Age, menopause and hormone replacement therapy influences on cardiovascular risk factors in a cohort of middle-aged Chilean women

Maturitas 45 (2003) 205
/212 www.elsevier.com/locate/maturitas

Age, menopause and hormone replacement therapy influences on cardiovascular risk factors in a cohort of middle-aged Chilean women Camil Castelo-Branco b,*, J.E. Blu¨mel a, M.E. Roncagliolo a, J. Haya c, D. Bolf a, L. Binfa a, X. Tacla a, M. Colodro´n b b

a Fac. Medicina Sur, Hospital Barros Luco-Trudeau, U de Chile, Santiago, Chile Department of Gynecology and Obstetrics, Menopause Clinic, Hospital Clinic Provincial, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain c Hospital Santa Cristina, Madrid, Spain

Received 23 May 2002; received in revised form 27 February 2003; accepted 4 March 2003

Abstract Objective: To determine the prevalence of obesity and other cardiovascular risk factors (RF) in middle-aged women, to correlate them with each other, and to describe the prevalence of such a RF and their changes with aging, menopause and Hormone Replacement Therapy (HRT) in a cohort of Chilean workers. Material and method: In 1991
/1992 cardiovascular RFs were assessed in 467 women between 40 and 59 who were not taking HRT at that time. Five years later these women were re-evaluated. Results: Sedentarism (87.2%), dyslipidemias (71.5%), high blood pressure (13.5%), obesity (13.1%), smoking (12.4%) and diabetes (2.8%) were the more prevalent RF. These RF become more prevalent with age. In the second control, 5 years later, hypertension (20.9%), obesity (27.3%), smoking (20.8%) and diabetes (5.9%) were observed increased. Dyslipidemia did not changed, although triglyceride levels rose from 125.99/56.4 to 136.89/63.5 mg/dl (P B/0.01). Sedentarism dropped to 58.8%. Menopause did not deteriorate any of these RF. The use of HRT increased during the 5-years follow-up from 3.8 to 35%, and related to its use a decrease in LDL-cholesterol and an increase in HDL-cholesterol levels were detected. Conclusion: Middle-aged women included in this cohort have a high prevalence of RF; these deteriorate with age, but no with menopause. HRT improves the lipid profile. # 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Menopause; Hormone replacement therapy; Cardiovascular risk factors

1. Introduction

* Corresponding author. E-mail address: [email protected] (C. Castelo-Branco).

Usually cardiovascular diseases (CVD) have been linked to males, however, the percentage of women who die for this cause is higher than the

0378-5122/03/$ - see front matter # 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0378-5122(03)00140-3

206

C. Castelo-Branco et al. / Maturitas 45 (2003) 205
/212

one of men [1]. These diseases are the main cause of morbi-mortality as well as an important loss in quality of life. Additionally, CVD also have a significant effect on the cost in healthcare because of the loss of people in labor capacity, mainly for the increasing relevance that women have gone acquiring [2]. The prevalence of CVD is influenced by the risk factor (RF), which have gone changing in the last decades; i.e. cardiovascular mortality has decreased in United States and other developed countries basically due to a better hypertension control [3]. Other RF in North American women have also changed: smoking has declined, while obesity and sedentarism have increased [4]. A singular aspect in women cardiovascular RF is ovarian function. Most of the reports, clinical and experimental, point toward a cardioprotective effect of estrogens [5]; however, recent studies designed to confirm primary and secondary prevention of CVD with hormone replacement have reported conflicting data [6,7]. In order to analyze the prevalence of cardiovascular RF in Chilean women and changes produced by age, menopause and hormone replacement therapy (HRT), we design this cohort study in 1991 and data was re-evaluated in 1996.

ally, women who used antihypertensive or hypoglycemic drugs indicated by a doctor were also considered into these groups. Dyslipidemia was defined according the National Cholesterol Education Program [12].

2.2. Design This study was undertaken with women recruited for the Barros Luco Study, a prospective study following up the changes in cardiovascular RFs. It was carried out at the Preventive Medical Examination Unit of the South Metropolitan Health Service during the annual check-up. The physical examination and questionnaire were given by a professional with 10 years experience in health examination. The data were gathered in a pre-coded, pre-tested questionnaire. Women were asked for personal and family histories of morbidity, drug use, and alcohol and tobacco consumption habits. Each woman’s weight in kilograms and height in centimeters were recorded. The Body Mass Index (BMI) was calculated by dividing the weight in kilos, by the height squared in meters [13].

