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ORIGINAL RESEARCH |
From the Department of Women’s and Children’s Health, Section of Obstetrics and Gynecology, University Hospital, Uppsala, Sweden.
Address reprint requests to: Tord Naessen, MD, PhD, Section of Obstetrics and Gynecology, University Hospital, SE-751 85 Uppsala, Sweden, E-mail: tord.naessen{at}kbh.uu.se
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Abstract |
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Methods: Pairwise comparisons between 18 long-term users of 17ß-estradiol (E2) implants (mean age 67.8 years, mean duration of treatment 18.8 years, range 5.8–33.9 years) and 18 age-matched (± 2 years) nonusers. We used color Doppler ultrasound to assess pulsatility index (PI) and resistance index (RI) in common, external, and internal carotid arteries.
Results: Estrogen users compared with age-matched non-users had significantly lower mean values for common carotid RI, -4%; -0.04 (95% confidence interval [CI] -0.07, -0.03, P = .036) and marginally significant for PI, -12%; -0.25 (95% CI -0.54, 0.04, P = .087). Differences in external and internal carotids were smaller and insignificant. Age was a determinant of internal carotid vascular resistance in estrogen users and nonusers. Increasing pairwise differences in external carotid vascular resistance with advancing age (r = 0.55; P = .02), with magnitudes of mean group differences indicate a modest but true effect of long-term estrogen therapy on vascular resistance in common carotids, less in external, and negligible in internal carotid arteries. The study had an 80% power to detect a 10% mean difference (0.08 units) in common carotid RI at the 5% level. The standard deviation was considerably lower for estimates of RI than for PI.
Conclusion: Long-term estrogen therapy was associated with minor reduction of vascular resistance in common carotid, less in external, and negligible in internal carotid arteries. Effects on carotid vascular resistance do not seem to be a major mechanism in the long-term protective effect of estrogen therapy on cardiovascular risk.
After initial increased risk of thromboembolic complications,1,2 menopausal estrogen therapy reduces incidence of and deaths from cardiovascular disease by 40–60%, according to the observational studies,3,4 with no substantial negative influence of added progestins.5 The findings concerning effects on the risk of stroke are more controversial, with some studies indicating effects6 and others not.7 For many years, attention was focused on improvements in serum lipids and lipoproteins as the principal mechanisms for cardiovascular effects. Current estimates are that only 25–30% of that effect is mediated through improvement of the serum lipid profile3,8,9 and that the rest occur through direct actions on the artery wall, such as effects on connective tissue elements,10 atherosclerotic accumulation independent of effects on serum lipid levels,11 and endothelium-dependent vasodilation.12
Downstream resistance to flow, estimated as arterial pulsatility index (PI),13 increases with time from menopause.14 Aging is associated with progressive deterioration of endothelial function. Short-term estrogen therapy enhances endothelium-dependent vasodilation in brachial arteries in healthy postmenopausal women,15 and those with cardiovascular risk factors.16 Short-term estrogen therapy also increases blood flow in the internal carotid artery,14,17 middle cerebral artery,17 brachial artery,18,19 aorta,20 and femoral artery.21
An improvement in carotid PI after estrogen therapy has been proposed as a marker for a cardioprotective effect of estrogen therapy,22,23 but other studies indicated that effects on peripheral vascular resistance might be transient and diminish with duration of therapy.18,20 The aim of the present study was to estimate PI and resistance index (RI) in the carotid arteries in long-term estrogen users and compare results with values in age-matched nonusers.
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Materials and Methods |
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All implant users had hysterectomies, usually for bleeding problems or leiomyomata. The E2 was a 20-mg pellet implanted subdermally every 6 months (Oestradiol implant 20 mg; Organon Laboratories Ltd., Cambridge, UK). Indications for treatment were prevention or treatment of climacteric symptoms. In a few women the dose was adjusted individually on the basis of such symptoms: one was given 40 mg during most of her treatment periods and three (including the one given the higher dose) had intervals shorter than 6 months. The 18 age-matched women had no previous estrogen replacement and were selected from the population registry in the same municipality as the treated women, matched for age (± 2 years), and recruited through mailed invitations. For each case the first subsequent woman in the registry who fulfilled those criteria was chosen as a control. Each subject gave informed consent and the study was approved by the local ethics committee of Uppsala University, Sweden.
