Background
Hormone replacement therapy (HRT) is recommended to post-menopausal women to control menopausal symptoms and prevent osteoporosis. The management of women with peripheral arterial disease (PAD) and who are taking HRT is controversial.
Aim
To summarise what is known about HRT and its effect on the natural progression of PAD and its subsequent treatment.
Methods
A MEDLINE (1966–2004) and Cochrane library search for articles relating to HRT and PAD was undertaken.
Results
The potential benefits of unopposed estrogen therapy on atherosclerotic progression and limb microcirculation are outweighed by the increased risk of endometrial dysplasia and thrombotic complications. Only one major study (Rotterdam) specifically assessed the impact of HRT on the clinical course of PAD. The findings suggested a decreased risk of PAD among healthy post-menopausal women taking HRT which contrasts with the sub-group analyses of other major studies (HERS/HERS II). HRT appears to reduce the primary success rates of both endovascular and open surgical revascularisation in patients with PAD.
Conclusions
Further studies are required to investigate the effects of HRT on the progression of PAD and its management.
Keywords
Introduction
The effect of hormone replacement therapy (HRT) on the prevention and outcome of cardiovascular disease has been the subject of a number of clinical trials. Very few studies, however, have directly addressed the effect of HRT on peripheral arterial disease (PAD).
1
Three important clinical dilemmas exist when managing PAD in postmenopausal women:- 1.Should patients with PAD be advised to start, continue or discontinue taking HRT and how does this advice impact upon disease progression?
- 2.Does HRT impact on the benefits of best medical therapy (BMT) in patients with PAD?
- 3.Does HRT influence the short and long-term outcomes of vascular and endovascular intervention for the treatment of PAD?
Methods
We performed a MEDLINE (1966–2004) and Cochrane library search looking for articles relating to HRT, its effect on arterial physiology and the influence this has on the management of PAD. The terms hormone therapy, HRT, menopause, estrogens and progestogens were included amongst others. These were linked with terms such as cardiovascular disease, peripheral vascular disease and peripheral arterial disease. Further articles were identified by following MEDLINE links, by cross-referencing from the reference lists of major articles and by following citations for these studies. The studies were then graded and prioritised according to the level of the evidence presented.
Results
Studies examining the effect of HRT on cardiovascular disease progression and outcomes are summarised in Table 1.
Table 1Studies examining the effect of HRT on cardiovascular disease progression and outcome
| Trial | Author | Type | Patient no. | Mean follow-up | HRT | Summary | RR (95%CI) | |
|---|---|---|---|---|---|---|---|---|
| Type | Route | |||||||
| HERS | Hulley et al. 2 | RCT | 2763 | 4.1 years | (conjugated equine)Oestrogen+Progestin | oral | no overall reduction in CHD events in women with established coronary disease. Higher risk of CHD in first year | 0.99 (0.8–1.22) |
| HERS II | Grady et al. 3 | RCT | 2763 | 6.8 years | (conjugated equine) Oestrogen+Progestin | oral | Hormone therapy did not reduce risk of cardiovascular events in women with CHD | 1.0 (0.77–1.29) |
| WHI | Writing group 5 | RCT | 16608 | 5.2 years | Oestrogen+Progestin | oral | no benefit fot primary CHD prevention | 1.29 (1.02–1.63) |
| ERA | Herrington et al. 4 | RCT | 309 | 3.2 years | (conjugated equine) Oestrogen | oral | No alteration in progression of coronary atherosclerosis in women with established disease | N/A |
| (conjugated equine) Oestrogen+Progestin | oral | N/A | ||||||
| WEST | Viscoli et al. 57 | RCT | 664 | 2.8 years | Oestrogen | oral | In PNP women with recent CVA HRT did not reduce risk of any cardiac event | 1.2 (0.5–2.5) |
| EPAT | Hodis et al. 7 | RCT | 222 | 2 years | Oestradiol | oral | Average rate of progression of subclinical atherosclerosis was slower in healthy PMP women taking Oestradiol | N/A |
| PEPI | Writing group 15 | RCT | 875 | 3 years | conjugated equine oestrogen | oral | estrogen alone or in combination with progesterone improves lioproteins and lowers fibrinogen levels in PMP women | N/A |
| conjugated equine oestrogen+Progesterone | oral | N/A | ||||||
| Schulman et al. 58 | RCT | 293 | 6 months | iv oestrgen→oral oestrogen | iv/oral | acute hormaone therapy did not reduce ischaemia in PMP women with unstable angina | N/A | |
| iv oestrgen→oral oestrogen+progestin | iv/oral | N/A | ||||||
| Teede et al. 27 | RCT | 59 | 2 years | Oestradiol+Norethisterone | oral | May not be CVS beneficial in PMP women | N/A | |
