Women have been shown to have a lower incidence of vascular disease when compared to men. However, the incidence of vascular disease increases as women progress through menopause and reaches an incidence similar to that of men later in life. Women with peripheral vascular disease often have a delay in diagnosis, a higher incidence of asymptomatic disease, and poorer outcome after interventions. The differences in outcome have been attributed to a number of factors such as anatomic and hormonal differences. It is thought that estrogen deficiency is at least partially responsible for the increased risk of developing vascular disease after menopause, and thus hormone replacement therapy has been considered as a method to prevent progression of vascular disease. Conclusions drawn from a number of recent studies have resulted in a divergent view of hormone replacement therapy (HRT). This article explores the risk of peripheral vascular disease in women and the current state of research on hormone replacement therapy. The aims of this review are to present current perspectives on gender differences in the pathogenesis and outcomes of peripheral arterial disease (PAD). The effect of estrogen on atherogenesis, the role it plays in modulating the vascular endothelium, and the current evidence of the effects of HRT on vascular pathology is discussed. The most recent HRT clinical trials and present evidence for the benefits and risks of postmenopausal hormone replacement therapy are summarized. The effect of these issues on treatment practices is explained and suggestions are made for future directions of HRT and PAD research.
Introduction
Peripheral arterial disease (PAD) affects millions of patients and is a significant cause of morbidity and mortality. Significant vasculopathies include atherosclerotic occlusive disease, carotid artery occlusive disease, and abdominal aortic aneurysm. These diseases increase in prevalence with age and are associated with the presence of vascular risk factors such as cigarette smoking, hypertension, diabetes mellitus, and menopause. Although the prevalence of PAD is lower in women than in men,1 up to 25% of women aged 55 to 74 years may be affected with PAD, which can lead to significant morbidity such as loss of limb, stroke, or cardiovascular death.2 Research has shown that women may be afflicted with more asymptomatic disease and that those with vascular disease have a 2- to 4-fold increase in cardiovascular morbidity and mortality. Furthermore, outcomes after vascular operations, including patency rates and myocardial infarction, appear to be worse for women than those for men.36
Over the past 2 decades, there has been a growing awareness of the gender differences in vascular disease. It has been postulated that delays in diagnosis, anatomic differences, and clinicians’ underestimation of the magnitude of disease in women may contribute to differential prevalence rates and differences in outcomes. Although anatomic variations are not modifiable by the clinician, there are certain areas for early intervention to help improve vascular outcomes in women. Practical solutions include offering patients opportunities for education, counseling for preventive risk factor management, risk factor modification, and aggressive medical treatment.
Medical treatment generally consists of lipidlowering agents, platelet inhibitors, and hormone replacement therapy (HRT). The benefits of the first 2 drug classes have been well documented; however, the use of hormone therapy for cardiovascular risk reduction in postmenopausal women has been more controversial with several recent large-scale clinical trials reporting conflicting results.7 The findings, although far from conclusive, have cast doubt on the benefits of this therapy for cardiovascular health, and many questions remain unanswered.
One of the difficulties in assessing the literature on vascular disease and its treatment in postmenopausal women is that dramatic changes in clinical practice and disease knowledge have occurred over time. We have limited our review to randomized clinical trials and observational studies published within the past 15 years (1990- 2004), and to systematic reviews of literature published before this time. The aims of this review are to present current perspectives on gender differences in the pathogenesis and outcomes of peripheral arterial disease. We then discuss the effect of estrogen on atherogenesis, the role it plays in modulating the vascular endothelium, and the current evidence of the effects of HRT on vascular pathology. The most recent HRT clinical trials and present evidence for the benefits and risks of postmenopausal hormone replacement therapy are summarized. Finally, we discuss how these issues affect treatment practices and suggest future directions of HRT and PAD research.
Peripheral Arterial Disease in Postmenopausal Women
The major known risk factors for the development of atherosclerosis are hyperlipidemia, smoking, hypertension, diabetes mellitus, obesity, and homocysteinemia. Atherosclerotic occlusive disease is a significant cause of morbidity and mortality in postmenopausal women. The onset of peripheral arterial disease in women usually occurs 10-20 years later in women than in men.8 Menopause, whether surgically induced or naturally occurring, is associated with an increased risk of arterial disease.