2. Material and methods

2.3. Methods

2.1. Subjects

Blood samples were taken after twelve hours fasting. Glucose was measured using the hexokinase method (Sigma, Sigma Chemical Co, St Louis, MO, USA). When glucose was /120 mg/ dl, the measurement was repeated a week later. Total cholesterol and triglycerides were assessed using an enzymatic colorimetric method (Sigma, Sigma Chemical Co). HDL cholesterol subfraction was obtained from the cholesterol in the supernatant, after precipitation with Mg
/Dextran sulfate (Sigma, Sigma Chemical Co). LDL cholesterol was calculated according Friedewald’s method [14]. The variation coefficients for normal ranges of total cholesterol, HDL and triglycerides were 1.6, 3.9 and 3.9% intra-assay and 4.2, 4.6 and 3.9% inter-assay, respectively. Glucose had a 1.1% intraassay and 2% inter-assay variation.

A total of 576 women between 40 and 59 years were studied in 1991
/1992. Five years later, in 1996
/1997, 467 (81.2%) were re-examined. The clinical characteristics of women in the first evaluation have been previously reported [8]. According to the socio-economical status subjects were: no qualified workers (22%), technical type occupations (54.8%), administrative functionaries (13%), teachers (6%) and only 4.2% were qualified professionals. Subjects were defined as sedentary if carried out less than 15 min of physical activity twice per week [9], hypertense when systolic arterial pressures ]/ 140 mmHg or diastolic ]/90 [10]; and diabetics, when basal glucose /125 mg/dl [11]. Addition-

C. Castelo-Branco et al. / Maturitas 45 (2003) 205
/212

2.4. Statistical analyses The data were analyzed with the 6.04 version of the Epi-Info programme (Centers for Disease Control, Atlanta, GA, USA; WHO, Basle, Switzerland). In order to obtain RF averages, grouped by age, values beyond three standard deviations were eliminated; whereas to obtain the percentage of women who had some altered factor, the entire sample was considered. Women under hypolipemiant drugs were not considered for the analysis of the lipid profile. Equally, glucose averages were calculated without considering the values of those that used hypoglycemic drugs. Both drugs (hypolipemiant and hypoglycemiant) may have other vascular effects, i.e. statins experts effects on endothelial function and as a consequence on blood pressure [15]. However, these is a minor effect and patients have been included for all the other analyses. Differences between the groups were evaluated with ANOVA or the Kruskall
/Wallis test, according to the homogeneity of the variance as measured by the Bartlet test. Percentage differences were evaluated with the x2 test. Results were expressed as mean9/standard deviation. Differences were considered statistically significant when P B/0.05.

3. Results A total of 467 women between 40 and 59 years (mean: 48.09/4.8) were studied (Table 1). The most frequent medical reports are given in Table 1. In addition, three of each four women (75.8%) underwent some type of major surgery, such as caesarean section (29.6%), cholecystectomy (27%), surgical sterilization (17.6%), apendicectomy (12%), hysterectomy (9%), oophorectomy (6.2%), mammary nodules (4.5%) and varixes (4.1%). Among the interviewed women, 17.6% consumed alcohol, 12.4% were smokers, 26.6% former smokers and 61% never smokers. A 17.9% of women less than 45 years were smokers whereas over 55 only were a 3.4% (P B/0.008). Sedentarism was highly prevalent affecting an 87.2% of women. Hypertension was noted in a 13.5% of women in

207

Table 1 Age groups and medical reports in the studied cohort at first control Age

N women

Percentage

40
/44 45
/49 50
/54 55
/59 Illnesses

140 150 119 58 Percentage

30.0% 32.1% 25.5% 12.4% Age of diagnosis

Psychiatric Allergic Tuberculosis Fractures Rheumatologic diseases Goiter Cervix
/uterine cancer Diabetes mellitus Kidney lithiasis Valve heart diseases