| Falkeborn et al. 59 | Prospective cohort study | 23174 | 5.8 years | Conjugated Oestrogen/oestradiol | oral | Cardiovascular protective | 0.69 (0.54–0.86) | |
| Other oestrogen | oral | No Cardiovascular protection | 0.9 (0.74–1.08) | |||||
| Oestradiol+Lenonogesterola | oral | Cardiovascular protective | 0.53 (0.3–0.87) | |||||
The effect of HRT on the arterial wall and atherosclerosis
Several studies
2
, 3
, 4
, 5
have examined the effects of HRT in relation to coronary events, but few have examined its impact on the progression of atherosclerosis in the peripheral arterial system. Change in carotid intima-media thickness correlates well with the sub-clinical progression of generalized atherosclerosis.6
Various studies, including one large randomised, double-blind, placebo-controlled trial (the Estrogen in the Prevention of Atherosclerosis (EPAT) study)7
measured carotid intima-media thickness and demonstrated that unopposed estrogen therapy slows or halts the progression of atherosclerosis.8
By contrast, other studies such as the Atherosclerosis Risk in Communities (ARIC) study,9
and the more recent Healthy Women's Study10
reported no beneficial effect of HRT on carotid intimal thickening. The different findings of these studies may be due to the different types of estrogen used (17beta-estradiol vs conjugated equine estrogen) and the fact that by studying different age groups, different stages of disease were targeted. This is particularly relevant since patients seen by vascular specialists are more likely to be older with more advanced atherosclerosis and may not enjoy the full benefits seen in healthy postmenopausal women without pre-existing cardiovascular disease.7
The differences in the effect that estrogen has on different stages of atherosclerosis may be secondary to its effects on the endothelium which becomes dysfunctional early in the development of atherosclerosis;11
this said there is evidence that estrogen promotes endothelial function and augments endothelium-dependent vasodilatation at the micro- and macrovascular levels. Conjugated equine estrogen has been shown to reduce the accumulation of collagen and attenuate the fall of elastin content in monkey aortas.12
In this way, HRT may also have a beneficial effect on arterial wall stiffness.HRT and the coagulation cascade
Clinical trials
2
and experimental evidence indicates that the overall effect of HRT is to stimulate coagulation, inhibit anticoagulation and stimulate fibrinolysis.13
, 14
, 15
This effect is by no means certain, however, as both the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial15
and other experimental studies have demonstrated a reduction in plasma fibrinogen levels in those on combined HRT (cHRT). It is, as yet, unclear to what extent the addition of progesterone attenuates the oestrogenic prothrombotic tendency.16
Subgroup analysis of data from the Heart and Estrogen/Progestin Replacement (HERS) study2
demonstrated that estrogen increases the risk of early acute cardiovascular events in those women genetically predisposed to arterial thrombosis.17
, 18
In this study, an early increased risk of venous thromboembolism (VTE) was also identified and this has been reinforced by findings in other prospective and case-control studies.14
HRT is now contraindicated in patients with a history of myocardial infarction or VTE.19
The prothrombotic properties of HRT may account for the increased risk of thrombotic cardiovascular events in the first year after starting cHRT, as demonstrated in the HERS and Rotterdam studies, and this risk may be attenuated beyond the first year by the beneficial effect on lipid profile. Patients with PAD starting HRT may be at increased immediate risk of thromboembolic events that extends for weeks following cessation of drug administration. While oral HRT at least doubles the risk of VTE,2
, 20
the Estrogen and Thromboembolism Risk Study Group (ESTHER)21
found transdermal HRT does not appear to have the same effect. It would not be unreasonable to stop oral HRT 4–6 weeks prior to endovascular or surgical revascularisation particularly in those patients with PAD who have additional risk factors for VTE.The impact of different types of HRT on arterial structure and physiology
The dose and types of estrogen and progesterone used in major studies of post-menopausal HRT are shown in Table 2. In the UK, there are a range of combined treatments available but the most widely used contain 1–2 mg of estradiol (Climesse © , Climagest©, Elleste-Duet©, Femoston©, Nuvelle© etc.) or 0.625 mg conjugated equine estrogen (Prempak C©). The type and dose of progestin is more variable but most treatments in common use include a dose of 1 mg norethisterone acetate for 10–14 days (Climesse©, Climagest©, Elleste-Due©t, Evorell©) or 75 mg of levonorgestrel (Prempak C©, Nuvelle©).