A number of studies have addressed gender differences in surgical outcomes for carotid artery disease, PAD, and aortic aneurysmal disease. The majority of these studies indicate that women have poorer outcomes following vascular operations compared to their male counterparts.4’8-11 Even though there is no clear explanation for these findings, a number of theories exist. These include gender- related structural differences, lack of physician awareness of the disease process, or a lower degree of suspicion in treating vascular disease in women. The question then arises about which strategies, both medical and surgical, can be employed by physicians to improve outcomes in female patients afflicted by arterial disease.
Carotid Artery Disease
Carotid artery disease is approximately 1.5 times more prevalent in men than women. However, in some studies (Table I) women appear to have worse outcomes compared to men. In a retrospective study, Sarac and colleagues12 reviewed 3,422 carotid endarterectomies performed at their institution. Their data demonstrated that women had a higher postoperative mortality rate and female gender was an independent predictor of postoperative stroke or transient ischemie attack. Similarly, a study by Lane et al9 (n = 361) indicated that men and women had similar stroke rates at 5 years but also found that women using HRT showed a trend toward increased stroke rate at 30 days. Furthermore, Ballotta et al13 reported confirmatory data showing that women have increased late occlusive events after carotid surgery. Although several other studies conclude that women have a similar risk of stroke following carotid revascularization, it is generally concluded that women with carotid artery disease have inferior outcomes when compared to male cohorts.
Table I. Studies comparing outcomes of carotid artery surgery in women versus men.
Peripheral Arterial Disease
Lower extremity peripheral arterial disease exists in 16-19% of the elderly population and is associated with an increased risk of cerebrovascular and cardiovascular events.8 Intermittent claudication is the most common presenting symptom for patients with PAD, but alone it is an insufficient diagnostic indicator for PAD. In a study of the detection of PAD, only 6.7% of female participants were found to have claudication.14 However, ankle brachial indexes (ABI) revealed that more than 35% of female participants had significant PAD, albeit no specific symptomatology existed. Additionally, women with intermittent claudication have been found to have a lower probability of successful conservative therapy, thereby necessitating surgical intervention.15 The University of Maryland reported that more than 50% of the women who present with claudication have limbthreatening ischemia.16 Many of these patients proceed directly to amputation without any opportunity for operation. Unfortunately, previous studies have shown that even women who are presented with the opportunity for intervention have far less successful outcomes than men after peripheral vascular reconstruction.4,10
A number of studies have examined gender differences in outcomes following lower extremity vascular bypass grafting. Multivariate analysis by Magnant et al10 revealed that the patency rates in women were significantly lower than in men at 3-year follow-up. Additional analysis has demonstrated that female gender is a significant independent predictor of graft occlusion.4 Overall, data from studies of various vascular operations for women with PAD show that women have a higher rate of occlusion and that gender is an independent factor in inferior outcomes of lower extremity revascularization procedures.
Abdominal Aortic Aneurysms
Women typically present with abdominal aortic aneurysms (AAA) at an older age and are less likely to receive elective or emergent operation for an AAA. Furthermore, women who do receive an operation have a 40-45% greater risk of dyin\g when compared to their male counterparts.11 Although it is not clear why women have worse outcomes, it is important that clinicians recognize this when discussing morbidity and mortality with their female patients.
Estrogen and Atherosclerosis
Women today spend nearly 30% of their life in menopause, and the number of menopausal women continues to increase as the population ages.5 Endogenous estrogen production diminishes with menopause. This decrease in a woman’s estrogen levels may have multiple detrimental effects on vasculature, overall lipid profile, and both the fibrinolytic and coagulation systems. The long-term effects of these physiologic changes may lead to accelerated atherosclerosis and an increase in clinically apparent cardiovascular, cerebrovascular, and PAD.
Estrogen plays numerous roles in the regulation of vascular endothelium, proliferation, and the inflammatory response. There are several different forms of estrogen; however, the main source of endogenous circulating estrogen is 17-β estradiol. Estrogen is a hormone that complexes with an intracellular receptor via passive diffusion through the cell membrane. There are 2 forms of the estrogen receptor: alpha and beta. Vascular cells and endothelial cells express both the α and β form of the estrogen receptor.17,18 The binding of estradiol to the receptor initiates the formation of a ligand-receptor complex, which then travels to the cell nucleus targeting specific regions of the genome, causing transcriptional activation of various target genes. Currently, estrogen is believed to activate more than 12 different target genes, which are associated with vascular physiology. The actions of estrogen on vascular endothelium and physiology are summarized in Table II. In this section, we discuss estrogen’s differing mechanisms of action and the role it plays in atherogenesis.
