lipid-lowering therapies, diet, or exercise (7, 19, 20). Furthermore, its link with cardiovascular disease may involve prothrombotic mechanisms that differ from effects of other lipid particles (19). It has been proposed that sex hormones may protect females to a large extent from the potentially deleterious effects of inherited high Lp(a) levels until menopause (19), hence its inclusion in this review. Elevation of the amino acid homocysteine is associated with arterial and venous thromboembolic disease, and measurement of fasting homocysteine has also been proposed to help target individuals at greatest risk of acute events (21).

CRP, IL-6, and homocysteine-like Lp(a) appear to be influenced by endogenous sex steroid levels and exogenous hormone therapy. Thus, in the light of conflicting results of randomized controlled trials of hormone therapy (5, 11) and previous epidemiological and clinical research indicating estrogen to be cardioprotective (4, 22, 23), we have reviewed the published data pertaining to the measurement of these inflammatory and other unique biomarkers in women of differing ages and the known effects of menopause and menopausal therapy.

	Inflammatory and other biomarkers and cardiovascular disease risk

Top Abstract Introduction Inflammatory and other... Inflammatory and other... Effects of exogenous... Oral estrogen Transdermal estrogen Progestin effects Tibolone and selective estrogen... Conclusion References

 
Of the inflammatory markers, CRP may provide the strongest risk prediction for cardiovascular disease in women (24), with the detection of elevated levels an alternative method of identifying those individuals at high risk of atheromatous plaque rupture, central to the process of arterial thrombus formation (25). Debate exists about the utility of CRP as a marker of cardiovascular risk, given its role as an acute-phase reactant and hence its elevation in the presence of any inflammatory focus or injury. This has been countered somewhat by the development in recent times of an ultrasensitive assay, which has been shown to have a degree of measurement stability similar to that of total cholesterol (26). CRP has been associated with the severity of atherosclerosis, measured noninvasively at several sites (27, 28, 29) and increasing quartiles of CRP correlated with increasing risk of cardiovascular disease in women (30, 31). Although elevated levels of CRP are predictive of death from coronary artery disease in those with angiographically proven disease, this effect is lost in subjects treated with statins (32). Lower levels of CRP have been associated with increasing levels of fitness in a cross-sectional study of African-American, Native American, and Caucasian women (33). Measurement of CRP alongside standard lipid screening may be a potential method of more accurately predicting global cardiovascular risk.

The cytokine IL-6 is a potent inducer of the hepatic acute-phase response and hence a regulator of CRP and may have a key role in the etiology of coronary heart disease (34). IL-6 not only generates increased levels of CRP but also increases fibrinogen, blood viscosity, platelet numbers, and activity. Circulating IL-6 stimulates the hypothalamic-pituitary- adrenal axis, and elevated levels are associated with insulin resistance, hypertension, and central obesity, all of which are risk factors for the development of cardiovascular disease (34).

In men increased levels of IL-6 are associated with elevated triglycerides and fibrinogen, increased frequency of symptomatic coronary artery disease and abnormalities on electrocardiogram (35), and increased risk for myocardial infarction in apparently healthy individuals (36). A nested case-control study of 366 women among 28,000 apparently healthy postmenopausal women linked IL-6 to increased risk of cardiovascular events (37). Another study of 620 late postmenopausal women reported a higher risk for all-cause mortality in women with levels of IL-6 in the highest tertile, even after adjustment for potential confounders (38). IL-6 is greater in patients with coronary heart disease vs. controls (39) and among women with coronary heart disease; those with the highest IL-6 levels had a greater risk of death (38). High IL-6 is associated with type 2 diabetes (40) and smoking (41), both important cardiovascular disease risk factors. In the WHI study, significantly higher baseline IL-6 and CRP levels were detected in the 304 women who developed incident coronary heart disease, compared with controls (42).

Elevated levels of homocysteine have been linked to both atherothrombosis and thrombogenesis (43, 44) and stroke and myocardial infarction in women (44). Furthermore, endothelium-dependent vasodilatation appears to be impaired in hyperhomocysteinemic older people, compared with age-matched normohomocysteinemic individuals (45).