Carotid artery blood flow characteristics were imaged by color Doppler ultrasonography (Acuson 128/10, Acuson Corp., Mountain View, CA) with a 5-MHz linear transducer and a 75-MHz high-pass filter to reduce noise. Examinations were done under standardized conditions in a quiet room with a constant temperature of 24C and soft lighting, late in the afternoon at least 4 hours after subjects ate. The common carotid artery was assessed approximately 2 cm proximal to the bulb, and internal and external carotids 2 cm distal to the bulb. The gate opening was 2 mm. Each of the arteries was identified by specific anatomy and waveform characteristics. When three consecutive cardiac cycles (waveforms) of adequate quality were recorded, PI and RI were calculated automatically by ultrasound equipment according to the equations PI = peak systolic frequency shift minus end-diastolic frequency shift divided by mean frequency shift over one cardiac cycle, and RI = peak systolic frequency shift minus end-diastolic frequency shift divided by peak systolic frequency shift.13 Scans were done by one investigator (OB), who was masked to estrogen therapy. Means of left and right carotid recordings were used in analysis.
Serum samples, not standardized by time since last insertion of E2 implant, were drawn between 8 AM and 10 AM after overnight fast and frozen at -70C until analyzed in batches. Serum E2 levels were measured by a fluoroimmune assay (AutiDelfia; Pharmacia, Wallac Oy, Finland) with an intra-assay variation of 2.7%. Sex hormone binding globulin was measured by a radioimmunoassay at Medilab (Malmö, Sweden) with an intra-assay variation of 3.0%. Serum concentrations of FSH were measured consecutively, routine in the Department of Clinical Chemistry, by Delphia hFSH (Pharmacia). The total coefficient of variation was 3.6%.
Pairwise differences between long-term estrogen users and age-matched nonusers were tested by paired t test for normally distributed variables and by Wilcoxon signed-rank test for those not distributed normally. Normality of differences was tested by Shapiro-Wilk W test. McNemar test was used for comparing distributions of categoric variables. Correlations between variables were analyzed by Spearman rank correlation tests. Pairwise differences in vascular resistance regressed on age were tested by linear regression because variables were normally distributed. We assessed the independent effect of age and serum E2 levels on vascular resistance in a multivariable analysis after adjusting for respective covariate. To test the effect of estrogen therapy on vascular resistance with advancing age, we calculated the difference in vascular resistance between each treated subject and her age-matched control and regressed pairwise differences on age (using the age of treated women). To avoid false interpretations from low power, post-hoc power analysis was used to calculate the detectable mean difference in PI and RI with a power of 80% at the .05 level. All statistical analyses were done with the statistical program packages JMP or SAS (SAS Institute Inc., Cary, NC).
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Results |
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).
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). After excluding subjects who took antihypertensive drugs, point estimates remained similar to the second or third decimal (except for the external carotids), and tests of pairwise differences also remained similar.
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). With increasing age, pairwise differences in vascular resistance increased significantly for external carotid PI (r = 0.55; P = .02) and RI (r = 0.56; P = .024), whereas correlation coefficients for the internal carotid were low (r < 0.2).
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.001) and common carotids (P = .046) but not in the internal carotid. In estrogen users, serum E2 values correlated negatively with PI and RI in external carotids (r < -0.5 and P < .05 in both cases) and correlated negatively with marginal significance in internal carotids. There were no associations between serum E2 levels and vascular resistance in estrogen users after adjustment for age (Table 3
). Post-hoc power analysis found an 80% power at the 5% level to detect a 10% (0.08 units) mean group difference in common carotid RI and a 13% difference (0.11 units) in external carotid RI. |
Discussion |
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A persistent effect of long-term estrogen therapy on vascular resistance was supported by the finding that carotid PI in long-term estrogen users was similar to that in women early after menopause,25 whereas values in nonusers were higher. The mean relative pairwise difference in common carotid PI (12%) was numerically similar to the reported relative changes in internal carotid PI after treatment with transdermal E2 50 µg/day for 22 weeks,14 2 mg of oral E2 for 20–24 weeks,22 or transdermal E2 50 µg/day for 6 months combined with cyclic norethisterone acetate.23 However, internal carotid PI, the only carotid artery examined in those studies, did not differ between long-term estrogen users and nonusers in the present study.
