Oestrogen and vascular disease

T h e review article by Harvey’ on oestrogen and vascular disease was informative. We believe, however, that there are some issues that need further clarification.

Firstly, the author mentioned that little is known about the addition of progestogen to oestrogen and its effects on cardiovascular outcome. There was n o reference, however, to the publication by Grodstein and colleagues in the Nurses’ Health study,’ which found that there was a marked decrease in the risk of coronary heart disease in women who took oestrogen with progestogen (RR 0.39, 95% CI 0.19 to 0.78) or oestrogen alone (RR 0.60, 95% CI 0.43 to 0.831, compared to women who did not use hormones. T h e authors concluded that the addition of progestogen did not diminish the cardioprotective effects of postmeno- pausal oestrogen therapy.

Secondly, there is growing indirect evidence that supports the fact that oestrogen may have some beneficial effects on cardiac structure and function. The prevalence of left ventricular hypertrophy (LVH) increases disproportionately in women as compared with men. In the Framingham study, male subjects had a 15% increase in risk of LVH for each decade of increment in age, as opposed to female subjects who had a 67% increased risk.? T h e prevalence of LVH measured by echocardiography was 8% in men under the age of 30, rising to 33% in men aged 70 years and over. In women the increase was from 5% to 49%). It is also known that LVH measured echocardiographically is an independent risk factor of mortality and confers a worse prognosis in w0men.l

In a recently published case controlled study, we examined the relationship between hormone replace- ment therapy (HRT) and left ventricular (LV) wall t h i ~ k n e s s . ~ In our study, we found that a group of post- menopausal women with no cardiovascular risk factors, who had been on HRT for more than ten years, had a reduced LV mass measured by echocardiography, compared to a control group. This difference remained statistically significant even after adjusting for age, body mass index, systolic blood pressure and alcohol consumption. All these are factors that have been previously implicated in the development of LVH.

From a functional point of view, a Finnish group found that HRT was associated with a higher early-to- atrial peak transmitrnl velocity ratio.” This shows an augmentation of early diastolic filling and improved LV diastolic function.

On a molecular level, functional oestrogen receptor 13 is also present in myocardial cells. This receptor is thought to regulate the expression of nitric oxide synthases.’

We recognise that the mechanisms of the cardio- protective role of oestrogen have not been fully elucidated. However, we feel that its effects on cardiac structure and function need to be evaluated further, as they may explain some of the beneficial effects of HRT on reduction of cardiovascular mortality.

W. IZ. LIM, Research Fellow,

Centre for Applied Gerontology, Melbourne, Vic,

G. CAPLAN, Director,

Post Acute Care Services, Prince of Wales Hospital,

Sydney, NSW.

References 1. Harvey P. Oestrogen and vascular disease. Aust NZ J Med

2. Grodstein F, Stampfer MJ, Manson JE er al. Postmeno- pausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med 1996; 335: 453-61.

3.Levy D, Anderson KM, Savage DD, Kannel WB, Chriastensen JC, Castelli WP. Echocardiographically detected left ventricular hypertrophy: prevalence and risk factors. The Framingham heart study. Ann Intcrn Med

4.Liao Y, Cooper RS, Mensah GA, McGee DL. Left ventricular hypertrophy has a greater impact on survival in women than in men. Circulation 1995; 92: 805-10.

5 . Lim WK, Wren B, Jepson N, Roy S, Caplan G. Effect of hormone replacement therapy on left ventricular hyper- trophy. Am J Cardiol 1999; 83: 1132-4.

6 . Voutilainen S, Hippelainnen M, Hulkko S, Karpinnen K, Ventila M, Kupari M. Left ventricular diastolic function doppler echocardiography in relation to hormone replace- ment therapy in healthy postmenopausal women. Am J Cardiol 1993; 71: 614-7.

7. Mendelsohn ME, Karas RH. The protective effects of cstrogen on the cardiovascular system. X Engl J Med 1999; 340: 1801-11.

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1988; 108: 7-13.

