Do we need clinical trials to test the ability of transdermal HRT to prevent coronary heart disease?
© BioMed Central Ltd 2001
Published: 10 September 2001
Postmenopausal hormone replacement therapy (HRT) with oral oestrogen was predicted to reduce coronary heart disease (CHD) risk by 50%. Randomized controlled trials show no such benefit, however, pointing instead to an initial increase in CHD events. Although the cardiovascular effects of transdermal HRT are largely unknown, improvements in arterial function are maintained when oestrogen is administered transdermally. Transdermal HRT also avoids the increased plasma levels of C-reactive protein (CRP) that are seen with oral HRT. However, the clinical significance of this general reduction in hepatic over-synthesis of plasma proteins is difficult to assess. Nevertheless, the available evidence on transdermal HRT appears to justify a formal clinical trial.
Keywordscoronary heart disease hormone replacement therapy oestradiol progestin transdermal delivery
The claim that postmenopausal hormone replacement therapy (HRT) reduces coronary heart disease (CHD) risk by 50% has until recently been a mantra in female health care and, to a lesser extent, in preventive cardiology . This belief originated in the 1960s and is based on the logic that if the menopause causes CHD (a dubious proposal at best) then oestrogen replacement should prevent the disease. Plasma lipoprotein levels were an aspect of metabolism that was at the core of cardiovascular research at that time, and the changes in response to oestrogen were encouraging .
A low incidence of CHD was subsequently shown in observational (nonrandomized) studies of HRT users . This association was strengthened by the antiatherosclerotic effect of oestrogen demonstrated in fat-fed animals , which was consistent with the identification of this steroid as a powerful vasoactive agent.
Administration of HRT through skin patches has become a common treatment option in postmenopausal women , resonating with the late 20th century distrust of 'pills'. By providing relatively stable blood hormone levels, it was expected to reduce side effects and improve compliance. The major disadvantages, aside from cost, are that patches may fall off or induce skin reactions. These problems have been minimized by advances such as 'matrix' patches that incorporate the steroid in the adhesive layer of the patch. Transdermal HRT is as effective as oral HRT in relieving climacteric symptoms, such as hot flushes, and has comparable effects on bone metabolism and bone density. Some women prefer patches and others prefer pills, and with such a complex and multisystem condition as the menopause it was always unlikely that any one therapy would emerge as a clear favourite.
Differences in the cardiovascular risk profiles of oral and transdermal HRT
Differences that favour
Decrease in factor VII activity, fibrinogen,
and triglycerides levels
Neutral effect on C-reactive protein
Decrease in LDL and Lp(a) levels
Increase in HDL levels
Decrease in PAI-1 levels
Oral hormone replacement therapy and coronary heart disease
When oestrogen is given orally the liver reacts to the rapid increase or 'bolus' of hormone emerging in the hepatic portal vein by attempting to deactivate this seemingly alien material. Relatively large steroid doses are needed to overcome this 'first-pass' effect in order to ensure sustained and clinically relevant plasma hormone levels. One consequence of this overdosing is a dramatic increase in hepatic synthesis (and hence plasma levels) of many proteins, including those that are involved in haemostasis and blood pressure regulation .
Transdermal delivery of oestrogen was developed in part to avoid this over-synthesis, although a certain amount of hepatic stimulation may be desirable. For instance, oral oestrogen induces hepatic synthesis of apolipoprotein A-I and so increases plasma levels of high-density lipoproteins (HDLs) – a change that is often considered pivotal to the perceived cardiovascular benefit of HRT. The possibility that the transdermal route may have advantages or disadvantages over oral HRT in CHD prevention could form the basis of a clinical trial.