An improvement of internal carotid PI was seen after 6 months,14,22 and 1 year,23 of different estrogen regimens. Short-term estrogen therapy also increased blood flow in internal carotid artery,14,17 middle cerebral artery,17 brachial artery,18,19 aorta,20 and femoral artery.21 However, in one of the studies,18 the effect on the brachial artery ceased after 3 weeks of estrogen therapy, and in another study the effect on aortic PI ceased after 6 months of estrogen therapy.20 According to a randomized controlled study by Sorensen et al,26 brachial endothelial vasomotor function was not improved by 3 years of combined estrogen therapy. Thus, any effect of estrogen therapy on peripheral vascular resistance seemed to be transient and diminish during long-term treatment.18,20,26
In some studies supraphysiologic estrogen doses were used and the durations of follow-up were short.18,19,21 In the present study, estrogen therapy yielded physiologic levels of serum E2 and FSH within the normal range for fertile women. The long-term estrogen therapy in the present study (mean almost 19 years) might explain our modest or negative findings if the effect on internal carotid vascular resistance was transient and diminished after long durations of therapy, the same as that reported for peripheral vascular resistance.18,20 According to Cacciatore et al,23 however, internal carotid PI was still reduced after 1 year of combined estrogen therapy. In epidemiologic studies, results of effects of estrogen therapy on risk of stroke are less convincing than those for cardiac events. The findings in some studies indicated reduced risk of stroke,6 whereas in others there was no substantial effect.7
The present study compared two groups of women and was not a randomized follow-up study, so any differences between groups before the start of estrogen treatment (selection bias) might have affected our results. However, any bias at the time of menopause probably had limited influence on blood-flow characteristics almost 20 years later, compared with known effects of aging and presumed effects of estrogen therapy. Long-term estrogen users were slightly heavier, but that difference most likely was an effect of estrogen therapy, with preservation of bone and muscle mass, as noted in a previous report24; it was not adjusted for in the analysis.
A weakness of the study was small sample, which combined with sometimes insignificant differences between estrogen users and nonusers, might raise the possibility of a type II error. However, pairwise differences were numerically close to zero and far from statistical significance. Post-hoc power calculations showed an 80% power at the 5% level to detect a mean difference in common carotid RI of 10% between groups, which is smaller than the 13–25% changes in resistance to flow reported after estrogen therapy.17,23
Methods based on blood flow rates and configuration of the pulse curve, such as PI and RI, do not indicate properties of the arterial wall but primarily depend on peripheral resistance distal to the point of measurement. Prospective, controlled long-term studies are needed, preferably with simultaneous monitoring of changes in arterial PI and RI, inotropic effects, arterial stiffness (distensibility), and peripheral blood flow (vascular resistance), to gain a better understanding of the mechanism underlying the cardiovascular protective effect of long-term estrogen therapy.
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Footnotes |
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Received August 4, 2000. Received in revised form November 6, 2000. Accepted November 22, 2000.
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2. 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. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998;280:605–13.
3. Bush TL, Barrett-Connor CE, Cowan LD, Criqui MH, Wallace RB, Suchindran CM, et al. Cardiovascular mortality and noncontraceptive use of estrogen in women: Results from the lipid research clinics program follow-up study. Circulation 1987;75:1102–9.
4. Stampfer MJ, Colditz GA, Willett WC, Manson JE, Rosner B, Speizer FE, et al. Postmenopausal estrogen therapy and cardiovascular disease. Ten-year follow-up from the nurses’ health study [see comments]. N Engl J Med 1991;325:756–62.[Abstract]
5. 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 1996;335:453–61.
6. Paganini-Hill A, Ross RK, Henderson BE. Postmenopausal oestrogen treatment and stroke: A prospective study. BMJ 1988;297:519–22.
7. Petitti DB, Sidney S, Quesenberry CP Jr, Bernstein A. Ischemic stroke and use of estrogen and estrogen/progestogen as hormone replacement therapy. Stroke 1998;29:23–8.
8. Lobo RA. Clinical review 27: Effects of hormonal replacement on lipids and lipoproteins in postmenopausal women. J Clin Endocrinol Metab 1991;73:925–30.[Medline]
9. Nabulsi AA, Folsom AR, White A, Patsch W, Heiss G, Wu KK, et al. Association of hormone-replacement therapy with various cardiovascular risk factors in postmenopausal women. The Atherosclerosis Risk in Communities Study Investigators. N Engl J Med 1993;328:1069–75.