REPLY I appreciate the interest expressed in my review’ and agree that the results of the Nurses’ Health Study,’,’ a large, long-term, prospective observational study, suggest that the putative cardioprotective effects of oestrogen replacement therapy observcd in multiple epidemiological studies may be preserved when oestrogen is administered in combination with a progestogen. However, observational data pertaining to outcomes with combination oestrogen-progestogen regimens remain limited. It is worth noting that multiple studies in humans and experimental animals have

LETTERS AND CASE REPORTS Aust NZ J Mcd 1999; 29 827

suggested that the addition of a synthetic progestogen may attenuate or even reverse oestrogen associated cardioprotective effects. In addition, the effects of the progestogen on the vasculature are complex and dependent on multiple variables which include the dose, type, route and pattern of administration of the progestogen.'.' For example, synthetic progestogens have been shown to exert a relative vasoconstrictor effect on the vasculature, the magnitude of the effect being proportional to the relative 'androgenicity' of the p repa ra t i~n .~ '~ In direct contrast, studies have shown that native progesterone may have a net vasodilator and cardioprotective effect when administered in replace- ment Therefore, the profestogenic component of a hormone replacement regimen may be of equal importance and complexity to that of the oestrogen.

I note with interest the reference to the studies which support additional direct effects of oestrogen on myocardial structure and function. As discussed in the review,' multiple biologically plausible mechanisms have been identified which support the concept of oestrogen mediated cardioprotection. Oestrogen binding sites have been identified in a wide variety of organs, including the endothelial and smooth muscle cells of blood vessels, the myocardium and the brain.6 Oestrogen has been shown to exert a variety of effects on the heart and blood vessels through mechanisms which include local production of vasoactive hormones and direct anti-atherogenic effects.' In addition, studies suggest that oestrogen may influence the neural control of the cardiovascular system at all levels of organisation including the spinal cord and rostra1 medullary brain- stem centres closely linked to autonomic and baroreflex control mechanisms.8

Despite the accumulated body of evidence for oestrogen induced cardioprotection from observational and intermediary studies, the need for confirmatory data from large randomised controlled trials has been highlighted by the recent publication of the results of the Heart and Estrogedprogestin Replacement Study (HERS), the frst of the current large, prospective, randomised, placebo controlled studies to have been completed.9 HERS was designed to determine whether

oestrogedprogestogen combination hormone replace- ment therapy alters the risk of cardiovascular events and death in women with established cardiovascular disease. Treatment with oestrogen plus progestogen did not reduce the rate of coronary heart disease (CAD) events despite beneficial effects on plasma lipid profile. The results of this study call into question the inter- pretation of all of the epidemiological studies and particularly the role of hormone replacement therapy in secondary prevention of CAD. More information is now awaited from other randomised studies of primary and secondary prevention currently in progress.

PAULA HARVEY, Division of Cardiology,

University of Toronto Clinical Cardiovascular Physiology Laboratory,

Toronto General Hospital, Toronto, Canada.

References 1 . Harvey P. Oestrogen and vascular disease. Aust NZ J Med

2. Grodstein F, Stampfer MJ, Manson JE, Colditz GA, Willett WC, Rosner B et al. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med

3. Grodstein F, Stampfer MJ, Colditz GA, Willett WC, Manson JE, Joffe M et al. Postmenopausal hormone therapy and mortality. N Engl J Med 1997; 336: 1769-75.

4. Williams JK, Adams MR. Estrogens, progestins and coronary artery reactivity. Nature Med 1997; 3: 273-4.

5. Oparil S. Hormones and vasoprotection. Hypertension

6. McGill HC. Sex steroid hormone receptors in the cardio- vascular system. Postgrad Med J 1989; 85 (Suppl.): 64-8,

7. Gilligan DM, Badar DM, Panza JA, Quyyumi AA, Cannon RO. Acute vascular effects of estrogen in postmenopausal women. Circulation 1994; 90: 786-91.

8. Smmpf WE. Steroid hormones and the cardiovascular

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1996; 335: 453-61.

1999; 33: 170-6.

89-90.

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system: direct actions of estradiol, progesterone, testosterone, gluco- and mineralcorticoids, and soltriol [vitamin D] on central nervous regulatory and peripheral tissues. Experientia 1990; 46: 13-25. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998; 280: 605-13.

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