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Carotid intima-media thickness in surgical menopause: women who received HRT versus who did not
Maturitas 42 (2002) 37 – 43 www.elsevier.com/locate/maturitas
Carotid intima-media thickness in surgical menopause: women who received HRT versus who did not Veli Mihmanli a,*, Ismail Mihmanli b, Kadir Atakir b, Fatih Kantarci b, Turgut Aydin a, Yucel Sengun a, Omer Uysal c a
Department of Obstetrics and Gynecology, SSK Okmeydani Training Hospital, Istanbul, Turkey b Department of Radiology, Cerrahpasa Medical Faculty, Istanbul Uni6ersity, Istanbul, Turkey c Department of Biostatistics, Cerrahpasa Medical Faculty, Istanbul Uni6ersity, Istanbul, Turkey Received 22 May 2001; received in revised form 3 January 2002; accepted 8 February 2002
Abstract Objecti6e: The effects of hormone replacement therapy (HRT) in the natural menopausal period have been extensively studied. However, these effects have almost none been studied in purely surgical menopause. The aim of this study was to measure intima-media thickness (IMT) of carotid arteries bilaterally in two groups of surgical menopausal women who received HRT versus who did not. Methods: A B-mode ultrasound unit was used for the measurements of the IMTs of carotid arteries in two groups. Measurements of Group 1 (n=65, untreated group) were compared with those of Group 2 (n=70, treated group), in 2-years of follow-up. Patients in Group 2 received daily doses of 0.625 mg of oral conjugated estrogen preparates. Serum estradiol levels, lipid profiles, and blood pressures were measured, pre and postoperatively. For the statistical analyses in terms of differences of IMTs between two groups, general factorial analysis of variation was used. Results: Among preoperative values of low-density lipoprotein (LDL), high-density lipoprotein (HDL), cholesterol, systolic and diastolic blood pressures, estradiol, and age, only the estradiol values showed significant difference between both groups. The statistical results concerning the postoperative IMT differences for both groups showed that there was a statistically significant difference when comparing both groups, showing an increase in IMT in Group 1. Conclusion: In surgical menopausal women, the direction of the HRT effect is in agreement with evidence from earlier studies on the effects of HRT in natural menopausal women. © 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Surgical menopause; Hormone replacement therapy; Intima-media thickness; Carotid; Ultrasound
Veli Mihmanli was the principal investigator, and implemented, designed, and supervised the study. Veli Mihmanli also did the analyses and prepared the manuscript. The other authors helped in the design of this study, implementation, analyses, and preparation of the manuscript. * Corresponding author. Present address: Osmaniye M. Koyalti S. No.: 3, Ozyurt Sitesi, B-B Girisi K. 2 D. 6, Bakirkoy, 34730-Istanbul, Turkey. Tel.: +90-212-586-1586; fax: + 90-212-632-0044. E-mail address: [email protected] (V. Mihmanli).
0378-5122/02/$ - see front matter © 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 7 8 - 5 1 2 2 ( 0 2 ) 0 0 0 2 8 - 2
38
V. Mihmanli et al. / Maturitas 42 (2002) 37–43
1. Introduction The intima-media thickness (IMT) of the carotid artery is a sonographic (morphological) parameter that depends on the degree of atherosclerosis and has been shown to be associated with most risk factors for atherosclerosis [1]. Recently, an increased thickness of carotid IMT determined by B-mode ultrasound has been shown to be directly associated with an increased risk of myocardial infarction and stroke in older adults without a previous history of cardiovascular disease [2]. The risk of cardiovascular disease in women before menopausal period is less than men within the same age group [3]. Although preliminary reports from recent ongoing studies have raised questions about cardioprotective effects of hormone replacement therapy (HRT), based on many other observational studies conducted since 1980s, that estrogen use is associated with reduced risk of cardiovascular disease [4– 9]. Almost all studies investigating the relationship of HRT and atherosclerosis in terms of IMT, do not separate patients into different groups for natural menopause and surgical menopause to elucidate the effect of HRT on the atherosclerosis. The aim of this study was to investigate the state of the carotid artery wall, a vessel interposed between the cerebrovascular and cardiovascular systems, with B-mode ultrasonography in women with surgical menopause. The results of this study may provide an opportunity to improve our understanding of the role of the HRT on vascular wall.