14
The significance, if any, of these variations is unclear. Acute administration of oestrogen is known to improve endothelium-dependent flow in the microcirculation in healthy postmenopausal women,22
and many studies in both animals and human subjects have suggested a relationship between estrogen and increased production of nitric oxide (NO), a potent vasodilator. One study showed that administration of estrogen increased levels of cGMP and presumably therefore NO in postmenopausal women.23
This effect did not occur when progesterone was also administered and interestingly the effect was only seen in smokers. Indeed, when vascular bed reactivity and the levels of NO in the circulation were examined in patients on oestrogen therapy compared with subjects on cHRT, the beneficial effects of long-term estrogen therapy appeared to be abolished by the addition of a Progestin.24
, 25
One study demonstrated improved skin vasodilatation in response to vasodilators in postmenopausal women taking estrogen replacement therapy.- Imthurn B.
- Rosselli M.
- Jaeger A.W.
- Keller P.J.
- Dubey R.K.
Differential effects of hormone-replacement therapy on endogenous nitric oxide (Nitrite/Nitrate) levels in postmenopausal women substituted with 17 beta-estradiol valerate and cyproterone acetate or medroxyprogesterone acetate.
J Clin Endocrinol Metab. 1997; 82: 388-394
11
Progestins, possibly by increasing plasma renin activity, have a potential pressor effect which may antagonise the effect of estrogen on vascular tone.26
Animal studies have also shown that medroxyprogesterone acetate may inhibit the beneficial effect estrogen has on connective tissue metabolism.12
These findings may explain why continuous cHRT has been shown to have no effect on systemic arterial compliance, pulse wave velocity and endothelial function in healthy postmenopausal women.27
Table 2The dose and types of oestrogen and progesterone used in major studies of post-menopausal HRT
| Trial | Route | Oestrogen | Progesterone | ||
|---|---|---|---|---|---|
| Type | Dose | Type | Dose | ||
| HERS 2 | oral | conjugate equine | 0.625 mg | medroxyprogesterone acetate | 2.5 mg |
| HERS II 3 | oral | conjugate equine | 0.625 mg | medroxyprogesterone acetate | 2.5 mg |
| WHI 5 | oral | conjugate equine | 0.625 mg | medroxyprogesterone acetate | 2.5 mg |
| ERA 4 | oral | conjugate equine | 0.625 mg | medroxyprogesterone acetate | 2.5 mg |
| WEST 57 | oral | 17β-estradiol | 1 mg | NA | NA |
| EPAT 7 | oral | miconized 17β-estradiol | 1 mg | NA | NA |
| PEPI 15 | oral | conjugate equine | 0.625 mg | cyclical medroxyprogesterone acetate | 10 mg/2.5 mg |
| cyclic micronized progesterone | 200 mg | ||||
The impact of HRT on the clinical course of PAD
The Rotterdam study,
1
a population-based prospective, longitudinal, observational study of 2196 women aged 55 to 80 years, suggested that HRT given for a year or more was associated with a decreased risk of PAD among postmenopausal women. However an important study limitation was the fact that 91% of the participants were taking unopposed estrogen. The findings of this study, however, appear to contradict several controlled trials2
, 3
, 4
, 5
examining the effects of HRT on the coronary and cerebral vasculature. Analysis of data from a group of patients with known coronary heart disease (CHD) in the HERS study2
, 3
, 28
showed that HRT did not significantly lower the number of peripheral arterial events in this group of patients.HRT and cardiovascular risk factor management
The recent Womens Health Initiative (WHI)
5
and the HERS II trials3
have shown no cardioprotective properties associated with HRT in postmenopausal women and this has also been demonstrated in a meta-analysis.29
, 30
Women with pre-existing cardiovascular disease were found to be at increased risk of cardiovascular events in the first year after commencing HRT2
while longer term use may actually protect against development of PAD.1
The HERS and HERS II trials did not demonstrate any significant difference in coronary events between women taking HRT and aspirin, and women taking HRT without aspirin (RR: 0.96(95%CI, 0.7–1.31) HRT+Aspirin vs. 1.01(95%CI, 0.83–1.22) HRT alone).
