1998 Stockton Press. All rights reserved 0950-9240/98 $12.00. COMMENTARY. Postmenopausal hormone replacement therapy in hypertensive women: is it ...
Journal of Human Hypertension (1998) 12, 319–321 1998 Stockton Press. All rights reserved 0950-9240/98 $12.00
COMMENTARY
Postmenopausal hormone replacement therapy in hypertensive women: is it time for a change in attitude? G Lloyd and G Jackson Cardiothoracic Centre, Gassiot House, Guy’s & St Thomas’ Hospital Trust, Lambeth Palace Road, London SE1 7EH, UK
Keywords: hormone replacement therapy; hypertension
For many years postmenopausal oestrogen replacement therapy was considered to be relatively contraindicated in women with hypertension. This reticence to use oestrogen or other forms of hormone replacement therapy (HRT) appears to stem from the experience with contraceptive dose oestrogen. The higher doses used in the oral contraceptive pill do appear to raise blood pressure among users by about 3–5%,1 although the blood pressure normally remains within the normal range. Rarely however, some women develop severe hypertension with endorgan damage. Epidemiological evidence suggests that the menopause itself, independent of increasing age, is associated with an elevation of diastolic blood pressure by 2–3 mm Hg and an increase in the year by year rate of rise of systolic blood pressure.2 Furthermore, it is not possible to extrapolate the effects of high dose contraceptive oestrogen to the physiological doses used in postmenopausal HRT.
Why should HRT effect blood pressure? Hypertension is characterised to a varying degree by abnormal vasoconstriction, salt and water retention and impaired endothelial function. Numerous investigators have now documented the vasodilatory effects of 17- oestradiol both in vivo and in vitro.3,4 This vasodilatory effect appears to effect both the peripheral, uterine and coronary circulations and is sufficient in magnitude to bring about anti-anginal benefits for women with coronary artery disease.5 The predominant mechanism appears to be restoration of impaired endothelial function, with paradoxical acetyl-choline induced vasoconstriction being restored to a normal vasodilatory pattern. This has been documented in the peripheral circulation utilising forearm blood flow studies and also in female coronary arteries during cardiac catheterisCorrespondence: Dr Guy Lloyd Received and accepted 9 December 1997
ation.3,4 Aside from increased nitric oxide release, in vitro models provide evidence for more than a single mechanism of action. Investigations using preconstricted rabbit coronary artery segments have demonstrated that even when the endothelium is denuded, vasodilation continues to occur and a calcium antagonist effect has been proposed.6 Oestradiol also antagonises the effects of endothelin-1, a potent vasoconstrictor7 substance whose metabolism is deranged in hypertensive patients. Oestradiol, especially in contraceptive doses, exerts a mineralocorticoid effect thus promoting sodium and water retention, however to offset this effect circulating plasma angiotensin-converting enzyme activity has been demonstrated to be lower among users of HRT.8 Oestrogen therapy has been demonstrated to increase aortic compliance and distensability providing a mechanism by which the course of systolic hypertension, prevalent in post-menopausal women might be influenced.9 A further mechanism whereby oestrogen could effect blood pressure is through the sympathetic nervous system, an association which is mediated both centrally and at the level of the catecholamine receptor. This modulation of autonomic function has been demonstrated to be of measurable importance indirectly using heart rate variability studies where high frequency (sympathetic) spectral power is reduced relative to low frequency (parasympathetic).10
Does HRT increase or reduce blood pressure? As far back as 1981 Christiansen et al11 demonstrated that a combination oestradiol/norethisterone HRT could bring about a reduction in diastolic blood pressure by about 10% while systolic blood pressure remained unchanged. In non-hypertensive patients oestradiol has been documented to bring about a drop in both systolic pressure in menopausal women and progesterone reduces blood
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pressure acutely in both sexes. However the largest investigation to look at the effects of HRT on blood pressure is the PEPI study which documented no significant effects in the oestrogen alone or oestrogen/progestin combinations over the 3-year follow-up period, despite favourable influences on plasma lipids and glucose tolerance.12 One reason why this may be at variance with other investigations is the use of conjugated equine oestrogens and medoxyprogesterone acetate as opposed to 17 oestradiol. What of HRT effects in hypertensive women? In this area there is a paucity of data. In this issue of the Journal of Human Hypertension, Manhem et al13 have demonstrated a 3 mm drop in daytime blood pressure among pre-existing hypertensive subjects given transdermal oestrogen. The effect, although modest, represents an important observation as it is one of the few prospective randomised trials of HRT in hypertensives in which blood pressure is the primary clinical end-point. Equally important is the observation that blood pressure did not rise. The principal limitation of this study is the restriction to 24-h effects. This is a relatively short period for upregulation of nitric oxide synthetase to occur which is a key factor in oestrogen mediated vasodilation. Lip et al14 documented no time dependent increase in blood pressure over a 36-month followup period in 75 hypertensive women commenced on HRT.14 However as there was no placebo arm in the study and as blood pressure is known to increase in a time dependent manner the possibility of a relative benefit among HRT users cannot be excluded. Mercuro et al15 published, in abstract form, a study of transdermal oestrogen in 10 hypertensive women. They documented more than 20 mm Hg drop in day and night-time systolic pressure with a more modest, but statistically significant, drop in diastolic pressures. There is, however, no large prospective study of HRT in hypertensive women published or underway to date. The forthcoming HERS study (using conjugated oestrogens and medoxyprogesterone) due for completion in 1999 contains a significant number of mild–moderate hypertensive women and although blood pressure is not the primary end-point, post hoc analysis may go some way to answering these important outstanding questions.