10. Baron YM, Galea R, Brincat M. Carotid artery wall changes in estrogen-treated and untreated postmenopausal women. Obstet Gynecol 1998;91:982–6.[Abstract]
11. Wagner JD, Clarkson TB, St. Clair RW, Schwenke DC, Shively CA, Adams MR. Estrogen and progesterone replacement therapy reduces low density lipoprotein accumulation in the coronary arteries of surgically postmenopausal cynomolgus monkeys. J Clin Invest 1991;88:1995–2002.
12. Tagawa H, Shimokawa H, Tagawa T, Kuroiwa MM, Hirooka Y, Takeshita A. Short-term estrogen augments both nitric oxide-mediated and non-nitric oxide-mediated endothelium-dependent forearm vasodilation in postmenopausal women. J Cardiovasc Pharmacol 1997;30:481–8.[Medline]
13. Maulik D. Principles of Doppler signal processing and haemodynamic analysis. In: Copel JA, Reed KL, eds. Dopler ultrasound in obstetrics and gynecology. New York: Raven Press, 1995:1–18.
14. Gangar KF, Vyas S, Whitehead M, Crook D, Meire H, Campbell S. Pulsatility index in internal carotid artery in relation to transdermal oestradiol and time since menopause. Lancet 1991;338:839–42.[Medline]
15. McCrohon JA, Adams MR, McCredie RJ, Robinson J, Pike A, Abbey M, et al. Hormone replacement therapy is associated with improved arterial physiology in healthy post-menopausal women. Clin Endocrinol (Oxf) 1996;45:435–41.[Medline]
16. Gilligan DM, Badar DM, Panza JA, Quyyumi AA, Cannon RR. Acute vascular effects of estrogen in postmenopausal women. Circulation 1994;90:786–91.
17. Penotti M, Nencioni T, Gabrielli L, Farina M, Castiglioni E, Polvani F. Blood flow variations in internal carotid and middle cerebral arteries induced by postmenopausal hormone replacement therapy. Am J Obstet Gynecol 1993;169:1226–32.[Medline]
18. Gilligan DM, Badar DM, Panza JA, Quyyumi AA, Cannon RR. Effects of estrogen replacement therapy on peripheral vasomotor function in postmenopausal women. Am J Cardiol 1995;75:264–8.[Medline]
19. Al-Khalili F, Eriksson M, Landgren BM, Schenck GK. Effect of conjugated estrogen on peripheral flow-mediated vasodilation in postmenopausal women. Am J Cardiol 1998;82:215–8.[Medline]
20. Pines A, Fisman EZ, Ayalon D, Drory Y, Averbuch M, Levo Y. Long-term effects of hormone replacement therapy on Doppler-derived parameters of aortic flow in postmenopausal women. Chest 1992;102:1496–8.
21. Riedel M, Oeltermann A, Mugge A, Creutzig A, Rafflenbeul W, Lichtlen P. Vascular responses to 17 beta-oestradiol in postmenopausal women. Eur J Clin Investig 1995;25:44–7.[Medline]
22. Jackson S, Vyas S. A double-blind, placebo controlled study of postmenopausal oestrogen replacement therapy and carotid artery pulsatility index. Br J Obstet Gynaecol 1998;105:408–12.[Medline]
23. Cacciatore B, Paakkari I, Toivonen J, Tikkanen MJ, Ylikorkala O. Randomized comparison of oral and transdermal hormone replacement on carotid and uterine artery resistance to blood flow. Obstet Gynecol 1998;92:563–8.[Abstract]
24. Naessen T, Persson I, Thor L, Mallmin H, Ljunghall S, Bergstrom R. Maintained bone density at advanced ages after long term treatment with low dose oestradiol implants. Br J Obstet Gynaecol 1993;100:454–9.[Medline]
25. Darj E, Bakos O, Naessen T, Persson I. Ultrasonographic blood flow measurement in the carotid arteries in postmenopausal women. Gynecol Obstet Invest 1999;47:20–5.[Medline]
26. Sorensen KE, Dorup I, Hermann AP, Mosekilde L. Combined hormone replacement therapy does not protect women against the age-related decline in endothelium-dependent vasomotor function. Circulation 1998;97:1234–8.
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