19.5% 18.6% 8.1% 6.9% 4.5% 4.5% 2.8% 2.8% 2.1% 1.7%

39.49/6.7 28.39/15.1 23.49/11.6 35.19/14.9 38.89/6.0 29.39/14.1 39.49/6.7 41.29/8.1 36.09/7.8 36.79/14.7

the first control, with increasing prevalence with age (Table 2). Likewise, systolic and diastolic mean pressure increased in older women. BMI progressively increased in women between 40 and 54-years-old, whereas after 55 years a decrease in BMI was observed (Table 2). Among the women included, a 54.2% was obese or overweight. A 2.8% of women were diabetic in the first exam (Table 2). The mean blood glucose in women under 45 years was lower (84.29/11.4 mg/dl) than the observed in women over 45 (87.19/12.1; P B/ 0.02). Cholesterol rose significantly with age, increasing from 208.59/41.2 mg/dl to 231.89/43.8 (P B/0.0001). Likewise, the percentage of women who had levels of cholesterol beyond the desirable range (200 mg/dl; NCEP) increased from 56.3% in women less than 45 years to 70.4% in women between 55 and 59 years. With aging, levels of HDL-cholesterol did not change and LDL-cholesterol showed a significant increase (from 134.99/ 37.1 mg/dl in 40
/44 years group to 149.29/37.2 mg/dl in 55
/59 years group P B/0.001). Accordingly, the percentage of women that had high LDL-cholesterol levels increased with age (54.6
/ 71.4%; P B/0.008). Mean triglyceride levels was 125.99/56.4 mg/dl; increasing from 113.19/50.5 mg/dl at 40
/44 years to 136.39/58.6 mg/dl at

208

C. Castelo-Branco et al. / Maturitas 45 (2003) 205
/212

Table 2 Studied cardiovascular RFs in the first control Age (years) Sedentarism % Systolic Pressure Diastolic pressure Hypertension % BMI Overweight % Obesity % Glucose Diabetes % Cholesterol % Over desirable range

40
/44 85.7 113.49/15.4 71.99/11.1 7.1 25.29/3.5 39.3 8.6 84.29/11.4* 2.1 208.59/41.2 56.3

45
/49 90.7 119.19/14.1 76.59/10.8 11.3 26.39/3.8 44.7 14.7 87.89/12.3 2.7 214.29/35.7 62.4

50
/54 84.9 121.29/17.2 78.39/13.0 15.1 26.29/3.9 38.7 18.5 86.69/13.8 3.4 231.79/40.7 75.9

55
/59 86.2 127.89/19.4 81.69/11.2 31.0 25.59/3.5 41.4 8.6 86.19/10.3 3.4 231.89/43.8 70.4

p B/0.0001 B/0.0001 B/0.0001 B/0.05 B/0.02 B/0.02 B/0.0001 B/0.01

Sedentarism, blood pressure (mmHg) and hypertension prevalence, BMI (kg/m2), obesity prevalence, glucose (mg/dl), diabetes prevalence, cholesterol levels (mg/dl) and percentage of women with cholesterol levels over the desirable range. A BMI between 25.0 and 29.9 kg/m2 classified women as overweight and, equal or superior to 30 as obese.

55
/59 years (P B/0.02); 8.4% of women under 45 years and 15.9% of those older had triglyceride levels over the desirable range (P B/0.03). Of the entire sample, 65.7% of women from 40 to 44 years had altered at less one of the parameters at the lipid profile, increasing to 80.7% in women from 50 to 54 years and to 75.9% in those over 55 (x2: 8.7; P B/0.03). In the first control, 3.6% of women did not have any cardiovascular RF, 20.2% had one, 50.7% two, 22.9% three, 2.1% four and 0.5% five RF. Women were re-evaluated 5 years later, and changes in RF were recorded in Table 3. In order to evaluate the effect of menopause on cardiovascular RF, 56 premenopausal women who did not use drugs that modified lipids, including hormones, and who had regular cycles during the 5years follow-up were compared with 72 premenopausal women in 1991
/1992 who presented menopause during that 5-years period. No significant differences on RF between both groups were observed (Table 4) and menopause did not modify significantly any RF. The HRT users increased from 3.8% in 1992 to 35% in 1997. In order to evaluate the role of HRT in RF we selected 115 premenopausal women at the first exam, who did not take estrogens and that 5 years later were in natural menopause. Of those; 43 (37.4%) were in HRT in 1997 and 72 (62.6%)

were not. In the first control, RF were not different between both groups; however, at second control HRT improved some of the RF (HDL levels increased (8.9 vs. /0.6%) and LDL decreased (/3.0 vs. 3.6%) significantly in HRT users) and did not deteriorate others (glucose levels increased a 6% in no users vs. 0.5% in users), (Table 5).

