(Stroke. 2000;31:2266-i.)
© 2000 American Heart Association, Inc.
Letters to the Editor |
Hormone Replacement Therapy and Intima-Media Thickness of the Common Carotid Artery: The Rotterdam Study
Haemostasis Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, England
Key Words: hormone replacement therapy • intima-media
thickness • randomized controlled trials
To the Editor:
We read with interest the population-based study by Westendorp et al,1 in which the authors describe an inverse association between hormone replacement therapy (HRT) use and carotid artery intima-media thickness. Nevertheless, we feel that the results of this study must be viewed with a little caution.
Cross-sectional population studies of HRT use have provided us with often-conflicting results of the effect of HRT on cardiovascular risk. Some studies, such as the Nurses’ Health Study,2 have suggested that HRT may have a significant cardioprotective effect. However, in the Framingham study,3 a retrospective analysis of estrogen use in 1234 postmenopausal women suggested that estrogen use was associated with a 50% increase in cardiovascular mortality and morbidity with no difference in all-cause mortality.
Cross-sectional studies, by the nature of their design, have biases which cannot all be accounted for. Although some confounding factors such as age and cigarette smoking can be identified and allowed for when calculating risk ratios, other important factors such as social deprivation, educational levels, and access to health care professionals are more difficult to assess and quantify. Indeed, some of the supposed benefits of HRT may be attributable to a "healthy cohort effect."
For this reason, randomized prospective studies provide us with much clearer evidence on which to base clinical practice. The first large, randomized, placebo-controlled study of HRT use with cardiovascular death as an end point raised significant concerns regarding its safety in women with preexisting coronary artery disease.4 At the recent American College of Cardiology meeting in March 2000, the prospective randomized Estrogen Replacement and Atherosclerosis (ERA) trial did not demonstrate any significant benefit of HRT on coronary atherosclerosis progression.
The proposed cardiovascular protective properties of HRT were purported to be due to modifications in the lipid profiles. Indeed, HRT reduces LDL levels and raises HDL levels.5 6 A closer analysis of lipid profiles, however, suggests that these assumptions regarding HRT may need to be reassessed.
For example, one longitudinal study7 found that surgical
menopause is associated with an increase in total
cholesterol, which was reduced by HRT. However, in a
prospective longitudinal study of 17 women with surgically induced
menopause, 6 weeks of treatment with HRT was associated with an
increase in the proportion of small, dense LDL subfractions
(P
0.01) despite a decrease in total
cholesterol.8 These small, dense LDL
subfractions are significantly more atherogenic and indeed, a lipid
profile with a high proportion of these subfractions has been
identified as an independent risk factor for both coronary and
carotid artery disease.9 10 Because LDL subfractions are
not routinely measured in clinical practice, the reduction in total
cholesterol:HDL ratio with HRT use may give physicians a
false reassurance.
References
1.
Westendorp IC, Veld BA, Bots ML, Akkerhuis JM,
Hofman A, Grobbee DE, Witteman JC. Hormone replacement therapy and
intima-media thickness of the common carotid artery: the Rotterdam
study. Stroke. 1999;30:2562–2567.
2.
Grodstein F, Stampfer MJ, Colditz GA, Willett WC,
Manson JAE, Joffe M, Rosner B, Fuchs C, Hankinson SE, Hunter DJ,
Hennekens CH, Speizer FE. Postmenopausal hormone therapy and mortality.
N Engl J Med. 1997;336:1769–1775.
3. Wilson PW, Garrison RJ, Castelli WP. Postmenopausal estrogen use, cigarette smoking and cardiovascular morbidity in women over 50. The Framingham Study. N Engl J Med. 1985;313:1038–1043.[Abstract]
4. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E. Randomised trial of Estrogen plus Progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA. 1998;20:605–613.
5.
Medical Research Council’s General Practice Research
Framework. Randomized comparison of oestrogen versus oestrogen plus
progesterone hormone replacement therapy in women with hysterectomy.
BMJ. 1996;312:473–438.
6.
The Writing Group for the PEPI Trial. Effect of
estrogen or estrogen/progestin regimens on heart disease risk factors
in postmenopausal women: the Postmenopausal Estrogen/Progestin
Interventions Trial. JAMA. 1995;273:199–208.
7. Lip GY, Blann AD, Jones AF, Beevers DG. Effects of hormone replacement therapy on haemostatic factors, lipid factors and endothelial function in women undergoing surgical menopause: implications for prevention of atherosclerosis. Am Heart J. 1997;134:764–771.[Medline] [Order article via Infotrieve]
8.
Rajman I, Lip GYH, Cramb R, Maxwell SR, Zarifis J,
Beevers DG, Kendall MJ. Adverse change in low-density lipoprotein
subfractions profile with oestrogen-only hormone replacement therapy.
QJM. 1996;89:771–778.
9. Rajman I, Kendall MJ, Cramb R, Holder RL, Salih M, Gammage MD. Investigation of low density lipoprotein subfractions as a coronary risk factor in normotriglyceridaemic men. Atherosclerosis. 1996;125:231–242.[Medline] [Order article via Infotrieve]
10.
Landray MJ, Sagar G, Muskin J, Murray S, Holder RL, Lip
GY. Association of low-density lipoprotein subfractions with carotid
atherosclerosis. QJM. 1998;91:345–351.
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