2
, 3
Estrogen therapy has consistently been shown to reduce levels of circulating low density lipoproteins (LDL) and increase levels of high density lipoproteins (HDL),
2
, 15
, 31
, 32
and this may prevent progression of atherosclerosis.33
, 34
, 35
This does not, however, mean that the routine use of cHRT results in direct clinical benefit via this mechanism. Indeed, one of the most important randomised controlled trials (HERS) failed to show an overall cardiovascular benefit despite significant changes in lipid profiles.- Aengevaeren W.R.
- Kroom A.A.
- Stalenhoef A.F.
- Uijen G.J.
- Van der Werf T.
Low density lipoprotein apheresis improves regional myocardial perfusion in patients with hypercholesteraemia and extensive coronary artery disease. LDL-Apheresis Atherosclerosis Regression Study (LAARS).
J Am Coll Cardiol. 1996; 28: 1696-1704
4
During the HERS trial, a 14% decrease in LDL cholesterol occurred by the end of the first year of treatment compared with 3% in the placebo group. Despite this there appeared to be an increase in primary CHD events during this year (but a decrease in subsequent years). This may be related to the use of progesterone. It was shown in the PEPI trial that progesterone lessens the effect of estrogen on HDL cholesterol, and it is thought that progesterone attenuates the beneficial effect of oestrogen.15
, 36
, 37
However, two other trials using combined hormones have shown conflicting results.20
, 38
, 39
Statins (HMG-CoA reductase inhibitors) have been shown to reduce mortality in patients with coronary artery disease and elevated low-density lipoprotein (LDL) levels.
40
, 41
However, the absence of reductions in mortality by any other lipid lowering pharmacotherapy, despite significant LDL lowering, suggests that non-lipid effects may be important in mediating these benefits.42
Statins inhibit GTPase activation and preserve vascular function independently of their lipid lowering properties. Specifically, statins increase the bioavailability of endothelium-derived nitric oxide (NO) -a potent vasodilator- through the up regulation of endothelial nitric oxide synthetase (eNOS).43
Both human and animal models indicate that estrogen also has potent stimulatory effects on eNOS expression and activity.44
The clinical beneficial of this effect is doubtful, however, in light of the lack of mortality benefits reported by the HERS trial. An alternative hypothesis is that estrogen is associated with an early prothrombotic effect which acts in conflict with a more gradual beneficial effect on prevention of progression of atherosclerosis.13
Further comparison of the actions of statins and estrogen would appear to offer some support to this hypothesis: statins also appear to have an anticoagulation effect and this may account for some of their short term mortality benefits.Although simvastatin is better at lowering LDL cholesterol than oestrogen, one study did show that oestrogen replacement therapy was better at raising HDL cholesterol. It concluded that there was a modest additional benefit of adding oestrogen to a statin in relation to lipid profile outcome
49
Statins may also protect against some of the apparent negative effects of HRT seen in the immediate treatment period. An analysis of the HERS trial found that the increased cardiovascular mortality risk found for HRT users in the first year was attenuated by statins.45
A further beneficial effect of unopposed estrogen was shown in the Asymptomatic Carotid Artery Progression Study where changes in carotid intima-media thickness were reduced in women taking unopposed estrogen and no additional effect was identified in women receiving lovastatin.46
In addition to the beneficial effects on lipid profiles and vascular beds, unopposed estrogen therapy seems to have a favourable effect on glucose metabolism in patients with diabetes mellitus.47
There is a lack of consensus about the effects of HRT on blood pressure (BP). Cross-sectional studies have generally reported HRT as having no effect on BP.