Table II. Summary of vascular effects of estrogen.
Cytokines
Estrogen has been found to play a large role in cytokine- mediated inflammation.19 Monocytes express surface estrogen receptors, implicating a role for estrogen binding and modulation of cytokine release in monocyte function. Furthermore, monocytes play an integral role in atherosclerosis development owing to migration into the vascular wall and release of proinflammatory cytokines. Interleukin-1 (IL-I), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) are believed to play an important role as mediators of the vascular inflammatory response. Initial studies on the relationship between cytokine levels and estrogen were observed in women who had undergone hysterectomy and oophorectomy. These patients showed higher levels of IL-I and TNF-a secretion in comparison to patients receiving HRT.20 Furthermore, clinical studies on cytokine levels have shown decreased IL-6 expression in women receiving HRT compared to a placebo group.21 For example, Anwar et al22 recently reported that TNF-α contributed significantly to down-regulation of growth factors that were important to smooth muscle cell function and integrity. In addition, TNF-α and IL-I initiate a complex cascade of leukocyte migration, adhesion molecule expression, platelet activation, and thrombogenesis.23 Conversely, a small subset of patients from the Women’s Health Initiative study were evaluated for the role of IL- 6, HRT, and chronic heart disease (CHD).24 This particular study identified no association between IL-6 and HRT; however, elevated IL- 6 levels were associated with a 2-fold increased occurrence of coronary heart disease (CHD) events.
HRT Effect on Lipid Profile
Estrogen has long been associated with elevated levels of high- density lipoprotein (HDL) and decreased levels of low-density lipoprotein (LDL). In a small patient cohort, Walsh et al25 identified the benefit of estrogen on cholesterol. These investigators found that oral estrogen increased HDL and decreased LDL, but transdermal estrogen did not have a similar benefit. Other groups have reached comparable conclusions concerning the benefit of HRT and lipid profiles.26 Moreover, estrogen is also believed to play a role in preventing LDL oxidation, which is implicated in atherosclerotic plaque development. Koivu et al27 demonstrated that the severity of atherosclerotic plaque deposition and the number of plaques were decreased in 101 postmenopausal women who used HRT. Furthermore, these authors concluded that there was a direct association between HRT and a decrease in LDL oxidation, which resulted in reduced plaque severity. In addition, the use of HRT has also been associated with changes in triglyceride (TG) levels. A recent study of 300 oophorectomized women demonstrated that TG levels increased overall in the group randomized to treatment with conjugated equine estrogen. However, in patients presenting with initially high TG levels, HRT actually decreased the levels.28 Conversely, other studies have demonstrated no difference in TG levels with HRT use.29 Clinical trials have shown that HRT can affect the serum concentrations of cholesterol in patients with preexisting cardiovascular disease. However, the benefits of HRT therapy have not been shown to alter the outcomes of cardiovascular disease. Herrington and coinvestigators30 conducted a study of 309 women with coronary artery disease and HRT. The HRT group had a significant decrease in the LDL levels and a corresponding increase in the HDL levels. However, the alterations of the cholesterol levels were not associated with progression or regression of coronary atherosclerosis.
HRT Effects on Coagulation
Embolie events are a major concern in cardiac or vascular disease. The role of estrogen in coagulation has long been a point of debate owing to divergent data. Initially, it was hypothesized that the use of estrogen following menopause correlated with increased factor VII and factor VIII levels.31 However, more recent data suggest that estrogen is involved with components of both the coagulation pathway and the fibrinolytic pathway. In their study, Post et al32 recognized that women using oral HRT therapy had an increase in fibrinolytic variables and a decrease in procoagulant variables. In addition, data exist to show that HRT causes increased resistance to activated protein G.33,34 This may partly explain the procoagulant effects of HRT.