Lp(a) has both proatherogenic and prothrombotic properties. The apo(a) moiety of Lp(a) has significant homology with plasminogen, and in vitro Lp(a) appears to compete for the binding of plasminogen. This may result in inhibited fibrinolysis as apo(a) cannot be activated by tissue plasminogen activator (46). Elevated levels of Lp(a) have been independently linked to the severity of coronary artery lesions and increased risk of coronary heart disease events in women (16, 47, 48).

	Inflammatory and other biomarkers, endogenous hormone levels, and the menopause

Top Abstract Introduction Inflammatory and other... Inflammatory and other... Effects of exogenous... Oral estrogen Transdermal estrogen Progestin effects Tibolone and selective estrogen... Conclusion References

 
Following menopause women have higher hematocrits, blood and plasma viscosity, and fibrinogen levels (49), and there is a marked increase in coronary artery disease risk (50). The effects of menopause on cardiovascular risk markers have been explored as potential mechanisms for this increase in risk. The evaluation of the direct effects of hormonal changes on CRP and IL-6 is complicated by the concurrent changes in weight and insulin sensitivity that occur at this time. In a comparative study of postmenopausal women vs. premenopausal women, increased levels of CRP were found to be related to increased body fat, notably intraabdominal fat, and lower insulin-stimulated glucose disposal but not to menopausal status (51). This is consistent with raised levels of CRP in a group of morbidly obese women whose CRP levels fell significantly after gastric banding surgery (52). However, an increase in IL-6 has been reported after surgical menopause (53) and following natural menopause (54). Hypopituitarism is associated with increased cardiovascular disease related mortality (55, 56), and significantly greater levels of both IL-6 and CRP have been reported in women with hypopituitarism (57), suggesting a possible relationship between hormone deficiency and inflammation (57).

Hak et al. (58) study the effects of menopause on homocysteine levels by comparing levels in age-matched pre- and postmenopausal women and reported a mean increase of 7% (95% confidence interval 0.3–14%, P = 0.04) with menopause. Additional adjustment for plasma creatinine, body mass index, smoking habit, and alcohol intake did not influence this difference. Lp(a) levels also increase with age (59) and are higher after the onset of natural or surgical menopause (60, 61).

	Effects of exogenous postmenopausal hormone therapy

Top Abstract Introduction Inflammatory and other... Inflammatory and other... Effects of exogenous... Oral estrogen Transdermal estrogen Progestin effects Tibolone and selective estrogen... Conclusion References

 
The effects of postmenopausal hormone therapy on cardiovascular risk markers vary according to the formulation and route of administration, with oral estrogen therapy being the most extensively studied.

	Oral estrogen

Top Abstract Introduction Inflammatory and other... Inflammatory and other... Effects of exogenous... Oral estrogen Transdermal estrogen Progestin effects Tibolone and selective estrogen... Conclusion References

 
Increased cardiac (atherothrombotic) events and venous thromboembolic events have been reported in the first few years of the initiation of oral estrogen therapy in the form of CEE and MPA (5, 11) but not with estrogen alone (62).

Oral therapy with CEE or estradiol consistently increases CRP as seen in epidemiological studies and randomized controlled trials (Table 1) (42, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74). The increase in CRP is positively correlated with measures of body size, fat distribution, and weight gain among oral hormone therapy users and nonusers (68). The highest levels of CRP have tended to be in hormone therapy users within the highest quartile of visceral fat. A positive association of CRP with serum estrone levels among hormone therapy nonusers is consistent with this because following menopause estrone is primarily produced in adipose tissue. However, the use of opposed or unopposed hormone replacement therapy is not associated with postmenopausal weight gain, compared with placebo, suggesting that the rise in CRP with oral estrogen use is due to the estrogen rather than any potential increase in body mass (4, 75, 76, 77, 78). The addition of MPA to oral estrogen therapy appears to ameliorate the effect of oral estrogen on CRP (69, 73, 79).

