- Email: [email protected]
Lipoproteins and BMI: a comparison between women during transition to menopause and regularly menstruating healthy women
Maturitas 41 (2002) 177– 185 www.elsevier.com/locate/maturitas
Lipoproteins and BMI: a comparison between women during transition to menopause and regularly menstruating healthy women Gerd Hall a,*, Aila Collins b, Gyo¨rgy Csemiczky c, Britt-Marie Landgren a a
b
Department of Obstetrics and Gynaecology, Huddinge Uni6ersity Hospital, SE-14186 Huddinge, Sweden Department of Clinical Neuroscience, Psychiatry and Psychology Section, Karolinska Hospital, SE-171 76 Stockholm, Sweden c Department of Obstetrics and Gynaecology, Karolinska Hospital, SE-171 76 Stockholm, Sweden Received 2 January 2001; received in revised form 30 May 2001; accepted 11 June 2001
Abstract One hundred and forty-three women born 1942 were followed for 5 years during transition to menopause (49– 54 years of age). Changes in menopausal status, body mass index (BMI) and circulating lipoproteins cholesterol, (chol), low density lipoprotein (LDL), high density lipoprotein, (HDL) and total triglycerides (TG) were measured, once yearly and compared with a control group of normally menstruating healthy, non-smoking women 23 – 39 years old. Results: Chol was significantly higher PB 0.0001 in the study group visits 1 – 5 when compared with the controls and higher at visit 4 compared with visit 1 (PB 0.05) LDL was significantly lower in the study group and at visit 5 compared with visit 2 (P B0.05) HDL was significantly lower at visits 1 – 3 and 5 when compared with the controls (P B0.001) and to visit 4 (P B0.0001). TG was significantly higher in the study group (P B 0.0001) and increased significantly during the 5-year study. BMI was significantly higher in the older women (P B 0.00l) and increased during 5 years of study (PB0.0001). When multiple stepwise regression analyses were performed at visit 5 using education, menopausal status, use of hormone replacement therapy (HRT), BMI and smoking as predictor variables, postmenopausal status was found to be significantly associated with high LDL (PB 0.3), while high BMI significantly predicted low HDL and high TG levels. Perimenopausal status was significantly associated with high HDL levels. Conclusion: Age, BMI and menopausal status are significant predictors of circulating lipoprotein levels during transition to menopause. © 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Lipoproteins; BMI; Menopause
1. Introduction Menopausal transition is a period in women’s lives characterised by decreasing ovarian function. * Corresponding author.
It has been referred to as a period when changes in lipoproteins toward a more unfavourable pattern occur and as a consequence, the risk for coronary heart disease is increased [1–5]. Weight gain has also been reported during this period in life [6,7]. However, there is still no clear evidence
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 1 ) 0 0 2 5 8 - 4
G. Hall et al. / Maturitas 41 (2002) 177–185
178
that menopause and thus the decrease in circulating ovarian hormones, is a main cause of the changes in lipoprotein pattern. Other factors, such as age and life style are also important for the risk of coronary heart disease [8,9]. Weight gain, increasing age and smoking have been shown to induce unfavourable low density lipoprotein/high density lipoprotein (LDL/HDL) cholesterol (chol) ratios, and to raise total triglycerides (TG) and chol levels [6,7,10]. Hormone replacement therapy (HRT) has been shown in large epidemiological studies to protect against cardiovascular disease [11– 13]. It is still controversial whether HRT has a favourable effect on the lipoprotein pattern [14]. Furthermore, there is still a lack of knowledge of the changes in lipoproteins during transition to menopause in healthy women not seeking medical advice for climacteric symptoms. There are few longitudinal studies using community based samples and [4,15– 21] their results have been inconsistent. The aim of the present study was to follow the changes in lipoprotein pattern in a group of healthy women during transition to menopause and further to relate the changes to age and Table 1 Some sociodemographic characteristics at the first visit Number
%
Marital status Single Married Divorced Widow
7 11 22 3
5 78 15 2
Education Primary Secondary College
4 54 4
30 37 33
Employment Full-time Part-time
10 40
73 27
Occupation Higher professionals Lower professionals Service or clerical jobs Unskilled jobs House-wives Smokers
15 38 81 12 1 33
10 26 55 8 1 22
menopausal status as well as to normally menstruating women.