37
, 48
, 49
The PEPI trial15
did not show HRT (estrogen or combination estrogen and progesterone) as having any effect on BP in 875 patients followed up for 3 years. This may be related to the counter balance vasopressor effects of progestin to the vasodilator effects of oestrogen. In contrast, Scuteri et al. reported post-menopausal women taking both oestrogen and progestin to have a smaller increase in systolic BP compared to those not taking HRT over a mean follow up period of 5.7 years.50
These contradictory data suggest that national hypertension guidelines should be adhered to irrespective of the individuals HRT status.HRT and the medical management of intermittent claudication
Although no study has examined the effect of HRT on claudication distance in patients with PAD, estrogen therapy has been shown to improve exercise capacity in postmenopausal women with CHD possibly as a result of short term improvements in endothelial-dependent and non-endothelial-dependent vasodilation.
51
HRT and peripheral revascularisation
HRT has been shown to increase circulating levels of coagulation activation markers and it is well-recognised that patients with PAD have a pro-thrombotic haemostatic derangement.
52
Only one study has examined the influence of HRT on the outcome of peripheral angioplasty/stenting. A longitudinal observational study of 126 iliac angioplasties and 144 stents over a 5 year period found HRT significantly reduced primary patency rates (HRT users: 49% vs. non-HRT users: 74% 5-year primary patency rate).53
In another study examining the outcome of femoro-popliteal bypass grafting in women, HRT emerged as the only predictor of diminished primary graft patency54
with the risk of graft failure increasing with use of prosthetic material. The same findings applied irrespective of whether the subjects were on estrogen alone or cHRT.Discussion
In summary, unopposed oestrogen has an overall beneficial effect in preventing progression of atherosclerosis. There is an initial prothrombotic effect of treatment, which may lead to an increase in both arterial and venous thrombotic effects within the first year, with subsequent improvement in the rate of these events occurring possibly as a consequence of improved lipid profile. The addition of progesterone therapy (cHRT) appears to attenuate any beneficial effects from estrogen. In view of the high risk of endometrial dysplasia from unopposed estrogen
15
it is inadvisable to prescribe unopposed estrogen to postmenopausal women who have not had an hysterectomy. Those who have undergone hysterectomy may derive some benefit from unopposed estrogen; however, this group of patients has been excluded from most studies. Alternatives to ‘standard’ HRT, such as selective estrogen receptor modulators (e.g. raloxifene), appear to have beneficial effects on lipids without the deleterious effects on coagulation13
but there are no data assessing their effect on PAD.To address the important clinical dilemmas for the vascular specialist, we recommend to our patients with PAD that they should continue their HRT as there appears to be no significant effect on the prevention or progression of PAD (other than perhaps improving ability to increase exercise capacity in those with concomitant CHD).
51
However, unless strong clinical indications exist, we advise patients with PAD against starting on HRT in view of the initial increase in thrombotic cardiovascular events up to one year. This may also apply to patients with PAD who are admitted for any type of surgery.There is currently no clear evidence supporting the routine discontinuation of HRT prior to surgery. The Royal College of Obstetricians and Gynaecologists currently advise that HRT should be viewed as a risk factor for VTE and recommend the addition of appropriate thromboembolic prophylaxis, but not the routine cessation of HRT, prior to surgery.