Transdermal hormone replacement therapy and coronary heart disease
In the first randomized controlled trial of the effects of transdermal HRT on CHD end-points, the Papworth HRT Atherosclerosis Study, 255 women with angiographically defined CHD were randomly assigned to receive placebo or transdermal HRT . That study was terminated prematurely because of a higher incidence of myocardial infarction, stroke and venous thromboembolism in the transdermal HRT group – a similar pattern to that encountered in recent trials of oral therapy . There are obvious concerns that this trial was underpowered, a limitation that was exacerbated by a 40% dropout rate in HRT users. Some would argue that these results are not relevant to the average HRT user, but it should be remembered that the consensus has always been that HRT is especially beneficial in CHD patients .
Although transdermal oestradiol was no better than placebo in preventing atherosclerosis in fat-fed rabbits , the possibility of clinical benefit of transdermal HRT has been raised in a case–control study conducted by a manufacturer of the skin patches . The health records of 164,769 women in UK general practices were used to assemble an adjusted odds ratio for myocardial infarction of 0.75 (95% confidence interval 0.47–1.21) in women currently or recently using transdermal HRT, as compared with nonusers. The limitation of such an observational study is that women often choose HRT of their own volition, which leads to health and health care differences between HRT users and control individuals. Observational epidemiological studies cannot adjust adequately for baseline differences in socioeconomic status and other CHD risk factors. Even conventional risk factors such as hypertension and dyslipidaemia are poorly quantified in such surveys.
The coronary heart disease risk profile of transdermal hormone replacement therapy
The evidence for transdermal HRT is often inconclusive. Research is frequently contaminated by the concomitant use of different types and doses of progestins to prevent oestrogen-induced endometrial hyperplasia and cancer, with the route of progestin administration being less of an issue. Progestins can exhibit androgenic characteristics and in particular can reduce oestrogen-induced rises in plasma levels both of HDLs and of fasting triglycerides. This antagonism is, in theory, both undesirable and desirable . In light of this, a logical step is to look at surrogate measures of atherosclerosis.
When transdermal HRT was first introduced it appeared to be neutral in its effect on plasma lipoprotein metabolism , which was consistent with avoidance of hepatic first-pass metabolism. Larger and more sophisticated studies confirmed the lack of effect on HDL levels, but showed modest reductions in low-density lipoproteins and (less consistently) lipoprotein(a), as well as an intriguing fall in levels of fasting triglycerides . When a progestin was coadministered with transdermal HRT, HDL levels tended to fall. Therefore, transdermal HRT theoretically has beneficial effects on low-density lipoprotein (LDL), lipoprotein(a) and triglycerides, but has little effect on HDL – a lipoprotein that was previously considered the cornerstone of the cardiovascular benefits of HRT.
Glucose and insulin homeostasis
Some studies suggest that oestrogens and progestogens can induce a mild form of insulin resistance . Because insulin resistance may underlie many forms of CHD, claims for a beneficial effect of transdermal HRT in this area of cardiovascular risk were of obvious interest . At present, methodological arguments dominate this area of risk assessment, but recent studies using the classic 'euglycaemic clamp' technique fail to show any influence of transdermal HRT on insulin kinetics [17,18]. In this procedure, plasma glucose levels are continually monitored and kept stable or 'clamped' at a pre-agreed value, following intravenous infusion of insulin. In contrast to insulin resistance, an insulin-sensitive person needs more glucose to maintain this plasma glucose level, because they respond strongly to the insulin.
Coagulation and fibrinolysis
It was hoped that induction of a 'prothrombic' state linked with oral HRT could be avoided with transdermal oestradiol, because it has no effect on hepatic synthesis of coagulation factors and other proteins that are involved in haemostasis. The evidence for such a benefit is unconvincing, however. Reductions in factor VII activity and fibrinogen levels have been reported with transdermal therapy , which is consistent with a reduction in plasma levels of triglyceride-rich lipoproteins . This potential benefit has to be balanced against the claim that only oral oestrogen reduces plasma levels of the inhibitor of fibrinolysis plasminogen activator inhibitor (PAI)-1 . This in turn has been challenged by Falco et al , who claim that transdermal oestradiol reduces PAI-1 levels and improves fibrinolysis in CHD patients.