2. Material and methods
2.1. Study group The study group consisted of 143 women born 1942, who were followed during transition to menopause. For sociodemographic characteristics see Table 1. In an earlier phase of this population based study, 1399 healthy women, who were recruited through the Swedish population register, answered a questionnaire about general and reproductive health, use of estrogens and experience of menopausal symptoms [20]. Out of these 1399 women a random stratified sample reflecting educational level and parity was drawn. One hundred and sixty one women, who were not on HRT and not hysterectomised, received an invitation to participate in a longitudinal study including a somatic, gynaecological and psychological part. The women were 49 years old at study entry and were followed thereafter annually for a total period of 5 years. Our attitude was not to prescribe HRT if it was not demanded by the women. The HRT prescribed was transdermal estradiol at a dose of 50 mg per 24 h in combination with oral medroxy progesterone acetate (MPA) at a dose of 5 mg daily for 12 days each month. One hundred and forty-three women participated in the fifth visit. The first visit included questions about sociodemographic background, number of children and smoking habits, and about obstetric and gynaecological history and use of contraceptives. Each annual visit included general health screening, gynaecological examination, pap smear and blood sampling for lipoproteins. Mammography was offered, if not performed within 2 years. At each visit the women were asked about their menstrual status (they kept bleeding diary cards), HRT and experience of symptoms. The menstrual status was divided into five categories and defined as, premenopausal, if they had regular bleedings; perimenopausal, if they had irregular bleedings or last period within 12 months; postmenopausal if more than 12 months had passed since last period.
G. Hall et al. / Maturitas 41 (2002) 177–185 Table 2 Distribution of menopausal status in relation to consecutive visits (V1–V5) Menopausal status
Pre Pen Post HRT Hyst
Visit V1
V2
V3
V4
V5
72 56 9 10 0
56 46 18 26 1
8 56 17 58 6
10 29 22 77 9
4 16 32 82 9
Women using HRT and hysterectomised women (Table 2) formed separate groups.
2.2. Control group The control group consisted of 67 healthy, regularly menstruating non-smoking women 23– 39 years old, they had not used hormones, been pregnant or breastfeeding for at least 6 months prior to inclusion in the study. Blood for lipoproteins was drawn once in the follicular and once in the luteal phase, the mean of the two was used, since the values did not differ significantly. The women were fat fasting and rested sitting for 20 min before blood was drawn. The following lipoproteins were assessed, total chol; HDL; LDL and total TG. Blood was obtained for liver– kidney and thyroid function at the first and fifth visit in the study group.
2.3. Laboratory methods Lipoprotein levels were assessed according to the WHO Method Manual for Lipid, lipoprotein and apolipoprotein C [22]. Liver– kidney and thyroid function tests were performed at Biochemical Central Laboratory of Karolinska Hospital using standard methods.
2.4. Statistical methods Results are presented as arithmetic mean and S.D., when not appointed in the text; differences in distributions between groups were tested with 2-statistics and between means by using Stu-
179
dent’s t-statistics. Survival analysis was applied to menopause status data, where time to menopause was treated in the same way as time to death in ordinary survival analysis. The log rank test was used to test differences between groups. A multivariate stepwise regression model was developed in order to analyse the association between circulating lipoproteins and background variables that were considered important. The study was approved by the Ethics Committee of Karolinska Hospital, Stockholm, Sweden.