2. Materials and methods The study group initially chosen included 145 women scheduled to undergo total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH +BSO) for various types of benign gynecological pathologies. All patients were informed about expected outcomes of both surgical menopause and HRT. Sixty-five patients whose ages ranged between 46 and 49 (mean age of 46.991.0, mean9 stan-
dard deviation (S.D.)) chose not to receive HRT (Group 1). The remaining 70 patients, whose ages ranged between 45 and 49 (47.19 1.5), chose to receive HRT (Group 2) after surgery. All patients gave written informed consent. Patients in the treatment group received daily doses of 0.625 mg of oral conjugated estrogen preparates (Premarin, Wyeth) beginning day 8 after surgery. Exclusion criteria were a history of clinical manifestations of atherosclerosis (coronary artery disease, peripheral artery disease and cerebrovascular disease, or plaque detection during first ultrasonographic examination in carotid vessels), hyperlipidemia, systemic hypertension, diabetes mellitus, smoking, regular alcohol consumption, personal or family history of breast cancer, venous thromboembolism and liver or renal diseases. These conditions were excluded by means of the general examination and laboratory blood investigations. All patients were still menstruating before the surgery and no patient had a history of estrogen use. Ultrasonogrophic examinations were performed in a quiet, temperature-controlled room (22 °C). All patients rested for 10 min before the examination. The examinations were all done between 08:30 and 10:00 h, with patients after overnight fasting. Ultrasonographic examination was performed with B-mode ultrasound (Sonoline Omnia, Siemens, Germany) equipped with a 7.5 MHz linear transducer. Patients were examined in the supine position. All ultrasonographic measurements were performed and evaluated by a single experienced radiologist 3 days before TAH+ BSO and 2 years after surgery and he was blinded to HRT use among the patients. The mean interval of IMT measurements for Group 1 was 24.119 0.92 months, and 24.039 0.86 months for Group 2 (P= 0.730). With this technique, two parallel echogenic lines separated by an anechoic space can be visualized at levels of the artery wall. It was previously shown that these lines were generated by the blood-intima and media-adventita interfaces [10]. The distance between the two lines gives a reliable index. Ultrasound scans of the right (R) and left (L) distal centimeter of common carotid arteries (CCA), bifurcation and of the first proximal cen-
V. Mihmanli et al. / Maturitas 42 (2002) 37–43
timeter of internal carotid arteries (ICA) were performed (Figs. 1 and 2). Since the far wall was better visualized than the near wall, far wall IMT was calculated for each segment. All measurements were made at the time of scanning on frozen images of longitudinal scans by using the machine’s electronic caliper. The mean IMT was calculated using three frozen images representative of the same segment. Serum estradiol level and lipid concentrations including high-density lipoprotein (HDL), lowdensity lipoprotein (LDL), cholesterol, and systolic and diastolic blood pressures were measured before and after the operation, corresponding the day of the sonographic examination.
2.1. Statistical analysis The statistical package SPSS for Windows (version 6-1-3 SPSS Inc. Chicago, IL, USA) was used for data analysis. All data are expressed as mean 9S.D. The LDL, HDL, cholesterol, blood pressures and estradiol values were analyzed by general factorial analysis of variation (ANOVA). These variables were analyzed with a model including preoperative values of LDL, HDL, cholesterol, blood pressures and estrogen, and age as covariates. A second model using age, pre and
39
postoperative estradiol values, and preoperative IMT of each interested segment of the carotid artery as covariates was created and analyzed with general factorial ANOVA to determine whether the postoperative IMT value was significantly different. In all statistical analysis any P value of 0.05 or less was considered statistically significant.
3. Results Based on the exclusion criteria, ten patients did not meet study criteria. Six patients who had hyperlipidemia, two patients who had elevated glucose level, one patient who had hypertension, and the remaining one patient who had plaque formation on ultrasonographic examination were excluded. The reproducibility of ultrasonographic measurements was tested in 20 patients in whom IMT was measured by the same operator three times at 10 min intervals on successive images of the same area and analyzed by analysis of variance. The coefficient of variation demonstrated a high level of agreement. Body mass index (BMI) of Group 1 was 24.79 2.9 and 24.49 3.1 for Group 2, and comparison of two groups was not statistically significant
Fig. 1. IMT of distal common carotid artery in an untreated patient. Preoperative (a) and postoperative (b) measurements are seen between calipers, showing increase in IMT in 2-years of follow-up, 0.7 vs. 0.9 mm.
40
V. Mihmanli et al. / Maturitas 42 (2002) 37–43
Fig. 2. IMT of distal common carotid artery in a patient with estrogen preparates. Preoperative (a) and postoperative (b) measurements are seen between calipers. IMT is unchanged in 2-years of follow-up (0.6 mm).
(P = 0.289). Laboratory values of the study population are presented in Table 1. The pre and postoperative median estradiol values were 78 and 24 pg/ml for Group 1, and 79.5 and 79 pg/ml for Group 2, respectively. The IMT values are given in Table 2. There was a statistically significant difference in terms of IMTs when comparing both groups, showing an increase in IMT in Group 1. When the model, including preoperative values of LDL, HDL, cholesterol, blood pressures and estrogen, and age was analyzed, only the estrogen values showed significant difference between both groups.