More comparative studies are needed, with an emphasis on markers of haemostatic flux such as F1.2 and D-dimer. Although transdermal HRT is often perceived to be free of the increased risk for venous thromboembolism that is seen with oral HRT, the evidence for such an assertion is weak .
Transdermal oestradiol can reduce blood pressure  and, in particular, restores the night-time blood pressure 'dip' that is absent in some older individuals . The clinical significance of these small changes is uncertain, but raises the possibility that transdermal HRT may be a better choice for a subset of hypertensive women with genetic susceptibility to oral oestrogen.
Despite claims that transdermal oestradiol has less effect on plasma markers of endothelial function in comparison with oral therapy , a recent study  found substantial reductions in soluble intercellular adhesion molecule, E-selectin and vascular cell adhesion molecule-1. The disparities between studies may reflect the use of different study populations, such as CHD patients or smokers. One critical distinction between oral and transdermal HRT may exist in the effect on plasma levels of C-reactive protein (CRP), which is considered to be a marker of the inflammatory response in atherosclerosis. Oral HRT substantially increases plasma CRP levels, but this is not seen with transdermal therapy [28,29].
de Ziegler et al  first showed that transdermal oestradiol reduced vascular resistance in uterine arteries, and this was subsequently confirmed in both coronary and carotid arteries. Transdermal oestradiol improves forearm blood flow  and coronary vasomotion , although studies of treadmill performance in CHD patients are contradictory [33,34].
Despite some negative studies, there are sufficient clear indications of a theoretical benefit with at least some transdermal therapies in certain groups of women to conclude that transdermal HRT has the potential to improve arterial function. This is consistent with our understanding of the direct actions of oestradiol on the arterial wall.
The severe mismatch between observed and expected results for oral HRT in randomized controlled trials of CHD end-points challenges the validity of observational epidemiology, animal studies, and traditional CHD surrogates. Transdermal HRT is considered inferior to oral HRT for CHD prevention, because of the lack of effect on HDL and PAI-1. If the apparent lack of activation of CRP by transdermal HRT can be confirmed, and if the increased CRP levels seen in oral HRT users can be linked to their adverse clinical outcomes, then an adequately powered controlled trial of transdermal HRT in the prevention of CHD would be desirable. The lesson from recent HRT trials is that such a venture should not be started in the absence of a consensus regarding the study population (healthy women or CHD patients) and regarding the use of progestin.
C-reactive protein disease
hormone replacement therapy
plasminogen activator inhibitor.
- Stampfer MJ, Colditz GA: Estrogen replacement therapy and coronary heart disease; a quantitative assessment of the epidemiologic evidence. Prev Med. 1991, 20: 47-63.View ArticlePubMedGoogle Scholar
- Godsland IF, Wynn V, Crook D, Miller NE: Sex, plasma lipoproteins and atherosclerosis: prevailing assumptions and outstanding questions. Am Heart J. 1987, 114: 1467-1503.View ArticlePubMedGoogle Scholar
- Stampfer MJ, Colditz GA: Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiological evidence. Prev Med. 1991, 20: 47-63.View ArticlePubMedGoogle Scholar