4. Discussion In Chile one of every four women dies because of CVDs [1]. This mortality is influenced by several factors. Smoking, diabetes mellitus and hypertension increase in women CVD mortality in 118, 138 and 48%, respectively [16,17]. Additionally, cholesterol level over 240 mg/dl increases more than twice the risk of CVD [18], being low HDL-cholesterol level a strong predictor of risk in women [19], mainly when associates to high triglyceride levels [12]. Obesity, that is more prevalent in Chilean women than men [20], and sedentarism increase CVD mortality in 30 and 72%, respectively [21,22]. At first control, in 1991
/1992, a high prevalence of cardiovascular RF in middle age women was observed. A 50% of women had at less two RFs, which was in agreement with mortality by CVD in

C. Castelo-Branco et al. / Maturitas 45 (2003) 205
/212

Table 3 Changes on RFs between 1992 and 1997 Variables

1992

Number of women Age (years) Alcohol consumption (g/ month) Smokers (%) Sedentarism (%) Systolic pressure (mmHg)

420 322 48.29/5.1 52.89/5.1 0.0001 16.99/49.2 17.89/49.5

12.4 87.2 119.09/ 16.8 Diastolic pressure (mmHg) 76.29/12.0 Hypertension (%) 13.5 BMI (kg/m2) 25.29/3.5 Obesity (%) 13.1 Glucose(mg/dl) 86.29/12.3 Diabetes (%) 2.8 Total-cholesterol (mg/dl) 219.19/ 40.7 Altered cholesterol (%) 65.2 HDL-cholesterol (mg/dl) 50.39/11.9 low HDL-Cholesterol (%) 8.6 LDL-cholesterol (mg/dl) 141.19/ 36.6 Altered LDL-Cholesterol (%) 61.1 Triglycerides (mg/dl) 125.99/ 56.4 Altered triglycerides (%) 13.8 Altered lipid profile (%) 71.5

1997

20.8 58.8 123.19/ 17.6 74.89/10.1 20.9 27.69/4.2 27.3 88.89/11.9 5.9 221.19/ 39.6 69.6 51.99/11.3 7.3 141.39/ 38.0 58.7 136.89/ 63.5 14.4 75.5

P B/

0.001 0.0001 0.001

0.008 0.0001 0.0001 0.004 0.04

0.01

As some drugs may modify significantly the lipid profile the analysis was conducted in women who did not use them: in 1991
/1992, 36 women in oral contraceptive pill and 11 in HRT were excluded and in 1997 were excluded 6 women in oral contraceptives, 133 taking HRT and six using hypolipemiant drugs.

Chilean women. There was a significant increase in the different RF with age, except for obesity, that declined slightly after 55 years, and sedentarism. The prevalence of RF in this cohort is similar to the observed in other Chilean cohorts [9,23]. There was a worsening in some RF related to aging across the follow-up, such as hypertension, diabetes mellitus and obesity. Modification in some habits could have an important effect on the cardiovascular mortality incidence. Smoking increased twice during the 5-years period. On the other hand, the percentage of sedentary women fell from 87 to 58%, which may explain the lack of deterioration in lipids during the follow-up (Table