4. Discussion The incidence of coronary artery disease and cerebrovascular accidents among women increases significantly after menopause [11], and substantial epidemiological evidence suggests that this increased risk is due to lower postmenopausal estrogen levels [12,13]. With the subsequent decrease in estrogen levels after menopause begins, the progression of any existing atherosclerosis will be accelerated. Due to estrogen’s cardioprotective effects, postmenopausal women who receive HRT are less likely to develop atherosclerotic disease
[14–16]. Two factors account for the cardioprotective effects of HRT. Estrogen treatments improve blood lipid profiles in postmenopausal women, which accounts for approximately 25– 30% of HRT’s cardioprotective effects [17]. The remaining benefit is derived from the non-lipid effects of estrogen directly on the artery wall. Ultrasonographic investigation of the carotid artery is being undertaken increasingly to assess cardiovascular risk. Atherosclerotic disease in the carotid bulb has been associated with both coronary and cerebrovascular disease [18]. Carotid artery plaque formation has been detected with B-mode ultrasound in postmenopausal women [19]. Ultrasonographically detected elevated IMTs have been shown to precede carotid plaque formation [20]. There have been a lot of studies investigating the effect of HRT on the coronary and carotid arterial system whether there is an increased risk of infarction and stroke in postmenopausal women resulting from atherosclerosis. Also, there is a large body of the literature that documents ultrasonographically evaluation of the IMTs in postmenopausal women who undergo HRT or not [21–28]. Evaluation of women in menopausal period (largely natural menopause) has also been a topic of much interest in recent literature to
V. Mihmanli et al. / Maturitas 42 (2002) 37–43
document the effect of HRT on atherosclerosis [21 – 30]. In light of these studies, we have chosen to focus instead on the effects of HRT on carotid IMTs in women on whom TAH + BSO were performed. To the best of our knowledge, there are few publications dealing directly with the effects of HRT on carotid artery wall in purely selected patients who had undergone surgical menopause. Most prospective studies [21,23– 28] showed significant association between HRT and IMTs, stating that HRT prevents development of atherosclerosis. Also estrogen has a direct effect on arteries, because of its vasodilatory effect, reducing the risk of ischemic heart disease. Indeed, estrogen administration improves vascular tone in coronary and peripheral vessels of oophorectomized animals and postmenopausal women [31– 34]. Our results seem to support the results of the previous studies, showing that HRT leads to delay of thickening of the IMTs. Falkeborn et al. [35], on their case-control analysis in women with surgical menopause, stated that hysterectomy at premenopausal age or unilateral oophorectomy did not alter the risk of myocardial infarction. Whereas a four fold increase in relative risk was found in natural menopause. Also bilateral oophorectomy before menopause may increase the risk of myocardial infarction. This increased risk seems to occur as a consequence of the postmenopausal estrogen withdrawal [36]. Nabulsi et al. [37] stated that the reduced risk of atherosclerotic coronary disease associated with HRT, at least in the first two decades after natu-
41
ral menopause, was attributed more to the acute physiological effects of hormone replacement than to prevention of atherogenesis per se. But, how the removed ovaries affects IMTs are still unclear. Our study showed that HRT has a beneficial effect on the IMTs, documenting increase in IMTs in women with surgical menopause who did not receive HRT. However, increase in IMT in untreated group in the second year measurement was higher than expected. Care was taken to measure the carotid artery as far as the same area and at right angles. Although measurement of the IMT of carotid arteries with an electronic caliper is a rapid and low-cost method, it has quantitative limitations as the precision of this method (0.1 mm) is lower than that of more sophisticated quantitative methods (0.02– 0.06 mm) [38]. Moreover, this study is operator-dependent so that radiologist may prefer up-rounding to low-rounding during measurements. These above mentioned two factors are probably the result of higher measurement levels in our study. Baron et al. [39] stated that upright positioning the patient is easier and more accurate than supine positioning during carotid IMT measurement. Our study was being undertaken with the women in the supine position. This patient positioning may also have some effects on IMT measurement levels. Angerer et al. [22] claimed that HRT on IMTs in 1-year follow-up has no beneficial effect; albeit, their study includes only natural menopausal women. In that study this may partly be due to the follow-up time, which was not long enough to achieve benefits of HRT on IMTs.
Table 1 Laboratory values of patients who did not receive HRT (Group 1) and those who received (Group 2) Group 1 (n =65)
Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Estradiol (pg/ml) HDL cholesterol (mg/dl) LDL cholesterol (mg/dl) Total cholesterol (mg/dl)
Group 2 (n =70)
Preoperative
Postoperative
Preoperative
Postoperative
112914 71 98.0 85.6 9 25 41.99 7.1 122.69 27.3 178.99 17.7
113 9 13 71 9 7.0 23.9 9 7.8 41.7 9 6.1 120.2 9 26.1 177.6 9 15.1
110 914 70 97.0 83.4 9 20.9 40.9 9 6.8 120.6 9 29.9 179.3 9 15.7
110 914 70 97.0 83.3 9 18.9 40.8 9 6.3 118.6 9 25.7 176.9 9 14.4
Values are mean 9 S.D. LDL, low density lipoprotein; HDL, high density lipoprotein.