3. Results One hundred and sixty-one women were invited, 151 (94%) came to and 147 (91%) attended the first visit, the fifth visit was attended by 143 (89%) women. Six women moved out of town and two did not want to continue. During the study, nine women underwent hysterectomy and bilateral salphingo-oophorectomy, four due to myomas, one to endometriosis, two to endometrial and one to ovarian cancer and one to uterine sarcoma. One woman was treated for mammarian and one for kidney cancer. The women who developed cancer during the study were excluded from analyses. Serum kreatinine was within normal levels in all women (Table 3) abnormal liver enzymes were found in two women, one was treated for endometrial cancer and one was on multimedication for asthma and diabetes. Two women with hypothyreosis were treated with levo thyroxin. Other values outside the normal ranges were found in clinically healthy women. The number of women on HRT increased from ten at visit 1 (6%) to 82 (57%) at visit 5. At the first visit 72 women were premenopausal compared with four at the fifth visit (Table 2). A comparison of body mass index (BMI) between the study and control groups and between visits 1 and 5 in the study group is shown in Table 4. A significantly higher BMI was seen in the study group when compared with the control group (PB 0.0001). BMI increased significantly from visit 1 to 5 during transition to menopause (PB0.0001). In the control group 7.5% of women presented with BMI \ 27,
G. Hall et al. / Maturitas 41 (2002) 177–185
180
Table 3 Thyroid–kidney–liver function in 143 women at visit 5
S-TSH S-T-4 S-kreatinine S-ASAT S-ALAT S-bilirubin S-LP S-GT S-LD
Normal range
Mean
S.D.
Range
N-abnormal value
0.1–5.0 mE per l 60–150 mmol/l B120 mmol/l B0.60 ukat per l B0.60 ukat per l 4–22 mmol/l B4.6 ukat per l 0.80 ukat per l 3.9–8.0 ukat per l
1.90 114.95 72.24 0.51 0.48 11.25 2.53 0.48 6.40
1.45 19.21 9.29 0.17 0.21 9.07 0.71 0.58 1.18
0.01–10.00 75–204 54.00–107.00 0.29–2.13 0.23–2.26 2.30–99.00 0.90–5.30 0.20–6.60 0.00–9.90
11 2 0 19 21 5 2 8 13
compared with 21% at visit 1 and 32% at visit 5. Circulating levels of lipoproteins at visit 1– 5 in the study group and in the controls are shown in Figs. 1–4. Chol was significantly higher in the study group when compared with the controls (PB 0.0001) and at visit 4 compared with visit 1 (PB 0.0001). LDL was significantly higher in the study group, when compared with the controls (PB 0.000l). In the study group the levels were higher at visit 2 when compared with 5 (PB 0.005). HDL was significantly lower in the study group at visits 1–3 and 5 when compared with the controls. (P B0.0001), and higher at visits 3 and 4, when compared with 1, 2, and 5 (P B 0.0001). TG was significantly higher in the older women (PB 0.0001), and increased significantly during the study (PB 0.0001). When a multiple stepwise regression analyses was performed at visit 5 on chol, LDL, HDL, TG, using education, postmenopausal status, and the use of HRT, BMI and smoking as predictor variables, postmenopausal status was significantly associated with LDL, being higher in the postmenopausal women compared with pre and perimenopausal women (PB 0.3). For chol no variable had a significant role. HDL and TG was significantly predicted by BMI, heavier women having lower HDL and higher TG levels. Smoking was not significantly associated with the lipid levels. When a comparison was performed between the controls and the older (49 years) women, who were premenopausal at visit 1, the older women presented with significantly higher levels of chol, LDL and TG and lower HDL (Table 5). When
the women taking HRT were compared with postmenopausal women without HRT at the last visit no significant differences in lipoprotein patterns were observed.
4. Discussion Only a few prospective longitudinal studies have been performed in healthy women during transition to menopause [4,15–21]. The present study was population based and included 143 women from the Stockholm area who were followed for 5 years during transition to menopause from 49 to 54 years. Their BMI and lipoprotein patterns were compared with a control group of healthy normally menstruating women who were 23–39 years old. The older women were heavier at baseline than the controls and their BMI increased significantly during the study period of 5 years. Chol, LDL, and TG were higher and HDL was lower in the perimenopausal, older women. Menopausal status significantly predicted LDL with higher levels in postmenopausal women comTable 4 BMI* at visit 1 and 5 in 143 women and in 67 controls
Visit 1 Visit 5 Controls
Mean
S.D.