- Mendelsohn ME, Karas RH: The protective effects of estrogen on the cardiovascular system. N Engl J Med. 1999, 340: 1801-1811. 10.1056/NEJM199906103402306.View ArticlePubMedGoogle Scholar
- Jewelewicz R: New developments in topical estrogen therapy. Fertil Steril. 1997, 67: 1-12. 10.1016/S0015-0282(97)81846-8.View ArticlePubMedGoogle Scholar
- Speroff L: Postmenopausal hormone replacement therapy and coronary heart disease: clinical implications of recent randomized trial results. Maturitas. 2000, 35: 91-97. 10.1016/S0378-5122(00)00127-4.View ArticlePubMedGoogle Scholar
- de Ziegler D: Is the liver a target organ for estrogen?. In: The Menopause and Hormonal Replacement Therapy. Edited by Sitruk-Ware R, Utian WH. New York: Marcel Dekker, Inc;. 1991, 201-225.Google Scholar
- Clarke S, Kelleher J, Lloyd-Jones H, Sharples L, Slack M, Schofield PM: Transdermal hormone replacement therapy for secondary prevention of coronary artery disease in postmenopausal women [abstract]. Eur Heart J. 2000, 21(suppl): 212-Google Scholar
- Grady D, Rubin SM, Petitti DB, Fox CS, Black D, Ettinger B, Ernster VL, Cummings SR: Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med. 1992, 117: 1016-1037.View ArticlePubMedGoogle Scholar
- Blumel JE, Castelo-Branco C, Gonzalez P, Moyano C, Iturriaga M, Videla L, Sanjuan A, Cano A: Transdermal estrogens do not appear to modify the extent of lesional areas of aortic atherosclerosis in oophorectomized rabbits on a cholesterol-rich diet. Atherosclerosis. 2000, 148: 303-308. 10.1016/S0021-9150(99)00277-4.View ArticlePubMedGoogle Scholar
- Varas-Lorenzo C, Garcia-Rodriguez LA, Perez-Gutthann S, Duque-Oliart A: Hormone replacement therapy and incidence of acute myocardial infarction. A population-based nested case-control study. Circulation. 2000, 101: 2572-2578.View ArticlePubMedGoogle Scholar
- Crook D: Effects of estrogens and progestogens on plasma lipids and lipoproteins. In: Estrogens and Progestogens in Clinical Practice. Edited by Fraser IS, Jansen RPS, Lobo RA, White-head MI. London: Churchill Livingstone;. 1998, 787-798.Google Scholar
- Chetkowski RJ, Meldrum DR, Steingold KA, Randle D, Lu JK, Eggena P, Hershman JM, Alkjaersig NK, Fletcher AP, Judd HL: Biological effects of transdermal estradiol. N Engl J Med. 1986, 314: 1615-1620.View ArticlePubMedGoogle Scholar
- Crook D: The metabolic consequences of treating postmenopausal women with non-oral hormone replacement therapy. Br J Obstet Gynaecol. 1997, 104(suppl 16): 4-3.View ArticleGoogle Scholar
- Godsland IF: The influence of female sex steroids on glucose metabolism and insulin action. J Intern Med. 1996, 240(suppl 738): 1-60.Google Scholar
- Godsland IF: Female sex hormones and gonadal steroids. J Intern Med. 1996, 240(suppl 738): 3-60.Google Scholar
- Duncan AC, Lyall H, Roberts RN, Petrie JR, Perera MJ, Monaghan S, Hart DM, Connell JM, Lumsden MA: The effect of estradiol and a combined estradiol/progestagen preparation on insulin sensitivity in healthy postmenopausal women. J Clin Endocrinol Metab. 1999, 84: 2402-2407.View ArticlePubMedGoogle Scholar
- Vehkavaara S, Westerbacka J, Hakala-Ala-Pietila T, Virkamaki A, Hovatta O, Yki-Jarvinen H: Effect of estrogen replacement therapy on insulin sensitivity of glucose metabolism and pre-resistance and resistance vessel function in healthy postmenopausal women. J Clin Endocrinol Metab. 2000, 85: 4663-4670.PubMedGoogle Scholar
- Winkler UH, Kramer R, Kwee B, Schindler AE: Estrogen replacement in postmenopause, blood coagulation and fibrinolysis: comparison of a new kind of transdermal estradiol treatment with oral therapy with conjugated estrogens. Zentralbl Gynakol. 1995, 117: 540-548.PubMedGoogle Scholar