There has been intense scrutiny on HRT and its effects on blood coagulation within the past few years after the HERS trial demonstrated an increased risk of venous thromboembolism with HRT treatment.35 In accordance, the Women’s Health Initiative (WHI) trial36 also demonstrated a twofold increased risk of venous thromboembolism in the HRT group versus placebo group. Additionally, another study also concluded that women with a known procoagulant or hypercoagulable state should not use HRT. Female patients in this trial who had factor V Leiden mutation had a 15-fold increased risk of thrombolic events with HRT therapy.37
HRT: Benefits and Risks
The term HRT is most commonly used to describe hormone therapy consisting of conjugated equine estrogen and medroxyprogesterone acetate. Currently, HRT is used by millions of postmenopausal women. The major benefits include relief of vasomotor symptoms, sexual dysfunction, and fatigue, and a decrease in fracture risk. There was also the belief that HRT would have cardioprotective benefits. Preliminary investigations of the cardioprotective effects of estrogen were encouraged by the observation that as women passed menopause and reached postmenopausal status, the incidence of CHD approached that of men. This was hypothesized to be due to decreased circulating levels of estrogen.38 Much of the initial excitement over the cardioprotective benefits of HRT was motivated by studies demonstrating the beneficial results of hormone replacement therapy following the onset of menopause.39 These findings supported animal and basic research demonstrating protective effects of HRT on acute coronary outcomes40 as well as the beneficial effects of estrogen on lipid profiles.
Observational studies have suggested that HRT might prevent cardiovascular disease. For example, as part of a 10-year follow- up, the Nurses Health Study (n = 48,470) found a 44% relative risk reduction in the incidence and mortality of major coronary disease in individuals taking HRT.41 This reduction in incidence and mortality from coronary artery disease (CAD) was greatest in women with multiple risk factors for cardiovascular disease. These women were found to have a 50% reduction in all-cause mortality with hormone replacement therapy compared to an 11% reduction in risk in women without risk factors for CAD. In another study, Grodstein et al39 also concluded that women who use HRT for many years have a decreased risk of CHD. A systematic review of 25 published studies concluded that HRT confers cardioprotective benefits to women using unopposed estrogen (relative risk of 0.7O).42 In a subset of 7 studies from this meta-analysis, estrogen plus a progestin offered a risk estimate of 0.66.
However, observational studies may have been confounded by selection bias. Hemminki and McPherson43 reviewed 22 randomized trials of short-term estrogen therapy in which cardiovascular events were listed only as reasons for dropping out of a study or as an adverse event. These women were not included in any study’s final analysis, all of which demonstrated positive effects of estrogen therapy.42,43 Contradictory results have also been observed in peripheral artery disease and HRT treatment.44
Unlike previously published observational studies, recent randomized controlled trials do not show benefits in terms of secondary prevention of cardiovascular disease. In fact, there may be an increase in risk of cardiac and vascular events, especially during the first year of treatment. For example, the most recent statements from the Women’s Health Init\iative (WHI) and the Heart and Estrogen/Progestin Study (HERS), both large-scale, multicenter trials, report a failure to identify any benefit associated with the use of HRT for secondary prevention of cardiac events in postmenopausal women.36,45 The WHI (n = 16,608) was a randomized, placebo-controlled, double-blind trial designed to identify the potential risks and benefits of HRT. Results from the WHI, which were published in 2004, indicated a significant increase in the risk of adverse clinical vascular events in women receiving HRT compared to placebo.46 Part of the clinical trial was stopped early after results showed that estrogen-progestin combination resulted in increased risks of developing invasive breast cancer, heart disease, stroke, and thrombotic events.
Table III. Studies comparing HRT and effect on vascular disease.