Range
24.2 25.8** 22.6***
93.7 94.3 90.3
17.0–38.0 18.0–39.0 19.0–30.0
*, Calculated as weight (kg), height2 (m); **, controls vs. visit 1 PB0.0001; ***, visit 1 vs. visit 5 PB0.0001.
G. Hall et al. / Maturitas 41 (2002) 177–185
181
Fig. 1. Total cholesterol serum levels at visits 1 – 5 and controls (nmol/l).
pared with pre and perimenopausal women. The lipoprotein pattern changed with increasing BMI and age. BMI was significantly associated with HDL and TG, the heavier women presented with lower HDL and higher TG. When the older regularly menstruating women at visit 1 were compared with the controls, the lipoprotein patterns differed significantly. HDL was lower, chol, LDL and TG were higher in the older women. When the postmenopausal women on HRT at visit 5 were compared with those without HRT no differences in lipoprotein pattern were found. The present study illustrates the changes in the use of HRT, which have occurred during the 90s in Sweden, an increase from approximately 30 to 86 daily doses per 1000 women, from 1987 to 1998 [23]. This made it impossible to follow the transition to menopause in all women, since HRT was prescribed to women, who were still menstruating, thus the HRT group represents a mixture of menopausal status. The lack of differences in lipoproteins between postmenopausal women
with and without HRT is in contrast to other investigators, who report a positive effect of HRT on the lipoprotein pattern [11–13,18]. This may be explained by the possible source of bias seen in earlier studies [14,24] showing that women using HRT differ in many aspects from non-users. They exercised more, were leaner and generally more concerned about their health. The findings in the present study indicate that age and BMI may be as important for the lipoprotein pattern and thus also for the risk of coronary heart disease as menopausal status, at least in women during transition to and immediately after menopause. These results are partly in agreement with those of Poehlman et al. [7] and Do et al. [21] who found that the only risk factor which changed as a consequence of menopause was HDL, in contrast to our findings that both HDL and LDL levels were related to on menopausal status. It should be pointed out, that the women were only followed for 5 years and it may be necessary to have a longer follow up. We could not find any
182
G. Hall et al. / Maturitas 41 (2002) 177–185
Fig. 2. Low density lipoproteins (LDL) levels at visit 1 – 5 and controls (nmol/l).
Fig. 3. High density lipoproteins (HDL) levels at visit 1 – 5 and controls (nmol/l).
G. Hall et al. / Maturitas 41 (2002) 177–185
183
Fig. 4. Total triglycerides (Tot. TG) levels at visit 1 – 5 and controls (nmol/l). Table 5 Lipoprotein levels in younger (23–39 years) controls and premenopausal regularly menstruating women (49 years, nmol/l, mean9 S.D.) at visit 1 and in postmenopausal women at visit 5 (54 years) without and with HRT (nmol/l, mean 9S.D.) Lipoproteins
Total chol LDL RDL TG
Controls N = 67
Visit 1 premenopausal N =70
Visit 5 postmenopausal N =32
HRT N =82
Mean
S.D.
Mean
S.D.
P-values
Mean
S.D.
Mean
S.D.