55
In contrast, the current advice in the British national Formulary (BNF) is to stop treatment 4–6 weeks prior to surgery.Royal College of Obstetricians and Gynaecologists. Hormone Replacement Therapy and Venous Thromboembolism (19) - Jan 2004. www.rcog.org.uk/clingov1
14
It is well established that PAD is associated with a resting prothrombotic state which correlates with disease severity and that patients undergoing lower limb revascularisation procedures are at a high risk of peri-operative cardiac thrombotic events.52
, 56
Furthermore, HRT may have a deleterious effect on the success of both endovascular and open surgical revascularisation.53
, 54
In view of these factors we currently advise our patients to stop HRT 6 weeks prior to surgical or endovascular intervention.References
- Hormone replacement therapy and peripheral arterial disease. The Rotterdam Study.Arch Intern Med. 2000; 160: 2498-2502
- Randomised trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group.JAMA. 1998; 280: 605-613
- Cardiovascular disease outcomes during 6.8 years of hormone therapy. Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II).JAMA. 2002; 288: 49-57
- Effects of estrogen replacement on the progression of coronary-artery atherosclerosis.N Engl J Med. 2000; 343: 522-529
- Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative Randomized controlled trial.JAMA. 2002; 288: 321-333
- Reproducibility of carotid vessel wall thickness measurements: the Rotterdam Study.J Clin Epidemiol. 1994; 47: 921-930
- Estrogen in the prevention of atherosclerosis. A randomized double-blind, placebo-controlled trial.Ann Intern Med. 2001; 135: 939-953
- Hormone replacement therapy and intima-media thickness of the common carotid artery. The Rotterdam Study.Stroke. 1999; 30: 2562-2567
- No association of menopause and hormone replacement therapy with carotid artery intima-media thickness. Atherosclerosis Risk in Communities (ARIC) Study Investigators.Circulation. 1996; 94: 1857-1863
- Hormone therapy, lipoprotein subclasses, and coronary calcification: the Healthy Women Study.Arch Intern Med. 2005 Mar 14; 165: 510-515
- Estrogen improves endothelial function.Journal of Vascular Surgery. 1998; 27: 1141-1147
- Conjucated equine estrogen alone, but not in combination with medroxyprogesterone acetate, inhibit aortic connective remodelling after plasma lipid lowering in female monkeys.Arterioscler Thromb Vasc Biol. 1998; 18: 1164-1171
- Changes of hemostatic variables during HRT.Semin Vasc Med. 2003; 3: 85-92
- Hormone replacement therapy: prothrombotic vs. protective effects.Pathophysiol Haemost Thromb. 2002; 32: 329-332
- Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women.JAMA. 1995; 273: 199-208
- The effects of hormone replacement therapy on thrombin generation, fibrinolysis inhibition, and resistance to activated protein C: prospective cohort study and review of literature.Thromb Res. 2000; 99: 25-34
- The HERS trial results: paradigms lost?.Ann Intern Med. 1999; 131: 463-466
- Hormone replacement therapy, prothrombotic mutations, and the risk of incident nonfatal myocardial infarction in postmenopausal women.JAMA. 2001; 285: 906-913
British National Formulary September 2003; 6.4.1.1: 350–360.
- Evidence from randomised trials on the long-term effects of hormone replacement therapy.Lancet. 2002; 360: 942-944
- EStrogen and ThromboEmbolism Risk Study Group. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk.Lancet. 2003; 362: 428-432
- Estrogen improves endothelium-dependent, flow-related vasodilatation in postmenopausal women.Ann Intern Med. 1994; 121: 936-941
- Hormone replacement therapy in healthy postmenopausal women. Effects on intraplatelet cyclic guanosine monophosphate, plasma endothelin-1 and neopterin.Journal of Internal Medicine. 2000; 247: 463-470
- Effects of long-term oestrogen therapy versus combined hormone replacement therapy on nitric oxide-dependent vasomotor function.J Clin Endocrinol Metab. 2003; 88: 4348-4354
- Differential effects of hormone-replacement therapy on endogenous nitric oxide (Nitrite/Nitrate) levels in postmenopausal women substituted with 17 beta-estradiol valerate and cyproterone acetate or medroxyprogesterone acetate.J Clin Endocrinol Metab. 1997; 82: 388-394
- Blood pressure, arterial function, structure and aging: the role of hormonal replacement therapy in postmenopausal women.J Clin Hypertens. 2003; 5: 219-225
- A placebo- controlled trial of long-term oral combined continuous hormone replacement therapy in postmenopausal women: effects on arterial compliance and endothelial function.Clin Endocrinol. 2001; 55: 673-682