In the HERS study35 (n = 2,763) women were randomized to receive HRT (estrogen plus continuous medroxyprogesterone acetate) or placebo. No reductions in adverse cardiovascular events were observed after a mean follow-up of 4 years. Furthermore, the risk was actually slightly increased during the first year of treatment, and thus, the conclusion was made that there was no benefit of HRT on vascular outcomes. At the 6.8-year follow-up point, the study was halted early owing to an unacceptable increase in the number of adverse clinical events for venous thromboembolism, stroke, coronary heart disease, and breast cancer. The HRT group had a 29% increased risk of coronary artery disease and a 21% increase in venous thromboembolism.35 Other studies have found that hormone therapy is not consistently associated with a reduced or increased risk of stroke.47
The question remains whether estrogen may play a differing role in the periphery. Currently, a significant number of clinical trials have assessed effects of HRT on PAD (Table III). One of the first large studies, published in 2000 as part of the Postmenopausal Hormone Replacement Against Arteriosclerosis Trial, looked at the progression of carotid artery disease and HRT. After 2 years, the investigators found there was no difference in the carotid artery intimai thickness between the treatment and control group.48 The second study focused on femoral artery disease and also came to the conclusion that HRT has no benefit on PAD.49 In the Estrogen Replacement and Atherosclerosis (ERA) study (n = 309), both unopposed and opposed HRT did not influence the angiographie progression of coronary atherosclerosis.30 Lastly, in a subset of patients from the HERS trial, Byington et al50 also showed that HRT treatment did not decrease the overall intimai medial thickness of carotid artery disease in comparison to the control group. Similar results have been shown by others: that of no association between the use of HRT and carotid disease regression in postmenopausal women.51’52
All the previously mentioned studies were conducted with estrogen and progesterone HRT. Differing results have been observed with unopposed estrogen therapy. For example, Hodis and colleagues53 conducted a 2-year trial using unopposed estrogen therapy in young postmenopausal women and reported decreased progression of atherosclerotic disease in the carotid arteries. In addition, use of transdermal estrogen has shown a benefit in progression of carotid artery atherosclerosis.54 Finally, study length may also play a role in the conflicting results from these studies. The Rotterdam group demonstrated a 52% reduction in PAD in postmenopausal users of HRT. However, patients who used HRT for less than 1 year did not have any significant reduction in atherosclerotic progression.44
Conclusion
Women appear to have inferior outcomes following major vascular surgery even though there is an overall lower incidence of vascular disease in women compared to men. Despite evidence suggesting cardioprotective effects, estrogen or hormone replacement therapy cannot be recommended for all postmenopausal women. Studies and the media continue to provide conflicting and confusing information. Widely publicized conflicting results have altered both clinical and public opinions of the risks and benefits of HRT for cardiovascular protection. The studies presented in this review indicate potentially no benefit of combined estrogen-progesterone HRT for primary or secondary prevention of vascular disease. Furthermore, HRT may be associated with adverse clinical events and outcomes in certain women. Combination HRT (estrogen-progesterone) reduces the beneficial effect of estrogens on coronary arteries, increases the progression of coronary artery atherosclerosis, increases the thrombotic potential of atherosclerotic plaques, and may significantly lower high-density lipoproteins, thereby decreasing the cardioprotective benefit of estrogen therapy. However, unopposed estrogen may provide some degree of vascular protection. Preliminary findings from clinical trials suggest that estrogen-only HRT may be a beneficial treatment. This information merits additional research to assess the impact of estrogen alone on PAD.
As life expectancy increases, women can expect to live a considerable portion of their lives after menopause. When considering treatment options for preventing vascular disease, it is important to address not only benefit-versus-risk ratios but also how this treatment will affect the patient globally. Quality of life issues go beyond statistics and study findings. The quality of many women’s lives has been dramatically improved through the use of HRT. Without HRT, many women feel miserable, exhausted, and unable to cope with the symptoms of menopause. Yet, there are important vascular risks to consider in considering the use of HRT. Currently the use of HRT should be planned on a patient-by-patient basis and should be contraindicated in patients with hypercoagulability disorders. Future studies should assess the impact of estrogen alone on peripheral vascular disease and on whether the duration of HRT treatment plays a role in halting the progression of atherosclerosis.
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Liz Nguyen, MD, Debra R. Lues, BA, Peter H. Lin, MD, and Ruth L. Bush, MD, Houston, TX
Vase Endovasc Surg 38:547-556, 2004
From the Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston; and The Methodist Hospital, Houston, TX
Correspondence: Ruth L. Bush, MD, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston VAMC – 2002 Holcombe Blvd (112), Houston, TX 77030
E-mail: [email protected]
2004 Westminster Publications, Inc, 708 Glen Cove Avenue, Glen Head, NY 11545, USA
Copyright Westminster Publications, Inc. Nov/Dec 2004
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