V. Mihmanli et al. / Maturitas 42 (2002) 37–43
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Table 2 Mean IMTs of patients who did not receive HRT (Group 1) and those who received (Group 2) Group 1 (n=65)
R ICA R CCA R BIF L ICA L CCA L BIF
Group 2 (n = 70)
Preoperative
Postoperative
Preoperative
Postoperative
0.40 9 0.05 0.69 9 0.07 0.6990.06 0.4190.05 0.6990.07 0.689 0.05
0.47 9 0.04 0.80 90.09 0.80 90.07 0.489 0.05 0.80 90.08 0.79 9 0.08
0.41 9 0.05 0.69 9 0.06 0.69 9 0.05 0.43 9 0.04 0.69 9 0.06 0.68 9 0.06
0.41 9 0.05 0.69 9 0.06 0.69 9 0.06 0.42 9 0.04 0.69 9 0.06 0.68 9 0.05
Values are mean 9 S.D. R ICA, right internal carotid artery; R CCA, right common carotid artery; R BIF, right bifurcation; L ICA, left internal carotid artery; L CCA, left common carotid artery; L BIF, left bifurcation.
Although the results shown in our study indicate that HRT has beneficial effects on carotid IMTs, further studies, including larger numbers of patients, with longer and more standardized cardiovascular and neurologic follow-up, should be performed.
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[7] Mihmanli V, Mihmanli I, Kantarci F, Aydin T, Yilmaz MH, Ogut G. Carotid pulsatility indices in surgical menopause. Arch Gynecol Obstet 2002;266:96 – 100. [8] Mihmanli I, Mihmanli V, Kantarci F, Albayram MS, Atakir K, Cebi D, Ogut G, Cokyuksel O. The effect of an acute decrease in serum estrogen concentration on vessel walls: determination with color and pulsed Doppler ultrasound. Arch Gynecol Obstet, in press. [9] Mihmanli I, Mihmanli V, Kantarci F, Albayram MS, Atakir K, Cantasdemir M, Akman C. Effects of oophorectomy and hormone replacement therapy on the pulsatility indices of hepatic and renal arteries. J Ultrasound Med 2002;21:367 – 73. [10] Pignoli P, Tremoli E, Poli A, Oreste P, Paoletti R. Intimal plus medial thickness of the arterial wall: a direct measurement with ultrasound imaging. Circulation 1986;74:1399 – 406. [11] Colditz GA, Willet WC, Stampfer MJ, Rosner B, Spiezer FK, Hennekers CH. Menopause and the risk of coronary heart disease in women. New Engl J Med 1987;316:1105 – 10. [12] Bush TL, Barret-Connor E, Cowan LD, Criqui MH, Wallace RB, Suchindran CM, Tyroler HA, Rifkind BM. Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the lipid research clinics program follow-up study. Circulation 1987;75:1102 – 9. [13] Stampfer MI, Colditz GA. Estrogen replacement and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev Med 1991;20:47 – 63. [14] Gruchow HW, Anderson AJ, Barboriak JJ, Sobochinsky KA. Postmenopausal use of estrogen and occlusion of coronary arteries. Am Heart J 1988;115:956 – 63. [15] Sullivan JM, Van der Zwaag R, Hughes P. Postmenopausal estrogen use and coronary atherosclerosis. Ann Intern Med 1988;108:358 – 63. [16] Barret-Connor E, Bush TL. Estrogen and coronary artery disease in women. J Am Med Assoc 1991;265:1861 – 7. [17] Stevenson J. The metabolic and cardiovascular consequences of hormone replacement therapy. Br J Clin Pract 1995;49:87 – 90.