209

3) as the exercise has demonstrated to reduce total cholesterol and triglycerides and to increase HDL [12,24]. It is accepted that menopause may imply a worsening in several cardiovascular RF. Postmenopausal women have increments in total cholesterol, LDL-cholesterol and Apo B levels [25
/28], without changes [25] or decreases in HDL-cholesterol levels [26
/28] and slight changes in triglycerides, glucose, blood pressure or BMI [25,29]. However, in our study, we did not find impairment in cardiovascular RF related to menopause and, additionally, our results agree with data recently published from other cohorts [30,31]. These differences on the effect of menopause in cardiovascular RF may be due to the fact that, in countries with different CVD prevalence, the different studies analyzed populations genetic and socio-cultural diverse [32,33]. Improvements detected in this cohort on metabolic cardiovascular RF, such as lipids or glucose, related to HRT are in agreement with previously published data [27,28,34,35]; and additionally, HRT did not caused any increment in weight or blood pressure. These results match with data from Wing, who studied perimenopausal women in a 3-years follow-up, and found not difference in the weight gain among those women who developed menopause or those who did not [36]. Tchernof in an overview on the effect of menopause in obesity, stands out that menopause does not increases weight, but it causes a redistribution of the corporal fat, increasing the abdominal deposits [37]. Finally, in concordance with other studies [38,39] no changes in blood pressure among HRT users were observed. Interestingly, 32% of English doctors do not prescribe HRT to hypertense women [40] fearing to induce a higher hypertension; but still, hypertense women treated with oral estrogens show a drop of pressure levels [41]. In conclusion, cardiovascular RF are high prevalent in Chilean middle-age women and that RF are changing because of aging and the habits modification. Menopause did not modify significantly the risk and HRT improved basically lipid profile. As RF may be amended by life habit changes, it seems clearly urgent to implement

C. Castelo-Branco et al. / Maturitas 45 (2003) 205
/212

210

Table 4 Comparison of RFs among premenopausal women in 1991
/1992 according to menstrual condition in 1996
/1997 Premenopausal Variable

1992

N women Age (years) BMI (Kg/m2) Glucose (mg/dl) Cholesterol (mg/dl) HDL-C (mg/dl) LDL-C (mg/dl) Triglycerides (mg/dl) Systolic pressure Diastolic pressure

56 46.29/2.1 26.09/4.2 85.59/11.5 203.79/35.6 48.59/11.5 131.59/31.4 108.39/49.7 117.39/13.7 76.09/9.8

Postmenopausal % Variation 1997

1992

% Variation 1997

7.7 3.0 1.4 3.9 0.9 14.3 5.1 0.2

72 46.69/2.9 26.19/3.8 85.59/10.4 215.29/38.4 50.69/10.7 135.59/36.9 117.99/53.4 118.29/15.8 75.79/12.4

6.5 6.0 3.6 3.8 3.6 26.0 2.2 1.8

To eliminate the influence of aging, the first group only included into this analysis those women who stayed premenopausal and who had 45 or older at the first exam.

Table 5 Comparison of RFs among postmenopausal women regarding HRT use HRT no users Variable

1992

N women Age (years) BMI(kg/m2) Glucose (mg/dl) Cholesterol (mg/dl) HDL-C (mg/dl) LDL-C (mg/dl) Triglycerides Systolic pressure Diastolic pressure

72 46.89/2.9 26.19/3.8 85.39/10.4 215.29/38.4 52.49/11.3 135.59/36.9 117.99/53.4 118.29/15.8 75.79/12.4

HRT users

P B/

% Variation 1997

1992

% Variation 1997

6.5 6.0 3.6 /0.6 3.6 26.0 2.2 /1.8

43 46.49/3.0 25.59/3.1 88.39/15.1 218.99/38.1 49.09/10.4 142.49/36.6 129.79/54.8 120.79/17.7 75.99/10.4

5.9 0.5 3.3 8.9 /3.0 45.1 3.2% /0.6

0.05 0.03 0.04

As the HRT types and regimens used were numerous (transdermal, percutaneous, oral, combined, continuous, cyclic,. . .) no comparative analysis were done.

educational strategies to diminish the main cause of death among Chilean women.