HRT and cardiovascular health If the data to date points to a neutral effect of HRT on blood pressure the question arises: Should all hypertensive women receive HRT as a primary preventative strategy? The value of cholesterol lowering in patients with or at risk from coronary heart disease is well established. The 30% reduction in risk observed with statin therapy is of the same order as the risk reduction observed in the observational cohorts that have established the benefits of HRT. Yet the question of HRT as primary or secondary prevention is only rarely discussed in sharp contrast to the case of lipid-lowering agents. Furthermore, in the most recent publication from the nurses health study the benefit of HRT was observed almost exclusively among those subjects with cardiovascu-
lar risk factors.16 As hypertension is in the most part an asymptomatic disease, all treatment must be directed to the reduction in overall risk from hypertensive induced disease. It is well recognized that anti-hypertensive drugs, especially beta-blockers and thiazide diuretics, can bring about deleterious changes in plasma lipids and glucose tolerance. This may go some way to explain the disappointing effects of anti-hypertensives on the incidence of coronary heart disease. In the Christiansen et al11 study it was noted that the HRT/thiazide combination more than offset the increase in cholesterol observed with thiazides alone.
Conclusions The use of HRT in hypertensive women is hindered by the lack of clear prospective data. The present evidence points to, at worst, a neutral effect with at best, a mild anti-hypertensive effect of hormone replacement therapy. More importantly, the use of HRT is indicated in hypertensive women as part of a multiple risk factor intervention approach and should be encouraged.
References 1 Khaw KT, Peart WS. Blood pressure and contraceptive use. Br Med J 1982; 285: 403– 407. 2 Staessen J et al. The influence of menopause on blood pressure. J Hum Hypertens 1989; 3: 427– 433. 3 Gilligan DM et al. Effects of physiological levels of estrogen on coronary vasomotor function in postmenopausal women. Circulation 1993; 89(6): 2545–2551. 4 Collins P et al. 17-beta estrodiol attenuates acetylcholine-induced arterial constriction in women but not men with coronary heart disease. Circulation 1995; 92(1): 24 –28. 5 Rosano GMC, Sarrel PM, Poole-Wilson PA, Collins P. Beneficial effects of oestrogen on exercise induced myocardial ischaemia in women with coronary artery disease. Lancet 1993; 342: 133–136. 6 Jiang C et al. Endothelium independent relaxation of rabbit coronary arteries by 17-beta oestradiol in vitro. Br J Pharmacol 1991; 104: 1033–1037. 7 Jiang C, Sarrel PM, Poole-Wilson PA, Collins P. Acute effects of 17-beta oestradiol on rabbit coronary artery contractile response to endoethelin-1. Am J Physiol 1992; 263 (1 Pt2): H271–H275. 8 Proudler A et al. Hormone replacement therapy and serum angiotensin converting enzyme activity in postmenopausal women. Lancet 1996; 346: 89–90. 9 Rajkumar C et al. Hormonal therapy increases arterial compliance in postmenopausal women. JACC 1997; 30(2): 350–356. 10 Rosano G et al. Estrogen replacement therapy normalises the autonomic control of the cardiovascular system in menopausal women. JACC 1996; 27(2): 80A. 11 Christiansen C et al. Effects of natural estrogen/ gestagen and thiazide on coronary risk factors in normal postmenopausal women. A 2-year double blind placebo study. Acta Obstetricia et Gynecologica Scandinavica 1981; 60(4): 407– 412. 12 The writing group for the PEPI trial. Effects of oestrogen or oestrogen/progestin regimens on heart disease risk factors in postmenopausal women. JAMA 1995; 273: 199–208. 13 Manhem K, Ahlm H, Milsom I, Svensson A. Transdermal oestrogen reduces daytime blood pressure in
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hypertensive women. J Hum Hypertens 1998: 12: 323–327. 14 Lip G, Beevers M, Churchill D, Beevers DG. Hormone replacement therapy and blood pressure in hypertensive women. J Hum Hypertens 1994; 8: 491– 494.
15 Mercuro G, Zonca S, Cherci A. Effects of transdermal estradiol-17  on hypertension in postmenopasual women. JACC 1996; 27(2): 29A. 16 Grodstein F et al. Post menopausal HRT and mortality. NEJM 1997; 336(25): 1769–1775.
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