V. Mihmanli et al. / Maturitas 42 (2002) 37–43 [18] Craven TE, Ryu JE, Espeland MA, Kahl FR, McKinney WM, Toole JF. Evaluation of the association between carotid artery atherosclerosis and coronary artery stenosis. A case control study. Circulation 1990;82:1230 –42. [19] Punnonen RH, Jokela HA, Dastiden PS, Wevelo M, Laippale PJ. Combined estrogen-progestin replacement therapy prevents atherosclerosis in postmenopausal women. Maturitas 1995;21:179 –87. [20] Bonithon-Kopp C, Toubout PJ, Berr C, Leroux C, Mainard F, Courbon D. Telation of intima-media thickness to atherosclerotic plaques in carotid arteries. The vascular aging (E.U.A.) study. Arterioscler Thromb Vasc Biol 1996;16:310 – 6. [21] Vidovic IP, Demarin V, Grubisic G, Kuna K, Huzjan AL. Carotid artery intima thickness and flow velocity after discontinuation of hormone replacement therapy in postmenopausal women: follow-up study. Croat Med J 2001;42:54– 7. [22] Angerer P, Stork S, Kothny W, Schmitt P, von Schacky C. Effect of oral postmenopausal hormone replacement on progression of atherosclerosis: a randomized, controlled trial. Arterioscler Thromb Vasc Biol 2001;21:262 – 8. [23] Tremollieres FA, Cigagna F, Alquier C, Cauneille C, Pouilles J, Ribot C. Effect of hormone replacement therapy on age-related increase in carotid artery intima-media thickness in postmenopausal women. Atherosclerosis 2000;153:81 – 8. [24] 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 – 7. [25] de Kleijn MJ, Bots ML, Bak AA, Westendorp IC, Planellas J, Coelingh Bennink HJ, Witteman JC, Grobbee DE. Hormone replacement therapy in perimenopausal women and 2-year change of carotid intima-media thickness. Maturitas 1999;32:195 –204. [26] Teede HJ, Liang YL, Shiel LM, McNeil JJ, McGrath BP. Hormone replacement therapy in postmenopausal women protects against smoking-induced changes in vascular structure and function. J Am Coll Cardiol 1999;34:131 – 7. [27] Sator MO, Joura EA, Gruber DM, Wieser F, Jirecek S, Tschugguel W, Huber JC. The effect of hormone replacement therapy on carotid arteries: measurement with a high frequency ultrasound system. Maturitas 1998;30:63 – 8.
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[28] Baron YM, Brincat M, Galea R. Carotid artery wall thickness in women treated with hormone replacement therapy. Maturitas 1997;27:47 – 53. [29] Dubuisson JT, Wagenknecht LE, D’Agostino RB Jr, Haffner SM, Rewers M, Sad MF, Laws A, Herrington DM. Association of hormone replacement therapy and carotid wall thickness in women with and without diabetes. Diabetes Care 1998;21:1790 – 6. [30] 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 – 37. [31] Keaney JF, Shwaery GT, Xu A, Nicolosi RJ, Loscalzo J, Foxall TL, Vita JA. 17-b Estradiol preserves endothelial vasodilator function and limits low-density lipoprotein oxidation in hypercholesterolemic swine. Circulation 1994;89:2251 – 9. [32] Gilligan DM, Quyyami AA, Cannon RO. Effects of physiological levels of estrogen on coronary vasomotor function in postmenopausal women. Circulation 1994;89:2545 – 51. [33] Gilligan DM, Badar DM, Panza JA, Quyyumi AA, Cannon RO. Effects of estrogen replacement therapy on peripheral vasomotor function in postmenopausal women. Am J Cardiol 1995;75:264 – 8. [34] Mikkola T, Ranta V, Orpana A, Ylikorkala O, Viinikka L. Effect of physiological concentrations of estradiol on PGI2 and NO in endothelial cells. Maturitas 1996;25:141 – 7. [35] Falkeborn M, Schairer C, Naessen T, Persson I. Risk of myocardial infarction after oophorectomy and hysterectomy. J Clin Epidemiol 2000;53:832 – 7. [36] Barrett-Connor E. The menopause, hormone replacement, and cardiovascular disease: the epidemiologic evidence. Maturitas 1996;23:227 – 34. [37] Nabulsi AA, Folsom AR, Szklo M, White A, Higgins M, Heiss G. No association of menopause and hormone replacement therapy with carotid artery intima-media thickness. Circulation 1996;94:1857 – 63. [38] Kanters SDJM, Algra A, van Leeuwen MS, Banga JD. Reproducibility of in vivo carotid intima-media thickness measurements: a review. Stroke 1997;28:665 – 71. [39] Baron YM, Galea R, Brincat M. Carotid artery wall changes in estrogen-treated and -untreated postmenopausal women. Obstet Gynecol 1998;91:982 – 6.