References [1] Instituto Nacional de Estadı´sticas. Demografı´a. Repu´blica de Chile. Ed INE, 1998. [2] Instituto Nacional de Estadı´sticas. Los Adultos Mayores en Chile, Enfoques Estadı´sticos 1999;4:1
/4. [3] National Institutes of Health. National Heart, Lung, and Blood Institute. National High Blood Pressure Education Program. The Sixth Report of The Joint National Com-

mittee on prevention, detection, evaluation, and treatment of high blood pressure. NIH Publication No. 98-4080, 1997. [4] US Department of Health and Human Services. Physical Activity and Health: A Report of the Surgeon General. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, 1996. [5] Bush TL. Preserving cardiovascular benefits of hormone replacement therapy. J Reprod Med 2000;45(3 Suppl.):259
/73. [6] Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in

C. Castelo-Branco et al. / Maturitas 45 (2003) 205
/212

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. J Am Med Assoc 2002;288:321
/33. Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, Hsia J, Hulley S, Herd A, Khan S, Newby LK, Waters D, Vittinghoff E, Wenger N. Cardiovascular disease outcomes during 6.8 years of hormone therapy: heart and estrogen/progestin replacement study follow-up (HERS II). J Am Med Assoc 2002;288:49
/57. Blumel JE, Roncagliolo ME, Brandt A, Tacla X, Gramegna G. Prevalencia de factores de riesgo cardiovascular en mujeres. Cambios asociados con la edad, la menopausia y la terapia estroge´nica. Rev Soc Argentina Nutricio´n 1994;5(1):7
/12. Berrios X, Jadue´ L, Zenteno J, Ross MI, Rodriguez H. Prevalencia de los factores de Riesgo de Enfermedades Cro´nicas. Rev Med de Chile 1990;118:597
/604. US Department of Health and Human Services. Public Health Service. National Institutes of Health. The Sixth Report of The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. NIH Publication No. 98-4080, 1997. World Health Organization. Department of Noncommunicable Disease Surveillance. Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. WHO/NCD/NCS/99.2. 1999. Geneva. US Department of Health and Human Services. Public Health Service. National Institutes of Health. Second Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II) del National Cholesterol Education Program NIH Publication No. 93-3096, 1993. US Department of Health and Human Services. Public Health Service. National Institutes of Health. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in adults. NIH Publication No. 98-4083, 1998. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use the preparative ultracentrifuge. Clin Chem 1972;18:499
/502. Borghi C, Veronesi M, Prandin MG, Dormi A, Ambrosioni E. Statins and blood pressure regulation. Curr Hypertens Rep 2001;3:281
/8. Wolf PH, Modans JH, Finucane FF, Higgins M, Kleinman JC. Reduction of cardiovascular disease related mortality among postmenopausal women who use hormones. Am J Obstet Gynecol 1991;164(2):489
/94. Manson JE, Spelsberg A. Risk modification in the diabetic patient. In: Manson JE, Ridker PM, Gaziano JM, Hennekens CH, editors. Prevention of myocardial infarction. New York, NY: Oxford University Press, 1996:241
/ 73. Stamler J, Daviglus ML, Garside DB, Dyer AR, Greenland P, Neaton JD. Relationship of baseline serum cholesterol levels in three large cohorts of younger men

[19]

[20] [21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

[29]

[30]

[31]