- Peripheral arterial disease in randomized trial of estrogen with progestin in women with coronary heart disease.Circulation. 2000; 102: 2228-2232
- Postmenopausal hormone replacement therapy and the primary prevention of cardiovascular disease.Ann Intern Med. 2002; 137: 273-284
- Postmenopausal hormone replacement therapy: scientific review.JAMA. 2002; 288: 872-881
- Hormone therapy to prevent disease and prolong life in postmenopausal women.Annals of Internal Medicine. 1992; 117: 1016-1037
- Hormone replacement therapy and cardiovascular disease.Current Opinion Lipidology. 1999 Oct; 10: 429-434
- Effect of intensive lipid lowering on progression of coronary atherosclerosis: evidence for an early benefit from the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial.Am J Cardiol. 2005; 96: 61-68
- Heart Protection Study Collaborative Group. Effects of cholesterol lowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other high-risk conditions.Lancet. 2004; 363: 757-767
- Low density lipoprotein apheresis improves regional myocardial perfusion in patients with hypercholesteraemia and extensive coronary artery disease. LDL-Apheresis Atherosclerosis Regression Study (LAARS).J Am Coll Cardiol. 1996; 28: 1696-1704
- A prospective one year study on oestrogen and progestin in postmenopausal women: effects on clinical symptoms and lipoprotein lipids.Obstet Gynecol. 1989; 73: 759-766
- Influence of sex on blood pressure and left ventricular mass in adolescents: the Hypertension in Pregnancy Offspring Study.J Hum Hypertens. 1994; 8: 485-490
- The risk of acute myocardial infarction after oestrogen and oestrogen-progestogen replacement.Br J Obstet Gynaecol. 1992; 99: 821-828
- The use of hormone replacement therapy and the risk of stroke and myocardial infarction in women.J Epidemiol Community Health. 1989; 43: 173-178
- Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels.N Engl J Med. 1998; 339: 1349-1357
- Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).Lancet. 1994; 344: 1383-1389
- Pleiotropic effects of statins: benefit beyond cholesterol reduction? A meta-regression analysis.J Am Coll Cardiol. 2005; 46: 1855-1862
- The nonlipid effects of statins on endothelial function.Trends Cardiovasc Med. 2006; 16: 156-162
- Estrogen modulation of endothelial nitric oxide synthase.Endocr Rev. 2002; 23: 665-686
- Statin therapy in the heart and oestrogen/progestin replacement study.Minerva Ginecol. 2003; 55: 209-215
- Effects of lovastatin and warfarin on early carotid atherosclerosis: sex-specific analyses. Asymptomatic Carotid Artery Progression Study (ACAPS) Research Group.Circulation. 1999; 100: 14-17
- Hormone replacement therapy in postmenopausal women with diabetes mellitus: a risk-benefit assessment.Drugs Aging. 2000; 17: 399-410
- Estradiol with or without progesterone and ambulatory blood pressure in postmenopausal women.Hypertension. 1999; 33: 1190-1194
- Physiological doses of estradiol decrease nocturnal blood pressure in normotensive postmenopausal women.Am J Physiol. 1999; 276: H1355-H1360
- Hormone replacement therapy and longitudinal changes in blood pressure in postmenopausal women.Ann Intern Med. 2001; 135: 229-238
- Long-term oestrogen replacement therapy is associated with improved exercise capacity in postmenopausal women without known coronary artery disease.American Heart Journal. 2000; 139: 739-744
- Plasma levels of the molecular markers of coagulation and fibrinolysis in patients with peripheral arterial disease.Semin Thromb Hemost. 1996; 22: 35-40
- Influence of hormone replacement therapy on the outcome of iliac angioplasty and stenting.J Vasc Surg. 2001; 33: S85-S92
- Influence of hormone replacement therapy on graft patency after femoropopliteal bypass grafting.J Vasc Surg. 2000; 32 ([516–8]): 506-516
Royal College of Obstetricians and Gynaecologists. Hormone Replacement Therapy and Venous Thromboembolism (19) - Jan 2004. www.rcog.org.uk/clingov1
- Peri-operative myocardial injury in patients with critical limb ischaemia.Eur J Vasc Endovasc Surg. 2005; 29: 301-304
- A clinical trial of estrogen-replacement therapy after ischemic stroke.N Engl J Med. 2001; 345: 1243-1249
- Effects of acute hormone therapy on recurrent ischemia in postmenopausal women with unstable angina.J Am Coll Cardiol. 2002; 39: 231-237
- The risk of acute myocardial infarction after oestrogen and oestrogen-progestogen replacement.Br J Obstet Gynaecol. 1992; 99: 821-828
Article info
Publication history
Published online: August 07, 2007
Accepted:
June 1,
2007
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© 2007 European Society for Vascular Surgery. Published by Elsevier Inc.
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