Carotid intima-media thickness in surgical menopause: women who received HRT versus who did not Veli Mihmanli a,*, Ismail Mihmanli b, Kadir Atakir b, Fatih Kantarci b, Turgut Aydin a, Yucel Sengun a, Omer Uysal c a
Department of Obstetrics and Gynecology, SSK Okmeydani Training Hospital, Istanbul, Turkey b Department of Radiology, Cerrahpasa Medical Faculty, Istanbul Uni6ersity, Istanbul, Turkey c Department of Biostatistics, Cerrahpasa Medical Faculty, Istanbul Uni6ersity, Istanbul, Turkey Received 22 May 2001; received in revised form 3 January 2002; accepted 8 February 2002
Abstract Objecti6e: The effects of hormone replacement therapy (HRT) in the natural menopausal period have been extensively studied. However, these effects have almost none been studied in purely surgical menopause. The aim of this study was to measure intima-media thickness (IMT) of carotid arteries bilaterally in two groups of surgical menopausal women who received HRT versus who did not. Methods: A B-mode ultrasound unit was used for the measurements of the IMTs of carotid arteries in two groups. Measurements of Group 1 (n=65, untreated group) were compared with those of Group 2 (n=70, treated group), in 2-years of follow-up. Patients in Group 2 received daily doses of 0.625 mg of oral conjugated estrogen preparates. Serum estradiol levels, lipid profiles, and blood pressures were measured, pre and postoperatively. For the statistical analyses in terms of differences of IMTs between two groups, general factorial analysis of variation was used. Results: Among preoperative values of low-density lipoprotein (LDL), high-density lipoprotein (HDL), cholesterol, systolic and diastolic blood pressures, estradiol, and age, only the estradiol values showed significant difference between both groups. The statistical results concerning the postoperative IMT differences for both groups showed that there was a statistically significant difference when comparing both groups, showing an increase in IMT in Group 1. Conclusion: In surgical menopausal women, the direction of the HRT effect is in agreement with evidence from earlier studies on the effects of HRT in natural menopausal women. © 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Surgical menopause; Hormone replacement therapy; Intima-media thickness; Carotid; Ultrasound
Veli Mihmanli was the principal investigator, and implemented, designed, and supervised the study. Veli Mihmanli also did the analyses and prepared the manuscript. The other authors helped in the design of this study, implementation, analyses, and preparation of the manuscript. * Corresponding author. Present address: Osmaniye M. Koyalti S. No.: 3, Ozyurt Sitesi, B-B Girisi K. 2 D. 6, Bakirkoy, 34730-Istanbul, Turkey. Tel.: +90-212-586-1586; fax: + 90-212-632-0044. E-mail address: [email protected] (V. Mihmanli).
0378-5122/02/$ - see front matter © 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 7 8 - 5 1 2 2 ( 0 2 ) 0 0 0 2 8 - 2
38
V. Mihmanli et al. / Maturitas 42 (2002) 37–43
1. Introduction The intima-media thickness (IMT) of the carotid artery is a sonographic (morphological) parameter that depends on the degree of atherosclerosis and has been shown to be associated with most risk factors for atherosclerosis [1]. Recently, an increased thickness of carotid IMT determined by B-mode ultrasound has been shown to be directly associated with an increased risk of myocardial infarction and stroke in older adults without a previous history of cardiovascular disease [2]. The risk of cardiovascular disease in women before menopausal period is less than men within the same age group [3]. Although preliminary reports from recent ongoing studies have raised questions about cardioprotective effects of hormone replacement therapy (HRT), based on many other observational studies conducted since 1980s, that estrogen use is associated with reduced risk of cardiovascular disease [4– 9]. Almost all studies investigating the relationship of HRT and atherosclerosis in terms of IMT, do not separate patients into different groups for natural menopause and surgical menopause to elucidate the effect of HRT on the atherosclerosis. The aim of this study was to investigate the state of the carotid artery wall, a vessel interposed between the cerebrovascular and cardiovascular systems, with B-mode ultrasonography in women with surgical menopause. The results of this study may provide an opportunity to improve our understanding of the role of the HRT on vascular wall.
2. Materials and methods The study group initially chosen included 145 women scheduled to undergo total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH +BSO) for various types of benign gynecological pathologies. All patients were informed about expected outcomes of both surgical menopause and HRT. Sixty-five patients whose ages ranged between 46 and 49 (mean age of 46.991.0, mean9 stan-
dard deviation (S.D.)) chose not to receive HRT (Group 1). The remaining 70 patients, whose ages ranged between 45 and 49 (47.19 1.5), chose to receive HRT (Group 2) after surgery. All patients gave written informed consent. Patients in the treatment group received daily doses of 0.625 mg of oral conjugated estrogen preparates (Premarin, Wyeth) beginning day 8 after surgery. Exclusion criteria were a history of clinical manifestations of atherosclerosis (coronary artery disease, peripheral artery disease and cerebrovascular disease, or plaque detection during first ultrasonographic examination in carotid vessels), hyperlipidemia, systemic hypertension, diabetes mellitus, smoking, regular alcohol consumption, personal or family history of breast cancer, venous thromboembolism and liver or renal diseases. These conditions were excluded by means of the general examination and laboratory blood investigations. All patients were still menstruating before the surgery and no patient had a history of estrogen use. Ultrasonogrophic examinations were performed in a quiet, temperature-controlled room (22 °C). All patients rested for 10 min before the examination. The examinations were all done between 08:30 and 10:00 h, with patients after overnight fasting. Ultrasonographic examination was performed with B-mode ultrasound (Sonoline Omnia, Siemens, Germany) equipped with a 7.5 MHz linear transducer. Patients were examined in the supine position. All ultrasonographic measurements were performed and evaluated by a single experienced radiologist 3 days before TAH+ BSO and 2 years after surgery and he was blinded to HRT use among the patients. The mean interval of IMT measurements for Group 1 was 24.119 0.92 months, and 24.039 0.86 months for Group 2 (P= 0.730). With this technique, two parallel echogenic lines separated by an anechoic space can be visualized at levels of the artery wall. It was previously shown that these lines were generated by the blood-intima and media-adventita interfaces [10]. The distance between the two lines gives a reliable index. Ultrasound scans of the right (R) and left (L) distal centimeter of common carotid arteries (CCA), bifurcation and of the first proximal cen-
V. Mihmanli et al. / Maturitas 42 (2002) 37–43
timeter of internal carotid arteries (ICA) were performed (Figs. 1 and 2). Since the far wall was better visualized than the near wall, far wall IMT was calculated for each segment. All measurements were made at the time of scanning on frozen images of longitudinal scans by using the machine’s electronic caliper. The mean IMT was calculated using three frozen images representative of the same segment. Serum estradiol level and lipid concentrations including high-density lipoprotein (HDL), lowdensity lipoprotein (LDL), cholesterol, and systolic and diastolic blood pressures were measured before and after the operation, corresponding the day of the sonographic examination.