211

to long-term coronary, cardiovascular, and all-cause mortality and to longevity. J Am Med Assoc 2000;284(3):311
/8. Manolio TA, Pearson TA, Wenger NK, Barrett-Connor E, Payne GH, Harlan WR. Cholesterol and heart disease in older persons and women: review of an NHLBI workshop. Ann Epidemiol 1992;2:161
/76. Albala C, Vio F, Kain J. Obesidad: un desafı´o pendiente en Chile. Rev Med Chile 1998;126(8):1001
/9. Losonczy KG, Harris TB, Cornoni-Huntley J, Simonsick EM, Wallace RB, Cook NR, Ostfeld AM, Blazer DG. Does weight loss from middle age to old age explain the inverse weight mortality relation in old age. Am J Epidemiol 1995;141(4):312
/21. Mensink GB, Deketh M, Mul MD, Schuit AJ, Hoffmeister H. Physical activity and its association with cardiovascular risk factors and mortality. Epidemiology 1996;7(4):391
/7. Jadue´ L, Vega J, Escobar MC, Delgado I, Garrido C, et al. Factores de riesgo para las enfermedades no transmisibles: metodologı´a y resultados globales de la encuesta de base del programa CARMEN. Rev Med de Chile 1999;127(8):1004
/13. Dunn AL, Marcus BH, Kampert JB, Garcia ME, Kohl HW, III, Blair SN. Reduction in cardiovascular disease risk factors: 6-month results from Project Active. Prev Med 1997;26(6):883
/92. Peters HW, Westendorp IC, Hak AE, Grobbee DE, Stehouwer CD, Hofman A, Witteman JC. Menopausal status and risk factors for cardiovascular disease. J Intern Med 1999;246(6):521
/8. Schaefer EJ, Lamon-Fava S, Cohn SD, Schaefer MM, Ordovas JM, Castelli WP, Wilson PW. Effects of age, gender, and menopausal status on plasma low density lipoprotein cholesterol and apolipoprotein B levels in the Framingham Offspring Study. J Lipid Res 1994;35(5):779
/92. Castelo-Branco C, Casals E, Sanllehy C, Gonza´lez-Merlo J, Iglesias X. Effect of oophorectomy and hormone replacement therapy on plasma lipids. Maturitas 1993;17:113
/22. Castelo-Branco C, Casals E, Figueras F, Sanjua´n A, Vicente JJ, Balasch J, Vanrell JA. Two-year prospective and comparative study on the effects of tibolone on lipid pattern, behavior of apolipoproteins AI and B. Menopause 1999;6(2):92
/7. Do KA, Green A, Guthrie JR, Dudley EC, Burger HG, Dennerstein L. Longitudinal study of risk factors for coronary heart disease across the menopausal transition. Am J Epidemiol 2000;151(6):584
/93. Shelley JM, Green A, Smith AM, Dudley E, Dennerstein L, Hopper J, Burger H. Relationship of endogenous sex hormones to lipids and blood pressure in mid-aged women. Ann Epidemiol 1998;8(1):39
/45. Casiglia E, Ginocchio G, Tikhonoff V, D’Este D, Mazza A, et al. Blood pressure and metabolic profile after surgical menopause: comparison with fertile and naturally-menopausal women. J Hum Hypertens 2000;14:799
/805.

212

C. Castelo-Branco et al. / Maturitas 45 (2003) 205
/212

[32] Smith MH, Anderson RT, Bradham DD, Longino CF, Jr. Rural and urban differences in mortality among Americans 55 years and older: analysis of the National Longitudinal Mortality Study. J Rural Health 1995;11:274
/85. [33] Acs N, Vajo Z, Miklos Z, Siklosi G, Paulin F, Szekacs B. Postmenopausal hormone replacement therapy and cardiovascular mortality in Central-Eastern Europe. J Gerontol 2000;55:M160
/2. [34] Castelo-Branco C, Vicente JJ, Figueras F, Sanjua´n A, Martı´nez de Osaba MJ, Casals E, Pons F, Balasch J, Vanrell JA. Comparative effects of estrogens plus androgens and tibolone on bone, lipid pattern and sexuality in postmenopausal women. Maturitas 2000;34:161
/8. [35] Castelo-Branco C, Casals E, Sanllehy C, Dura´n M, Fortuny A, Vanrell JA. Effects of progestogen on lipids, lipoproteins, and apolipoproteins during transdermal estrogen replacement therapy with and without medroxyprogesterone acetate. J Reprod Med 1996;41:833
/8.

[36] Wing RR, Matthews KA, Kuller LH, Meilahn EN. Weight gain at the time of menopause. Arch Intern Med 1991;151(1):97
/102. [37] Tchernof A, Poehlman ET. Effects of the menopause transition on body fatness and body fat distribution. Obes Res 1998;6(3):246
/54. [38] Lip GY, Beevers M, Churchill D, Beevers DG. Hormone replacement therapy and blood pressure in hypertensive women. J Hum Hypertens 1994;8(7):491
/4. [39] Oparil S. Hypertension in postmenopausal women: pathophysiology and management. Curr Opin Nephrol Hypertens 1995;4(5):438
/42. [40] Lip G, Beevers M, Churchill D, Beevers DG. Do clinicians prescribe HRT for hypertensive postmenopausal women. Br J Clin Pract 1995;49(2):61
/4. [41] Szekacs B, Vajo Z, Acs N, Hada P, Csuzi L, Bezeredi J, Magyar Z, Brinton EA. Hormone replacement therapy reduces mean 24-hour blood pressure and its variability in postmenopausal women with treated hypertension. Menopause 2000;7(1):31
/5.