Combined estrogen-progestin therapy is associated with a reduction in Lp(a) (7, 48, 83, 84, 85, 86, 87, 88). The reduction in Lp(a) seen with combined oral estrogen-progestin therapy is not seen with either pravastatin or simvastatin in hypercholesterolemic postmenopausal women (7, 20), thus calling to question the importance of modifying this marker to modify cardiovascular risk.

	Transdermal estrogen

Top Abstract Introduction Inflammatory and other... Inflammatory and other... Effects of exogenous... Oral estrogen Transdermal estrogen Progestin effects Tibolone and selective estrogen... Conclusion References

 
Little is known of the cardiovascular effects of nonoral estrogen therapy. The Papworth study (89) was a randomized, controlled, secondary prevention study of transdermal hormone therapy in 255 women with a mean age of 66 yr. The end points were angina and cardiovascular death. There were 53 events in the hormone group and 37 in a control group resulting in a relative risk of 1.29 [intention to treat (0.84–1.95)] and a relative risk of 1.49 [per protocol analysis (0.93–2.36)]. These results were not significant; however, they parallel those noted with oral combined hormone therapy.

Transdermal estrogen has little or no effect on the markers of cardiovascular disease risk we have reviewed. Transdermal therapy is not associated with any change in CRP (Table 3) although Sattar et al. (90) reported a reduction in CRP when norethindrone was coadministered to women with type 2 diabetes mellitus. This is consistent with effect on the CRP when a progestin is used concurrently with oral estrogen therapy as described above. Evio et al. (91) randomized 42 healthy postmenopausal women to oral or transdermal estradiol and reported no significant changes in homocysteine in either group. Similarly most studies have shown no changes in Lp(a) with transdermal estrogen use (Table 3).

	Progestin effects

Top Abstract Introduction Inflammatory and other... Inflammatory and other... Effects of exogenous... Oral estrogen Transdermal estrogen Progestin effects Tibolone and selective estrogen... Conclusion References

 
The effect of exogenous estrogen on inflammatory markers is dependent not only on the route of administration but also on concomitant progestin administration. There are few studies looking at the direct effects of the progestin component of hormone therapy on inflammatory markers or cardiovascular disease. Wakatsuki et al. (69) demonstrated a dose-dependent inhibition of the rise in CRP with CEE alone with increasing doses of progestin (Table 1). No significant change was seen for IL-6 in any of the treatment groups in this study. Skouby et al. (73) attempted to assess the effects of various progestins on CRP in subjects given a fixed dose of oral estradiol valerate. A nontreatment group was included as the reference group (Table 1). Progestin regimens included cyproterone acetate, norethindrone acetate, intrauterine levonorgestrel, or long-cycle MPA (20 mg for 14/91 d). A significant increase in CRP was seen in the women receiving estradiol valerate plus norethindrone acetate or local levonorgestrel. No significant change in CRP was seen in those receiving cyclical or continuous cyproterone acetate or the reference group. A long-cycle regimen of estradiol valerate plus MPA (14/91 d) revealed an increase in CRP during the estrogen phase but subsequent modulation in the progestin phase. This study highlights the differing effects of progestins on one inflammatory marker and the need to investigate the implications in terms of the effects of different progestins on cardiovascular disease. Androgenic progestins such as norgestrel (86) and norethindrone (84) are known to independently lower Lp(a) and contribute to the reduction in Lp(a) when coadministered with any form of estrogen.

Concurrent MPA therapy has been implicated as a factor in increased cardiovascular event rates that have occurred in HERS and WHI (5, 11); however, no adverse effects of progestin therapy can be explained by simple effects on these risk markers. If anything, available data indicate that progestins may inhibit the proinflammatory effects of estrogen.