- Miller GJ: Lipoproteins and the haemostatic system in atherothrombotic disorders. Baillieres Best Pract Res Clin Haematol. 1999, 12: 555-575. 10.1053/beha.1999.0040.View ArticlePubMedGoogle Scholar
- Koh KK, Mincemoyer R, Bui MN, Csako G, Pucino F, Guetta V, Waclawiw M, Cannon RO: Effects of hormone-replacement therapy on fibrinolysis in postmenopausal women. N Engl J Med. 1997, 336: 683-690. 10.1056/NEJM199703063361002.View ArticlePubMedGoogle Scholar
- Falco C, Tormo G, Estelles A, Espana F, Tormo E, Gilabert J, Velasco JA, Aznar J: Fibrinolysis and lipoprotein(a) in women with coronary artery disease. Influence of hormone replacement therapy. Haematologica. 2001, 86: 92-98.PubMedGoogle Scholar
- Oger E, Scarabin PY: Assessment of the risk for venous thromboembolism among users of hormone replacement therapy. Drugs Aging. 1999, 14: 55-61.View ArticlePubMedGoogle Scholar
- Seely EW, Walsh BW, Gerhard MD, Williams GH: Estradiol with or without progesterone and ambulatory blood pressure in postmenopausal women. Hypertension. 1999, 33: 1190-1194.View ArticlePubMedGoogle Scholar
- Mercuro G, Zoncu S, Piano D, Pilia I, Lao A, Melis GB, Cherchi A: Estradiol-17beta reduces blood pressure and restores the normal amplitude of the circadian blood pressure rhythm in postmenopausal hypertension. Am J Hypertens. 1998, 11: 909-913. 10.1016/S0895-7061(98)00096-X.View ArticlePubMedGoogle Scholar
- Vehkavaara S, Hakala-Ala-Pietila T, Virkamaki A, Bergholm R, Ehnholm C, Hovatta O, Taskinen MR, Yki-Jarvinen H: Differential effects of oral and transdermal estrogen replacement therapy on endothelial function in postmenopausal women. Circulation. 2000, 102: 2687-2693.View ArticlePubMedGoogle Scholar
- Seljeflot I, Arnesen H, Hofstad AE, Os I: Reduced expression of endothelial cell markers after long-term transdermal hormone replacement therapy in women with coronary artery disease. Thromb Haemost. 2000, 83: 944-948.PubMedGoogle Scholar
- Sattar N, Perera M, Small M, Lumsden MA: Hormone replacement therapy and sensitive C-reactive protein concentrations in women with type-2 diabetes. Lancet. 1999, 354: 487-488. 10.1016/S0140-6736(99)02079-6.View ArticlePubMedGoogle Scholar
- Giltay EJ, Gooren LJ, Emeis JJ, Kooistra T, Stehouwer CD: Oral ethinyl estradiol, but not transdermal 17beta-estradiol, increases plasma C-reactive protein levels in men. Thromb Haemost. 2000, 84: 359-360.PubMedGoogle Scholar
- de Ziegler D, Bessis R, Frydman R: Vascular resistance of uterine arteries: physiological effects of estradiol and progesterone. Fertil Steril. 1991, 55: 775-779.PubMedGoogle Scholar
- Pinto S, Virdis A, Ghiadoni L, Bernini G, Lombardo M, Petraglia F, Genazzani AR, Taddei S, Salvetti A: Endogenous estrogen and acetylcholine-induced vasodilation in normotensive women. Hypertension. 1997, 29: 268-273.View ArticlePubMedGoogle Scholar
- Roque M, Heras M, Roig E, Masotti M, Rigol M, Betriu A, Balasch J, Sanz G: Short-term effects of transdermal estrogen replacement therapy on coronary vascular reactivity in postmenopausal women with angina pectoris and normal results on coronary angiograms. J Am Coll Cardiol. 1998, 31: 139-143. 10.1016/S0735-1097(97)00436-1.View ArticlePubMedGoogle Scholar
- Holdright DR, Sullivan AK, Wright CA, Sparrow JL, Cunningham D, Fox KM: Acute effect of oestrogen replacement therapy on treadmill performance in postmenopausal women with coronary artery disease. Eur Heart J. 1995, 16: 1566-1570.PubMedGoogle Scholar
- Webb CM, Rosano GM, Collins P: Oestrogen improves exercise-induced myocardial ischaemia in women. Lancet. 1998, 351: 1556-1557.View ArticlePubMedGoogle Scholar