2.1. Statistical analysis The statistical package SPSS for Windows (version 6-1-3 SPSS Inc. Chicago, IL, USA) was used for data analysis. All data are expressed as mean 9S.D. The LDL, HDL, cholesterol, blood pressures and estradiol values were analyzed by general factorial analysis of variation (ANOVA). These variables were analyzed with a model including preoperative values of LDL, HDL, cholesterol, blood pressures and estrogen, and age as covariates. A second model using age, pre and
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postoperative estradiol values, and preoperative IMT of each interested segment of the carotid artery as covariates was created and analyzed with general factorial ANOVA to determine whether the postoperative IMT value was significantly different. In all statistical analysis any P value of 0.05 or less was considered statistically significant.
3. Results Based on the exclusion criteria, ten patients did not meet study criteria. Six patients who had hyperlipidemia, two patients who had elevated glucose level, one patient who had hypertension, and the remaining one patient who had plaque formation on ultrasonographic examination were excluded. The reproducibility of ultrasonographic measurements was tested in 20 patients in whom IMT was measured by the same operator three times at 10 min intervals on successive images of the same area and analyzed by analysis of variance. The coefficient of variation demonstrated a high level of agreement. Body mass index (BMI) of Group 1 was 24.79 2.9 and 24.49 3.1 for Group 2, and comparison of two groups was not statistically significant
Fig. 1. IMT of distal common carotid artery in an untreated patient. Preoperative (a) and postoperative (b) measurements are seen between calipers, showing increase in IMT in 2-years of follow-up, 0.7 vs. 0.9 mm.
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V. Mihmanli et al. / Maturitas 42 (2002) 37–43
Fig. 2. IMT of distal common carotid artery in a patient with estrogen preparates. Preoperative (a) and postoperative (b) measurements are seen between calipers. IMT is unchanged in 2-years of follow-up (0.6 mm).
(P = 0.289). Laboratory values of the study population are presented in Table 1. The pre and postoperative median estradiol values were 78 and 24 pg/ml for Group 1, and 79.5 and 79 pg/ml for Group 2, respectively. The IMT values are given in Table 2. There was a statistically significant difference in terms of IMTs when comparing both groups, showing an increase in IMT in Group 1. When the model, including preoperative values of LDL, HDL, cholesterol, blood pressures and estrogen, and age was analyzed, only the estrogen values showed significant difference between both groups.
4. Discussion The incidence of coronary artery disease and cerebrovascular accidents among women increases significantly after menopause [11], and substantial epidemiological evidence suggests that this increased risk is due to lower postmenopausal estrogen levels [12,13]. With the subsequent decrease in estrogen levels after menopause begins, the progression of any existing atherosclerosis will be accelerated. Due to estrogen’s cardioprotective effects, postmenopausal women who receive HRT are less likely to develop atherosclerotic disease
[14–16]. Two factors account for the cardioprotective effects of HRT. Estrogen treatments improve blood lipid profiles in postmenopausal women, which accounts for approximately 25– 30% of HRT’s cardioprotective effects [17]. The remaining benefit is derived from the non-lipid effects of estrogen directly on the artery wall. Ultrasonographic investigation of the carotid artery is being undertaken increasingly to assess cardiovascular risk. Atherosclerotic disease in the carotid bulb has been associated with both coronary and cerebrovascular disease [18]. Carotid artery plaque formation has been detected with B-mode ultrasound in postmenopausal women [19]. Ultrasonographically detected elevated IMTs have been shown to precede carotid plaque formation [20]. There have been a lot of studies investigating the effect of HRT on the coronary and carotid arterial system whether there is an increased risk of infarction and stroke in postmenopausal women resulting from atherosclerosis. Also, there is a large body of the literature that documents ultrasonographically evaluation of the IMTs in postmenopausal women who undergo HRT or not [21–28]. Evaluation of women in menopausal period (largely natural menopause) has also been a topic of much interest in recent literature to
V. Mihmanli et al. / Maturitas 42 (2002) 37–43