P-values
4.93 2.92 1.65 0.81
90.81 90.78 90.31 90.24
5.44 3.74 1.42 1.00
90.80 9l.02 90.30 90.39
B0.0003 B0.0001 B0.0001 B0.0007
6.18 4.10 1.50 1.26
9l.28 9l.35 90.34 90.57
5.77 3.59 1.55 1.20
90.82 90.99 90.37 90.58
n.s. n.s. n.s. n.s.
possible explanation for the higher HDL levels at visit 4 as compared with the other occasions. Our findings are also in agreement with those of Matthews et al. [4] who followed a cohort of healthy middle-aged premenopausal women through to menopause and Fukami et al. [19] who reported a follow up study of 7 years. However, the study involved only 16 women. Andersson et al. [16] measured lipoproteins twice in 8 years and only found an increase in HDL, however, the definition of menopause was inadequate. Smoking did not play a significant role for the lipids. We
are carrying out further analyses of the relationship between life style factors and weight changes in this sample. Previous reports on TG have been inconsistent, some reporting an increase [15,25] and others no change [16,17], which may be explained by the study designs and definitions of menopause. Stevenson et al. [26] found that menopause, independent of age, was associated with adverse changes in lipids and lipoproteins. However, the study was cross sectional and involved women with a wide age range (18– 70 years).
184
G. Hall et al. / Maturitas 41 (2002) 177–185
In our study, it seems that age and menstrual status are the main cause for changes in lipoproteins. There is ample evidence that HRT has a positive effect on vasomotor symptoms and osteoporosis. The studies on prevention of coronary heart disease are inconclusive as well as the studies on Alzheimers disease and until further proof is shown on these issues it does not seem adequate to recommend HRT on those indications. Ageing itself is a great risk factor for different illnesses as well as hereditary factors, smoking, alcohol intake, diet and exercise. We should not withhold HRT from women who wish to use HRT for different reasons but we should not try to convince an otherwise healthy woman to use HRT for reasons we still have incomplete knowledge about. In summary the results of the present study indicate that BMI and menopausal status are important for the lipoprotein pattern in middle aged women.
Acknowledgements The study was funded by a grant from Riksbankens Jubileumsfond.
References [1] Tre´ mollie`res FA, Pouilles J-M, Cauneille C, Ribot C. Coronary heart disease risk factors and menopause: a study in 1684 French women. Atheriosclerosis 1999;142:415 – 23. [2] Mosinger BJ. Human low-density lipoproteins: oxidative modification and its relation to age, gender, menopausal status and cholesterol concentrations. Eur J Clin Chem Clin Biochem 1997;35:207 –14. [3] Lindquist O, Bengtsson C, Lapidus L. Relationships between the menopause and risk factors for ischaemic heart disease. Acta Obstet Gynecol Scand Suppl 1985;130:43 –7. [4] Matthews KA, Meilahn E, Kuller LH, Kelsey SF, Caggiula AW, Wing RR. Menopause and risk factors for coronary heart disease. New Engl J Med 1989;10:641 – 6. [5] Schaefer EJ, Lamon-Fava S, Cohn SD, Schaefer MM, Ordovas JM, Castelli WP, Wilson PWF. 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;35:779 – 92.
[6] Razay G, Heaton KW, Bolton CH. Coronary heart disease risk factors in relation to the menopause. Quart J Med New Ser 1992;85:307 – 8, 889 – 96. [7] Poehlman ET, Toth MF, Ades PA, Rosen CJ. Menopause-associated changes in plasma lipids, insulin like growth factor I and blood pressure: a longitudinal study. Eur J Clin Invest 1997;4:322 – 6. [8] Brochier ML, Arwidson P. Coronary heart disease risk factors in women. Eur Heart J 1998;19(Suppl. A):A45 – 52. [9] Bush TL, Fried LP, Barrett-Connor E. Cholesterol, lipoproteins and coronary heart disease in women. Clin Chem 1988;34B:B60 – 70. [10] Kannel WB. Metabolic risk factors for coronary heart disease in women: perspective from the Framingham study. Am Heart J 1987;114:413 – 9. [11] Barrett-Connor E, Grady D. Hormone replacement therapy, heart disease and other considerations. Ann Rev Public Health 1998;19:55 – 72. [12] Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992;117:1016 – 37. [13] Stampfer MJ, Colditz GA. Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev Med 1991;20:47 – 63. [14] Mattews KA, Kuller LH, Wing RR, Meilahn EN, Plantinga P. Prior to use of estrogen replacement therapy, are users healthier than nonusers. Am J Epidemiol 1996;143:971 – 8. [15] Lindquist O. Intravidual changes of blood pressure, serum lipids and body weight in relation to menstrual status: results from a prospective population study of women in Goteborg, Sweden. Prev Med 1982;11:162 – 72. [16] Anderson KM, Wilson PWF, Garrison RJ, Castelli WP. Longitudinal and secular trends in lipoprotein cholesterol measurements in a general population sample. The Framingham Offspring Study. Atherosclerosis 1987;68:59 – 66. [17] Van Beresteijn ECH, Korevaar JC, Huijbregts PCW, Schouten EG, Burema JM, Kok FJ. Perimenopausal increase in serum cholesterol: a 10-year longitudinal study. Am J Epidemiol 1993;137:383 – 92. [18] Matthews KA, Wing RR, Kuller LH, Meilahn EN, Plantinga P. Influence of the perimenopause on cardiovascular risk factors and symptoms of middle-aged healthy women. Arch Intern Med 1994;154:2349 – 55. [19] Fukami K, Koike K, Hirota K, Yoshikawa H, Miyake A. Perimenopausal changes in serum lipids and lipoproteins: a 7-year longitudinal study. Maturitas 1995;22:193 – 7. [20] Collins A, Landgren B-M. Psychosocial factors associated with the use of hormonal replacement therapy in a longitudinal follow-up of Swedish women. Maturitas 1999;28:1 – 9. [21] Do K-A, 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;151:584 – 93.
G. Hall et al. / Maturitas 41 (2002) 177–185 [22] Cooper GR, De Keersgleter W, Ezurra EJ, Rosseneu M, Shephered J, d’Arcangues C. Method Manual for Lipid, Lipoprotein and Apolipoprotein Determinations, 1989. [23] ACS, Apoteket AB. 0006 30. [24] Moorhead T, Hannaford P, Warskyj M. Prevalence and characteristics associated with use of hormone replacement therapy in Britain. Br J Obstet Gynaecol 1997;104:290 –7.
185
[25] Jensen J, Nilas L, Christiansen C. Influence of menopause on serum lipids and lipoproteins. Maturitas 1990;12:321 – 31. [26] Stevenson JC, Crook D, Godsland IF. Influence of age and menopause on serum lipids and lipoproteins in healthy women. Atheriosclerosis 1993;98:83 – 90.
Lipoproteins and BMI: a comparison between women during transition to menopause and regularly menstruating healthy women Gerd Hall a,*, Aila Collins b, Gyo¨rgy Csemiczky c, Britt-Marie Landgren a a
b
Department of Obstetrics and Gynaecology, Huddinge Uni6ersity Hospital, SE-14186 Huddinge, Sweden Department of Clinical Neuroscience, Psychiatry and Psychology Section, Karolinska Hospital, SE-171 76 Stockholm, Sweden c Department of Obstetrics and Gynaecology, Karolinska Hospital, SE-171 76 Stockholm, Sweden Received 2 January 2001; received in revised form 30 May 2001; accepted 11 June 2001
Abstract One hundred and forty-three women born 1942 were followed for 5 years during transition to menopause (49– 54 years of age). Changes in menopausal status, body mass index (BMI) and circulating lipoproteins cholesterol, (chol), low density lipoprotein (LDL), high density lipoprotein, (HDL) and total triglycerides (TG) were measured, once yearly and compared with a control group of normally menstruating healthy, non-smoking women 23 – 39 years old. Results: Chol was significantly higher PB 0.0001 in the study group visits 1 – 5 when compared with the controls and higher at visit 4 compared with visit 1 (PB 0.05) LDL was significantly lower in the study group and at visit 5 compared with visit 2 (P B0.05) HDL was significantly lower at visits 1 – 3 and 5 when compared with the controls (P B0.001) and to visit 4 (P B0.0001). TG was significantly higher in the study group (P B 0.0001) and increased significantly during the 5-year study. BMI was significantly higher in the older women (P B 0.00l) and increased during 5 years of study (PB0.0001). When multiple stepwise regression analyses were performed at visit 5 using education, menopausal status, use of hormone replacement therapy (HRT), BMI and smoking as predictor variables, postmenopausal status was found to be significantly associated with high LDL (PB 0.3), while high BMI significantly predicted low HDL and high TG levels. Perimenopausal status was significantly associated with high HDL levels. Conclusion: Age, BMI and menopausal status are significant predictors of circulating lipoprotein levels during transition to menopause. © 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Lipoproteins; BMI; Menopause
1. Introduction Menopausal transition is a period in women’s lives characterised by decreasing ovarian function. * Corresponding author.