	Tibolone and selective estrogen receptor modulators

Top Abstract Introduction Inflammatory and other... Inflammatory and other... Effects of exogenous... Oral estrogen Transdermal estrogen Progestin effects Tibolone and selective estrogen... Conclusion References

 
Tibolone is a compound that can be selectively metabolized by individual tissues to its estrogenic, progestogenic, or androgenic metabolites and hence exhibits tissue-specific hormonal effects. Tibolone also lowers SHBG, thus increasing free estradiol and testosterone levels (93). Tibolone significantly lowers total cholesterol, plasma triglycerides, HDL cholesterol and apolipoprotein A1. The decrease in HDL cholesterol has been attributed to an androgenic effect of the 4-isomer on hepatic lipase (94). Consistent with this most studies have reported a reduction in Lp(a) with tibolone (Table 4). Tibolone does not increase homocysteine (82) and no increase in thromboembolic events has been reported with this therapy (94). Tibolone has been reported to be associated with an increase in CRP in one cross-sectional study (70), but this requires confirmation.

Available data on the effects of SERMs are summarized in Table 5. Neither droloxifene, a structural analog of tamoxifen, nor raloxifene has been found to affect CRP in two different randomized trials (71, 80). Raloxifene modestly lowers homocysteine by approximately 3–8% and Lp(a) by about 7% (Table 5). Thus, despite the known increase in risk of venous thromboembolic events with raloxifene, there is no evidence that this therapy adversely influence ischemic heart disease. The Raloxifene Use for the Heart (RUTH) trial will provide much-needed data on the effects of the risk of coronary events of raloxifene 60 mg/d, compared with placebo (96).

	Conclusion

Top Abstract Introduction Inflammatory and other... Inflammatory and other... Effects of exogenous... Oral estrogen Transdermal estrogen Progestin effects Tibolone and selective estrogen... Conclusion References

In vitro research provides a sound basis for the hypothesis that exogenous postmenopausal hormone therapy might prevent the increase in cardiovascular events that follow menopause. However, recent randomized trials indicate an initial increase in events followed by a negative trend over time. Initial effects of exogenous hormone therapy on inflammatory markers may play a role in this phenomenon or may at least provide prognostic markers to identify those at greatest risk. Our review of the available data links elevated levels of CRP, IL-6, homocysteine, and Lp(a) in women with increased risks for coronary artery disease, events, and mortality. Homocysteine and Lp(a) have been shown to increase with age and/or menopause. There is limited evidence to support an increase in IL-6 with age and no data to support similar changes in CRP with the fall of endogenous sex steroid hormone levels at menopause. The relationships between these markers and postmenopausal sex steroid hormone treatment are not completely defined, with the current major limitation being a lack of appropriate placebo controlled studies from which to draw firm conclusions. Use of oral estrogen is associated with elevations in CRP, variable effects on IL-6, and reductions in both homocysteine and Lp(a). Transdermal estradiol appears to have little or no effect on any of these markers. The progestin component of postmenopausal hormone treatment appears to attenuate the effect of oral estrogen on CRP and independently lowers Lp(a) levels. However, analysis of the effects of progestins, when added to estrogen in studies to date, is complicated by differences in progestin type, dose, and the use of continuous vs. sequential regimens. Limited data indicate tibolone is associated with an increase in CRP, similar to that seen with oral estrogen use, no change in homocysteine, and a trend toward lowering of Lp(a). The data on SERMs are also limited. With raloxifene, the most studied SERM, CRP does not appear to change, whereas reductions in homocysteine and Lp(a) have been reported in all studies.

The relationship between cardiovascular disease and transdermal hormone therapy needs to be further investigated, as does the effect of other forms of hormone therapy, such as tibolone and SERMs on inflammatory markers, homocysteine, and cardiovascular disease event rates. Because markers of inflammation may become indicators of individuals who should receive primary prevention, it is also essential to first have normative data from the general population by age and also a better understanding as to how endogenous and exogenous hormonal variables influence inflammatory marker levels in women.

Finally, although evidence strongly supports inflammatory markers as predictors of acute events, it remains to be established that modifying circulating levels of these markers will influence outcomes (13).

	Footnotes

 
Abbreviations: CEE, Conjugated equine estrogen; CRP, C-reactive protein; HDL, high-density lipoprotein; Lp(a), lipoprotein (a); MPA, medroxyprogesterone acetate; SERM, selective estrogen receptor modifier.

Received December 10, 2002.

Accepted March 18, 2003.

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