document the effect of HRT on atherosclerosis [21 – 30]. In light of these studies, we have chosen to focus instead on the effects of HRT on carotid IMTs in women on whom TAH + BSO were performed. To the best of our knowledge, there are few publications dealing directly with the effects of HRT on carotid artery wall in purely selected patients who had undergone surgical menopause. Most prospective studies [21,23– 28] showed significant association between HRT and IMTs, stating that HRT prevents development of atherosclerosis. Also estrogen has a direct effect on arteries, because of its vasodilatory effect, reducing the risk of ischemic heart disease. Indeed, estrogen administration improves vascular tone in coronary and peripheral vessels of oophorectomized animals and postmenopausal women [31– 34]. Our results seem to support the results of the previous studies, showing that HRT leads to delay of thickening of the IMTs. Falkeborn et al. [35], on their case-control analysis in women with surgical menopause, stated that hysterectomy at premenopausal age or unilateral oophorectomy did not alter the risk of myocardial infarction. Whereas a four fold increase in relative risk was found in natural menopause. Also bilateral oophorectomy before menopause may increase the risk of myocardial infarction. This increased risk seems to occur as a consequence of the postmenopausal estrogen withdrawal [36]. Nabulsi et al. [37] stated that the reduced risk of atherosclerotic coronary disease associated with HRT, at least in the first two decades after natu-
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ral menopause, was attributed more to the acute physiological effects of hormone replacement than to prevention of atherogenesis per se. But, how the removed ovaries affects IMTs are still unclear. Our study showed that HRT has a beneficial effect on the IMTs, documenting increase in IMTs in women with surgical menopause who did not receive HRT. However, increase in IMT in untreated group in the second year measurement was higher than expected. Care was taken to measure the carotid artery as far as the same area and at right angles. Although measurement of the IMT of carotid arteries with an electronic caliper is a rapid and low-cost method, it has quantitative limitations as the precision of this method (0.1 mm) is lower than that of more sophisticated quantitative methods (0.02– 0.06 mm) [38]. Moreover, this study is operator-dependent so that radiologist may prefer up-rounding to low-rounding during measurements. These above mentioned two factors are probably the result of higher measurement levels in our study. Baron et al. [39] stated that upright positioning the patient is easier and more accurate than supine positioning during carotid IMT measurement. Our study was being undertaken with the women in the supine position. This patient positioning may also have some effects on IMT measurement levels. Angerer et al. [22] claimed that HRT on IMTs in 1-year follow-up has no beneficial effect; albeit, their study includes only natural menopausal women. In that study this may partly be due to the follow-up time, which was not long enough to achieve benefits of HRT on IMTs.
Table 1 Laboratory values of patients who did not receive HRT (Group 1) and those who received (Group 2) Group 1 (n =65)
Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Estradiol (pg/ml) HDL cholesterol (mg/dl) LDL cholesterol (mg/dl) Total cholesterol (mg/dl)
Group 2 (n =70)
Preoperative
Postoperative
Preoperative
Postoperative
112914 71 98.0 85.6 9 25 41.99 7.1 122.69 27.3 178.99 17.7
113 9 13 71 9 7.0 23.9 9 7.8 41.7 9 6.1 120.2 9 26.1 177.6 9 15.1
110 914 70 97.0 83.4 9 20.9 40.9 9 6.8 120.6 9 29.9 179.3 9 15.7
110 914 70 97.0 83.3 9 18.9 40.8 9 6.3 118.6 9 25.7 176.9 9 14.4
Values are mean 9 S.D. LDL, low density lipoprotein; HDL, high density lipoprotein.
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Table 2 Mean IMTs of patients who did not receive HRT (Group 1) and those who received (Group 2) Group 1 (n=65)
R ICA R CCA R BIF L ICA L CCA L BIF
Group 2 (n = 70)
Preoperative
Postoperative
Preoperative
Postoperative
0.40 9 0.05 0.69 9 0.07 0.6990.06 0.4190.05 0.6990.07 0.689 0.05
0.47 9 0.04 0.80 90.09 0.80 90.07 0.489 0.05 0.80 90.08 0.79 9 0.08
0.41 9 0.05 0.69 9 0.06 0.69 9 0.05 0.43 9 0.04 0.69 9 0.06 0.68 9 0.06
0.41 9 0.05 0.69 9 0.06 0.69 9 0.06 0.42 9 0.04 0.69 9 0.06 0.68 9 0.05
Values are mean 9 S.D. R ICA, right internal carotid artery; R CCA, right common carotid artery; R BIF, right bifurcation; L ICA, left internal carotid artery; L CCA, left common carotid artery; L BIF, left bifurcation.
Although the results shown in our study indicate that HRT has beneficial effects on carotid IMTs, further studies, including larger numbers of patients, with longer and more standardized cardiovascular and neurologic follow-up, should be performed.
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