It has been referred to as a period when changes in lipoproteins toward a more unfavourable pattern occur and as a consequence, the risk for coronary heart disease is increased [1–5]. Weight gain has also been reported during this period in life [6,7]. However, there is still no clear evidence
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 1 ) 0 0 2 5 8 - 4
G. Hall et al. / Maturitas 41 (2002) 177–185
178
that menopause and thus the decrease in circulating ovarian hormones, is a main cause of the changes in lipoprotein pattern. Other factors, such as age and life style are also important for the risk of coronary heart disease [8,9]. Weight gain, increasing age and smoking have been shown to induce unfavourable low density lipoprotein/high density lipoprotein (LDL/HDL) cholesterol (chol) ratios, and to raise total triglycerides (TG) and chol levels [6,7,10]. Hormone replacement therapy (HRT) has been shown in large epidemiological studies to protect against cardiovascular disease [11– 13]. It is still controversial whether HRT has a favourable effect on the lipoprotein pattern [14]. Furthermore, there is still a lack of knowledge of the changes in lipoproteins during transition to menopause in healthy women not seeking medical advice for climacteric symptoms. There are few longitudinal studies using community based samples and [4,15– 21] their results have been inconsistent. The aim of the present study was to follow the changes in lipoprotein pattern in a group of healthy women during transition to menopause and further to relate the changes to age and Table 1 Some sociodemographic characteristics at the first visit Number
%
Marital status Single Married Divorced Widow
7 11 22 3
5 78 15 2
Education Primary Secondary College
4 54 4
30 37 33
Employment Full-time Part-time
10 40
73 27
Occupation Higher professionals Lower professionals Service or clerical jobs Unskilled jobs House-wives Smokers
15 38 81 12 1 33
10 26 55 8 1 22
menopausal status as well as to normally menstruating women.
2. Material and methods
2.1. Study group The study group consisted of 143 women born 1942, who were followed during transition to menopause. For sociodemographic characteristics see Table 1. In an earlier phase of this population based study, 1399 healthy women, who were recruited through the Swedish population register, answered a questionnaire about general and reproductive health, use of estrogens and experience of menopausal symptoms [20]. Out of these 1399 women a random stratified sample reflecting educational level and parity was drawn. One hundred and sixty one women, who were not on HRT and not hysterectomised, received an invitation to participate in a longitudinal study including a somatic, gynaecological and psychological part. The women were 49 years old at study entry and were followed thereafter annually for a total period of 5 years. Our attitude was not to prescribe HRT if it was not demanded by the women. The HRT prescribed was transdermal estradiol at a dose of 50 mg per 24 h in combination with oral medroxy progesterone acetate (MPA) at a dose of 5 mg daily for 12 days each month. One hundred and forty-three women participated in the fifth visit. The first visit included questions about sociodemographic background, number of children and smoking habits, and about obstetric and gynaecological history and use of contraceptives. Each annual visit included general health screening, gynaecological examination, pap smear and blood sampling for lipoproteins. Mammography was offered, if not performed within 2 years. At each visit the women were asked about their menstrual status (they kept bleeding diary cards), HRT and experience of symptoms. The menstrual status was divided into five categories and defined as, premenopausal, if they had regular bleedings; perimenopausal, if they had irregular bleedings or last period within 12 months; postmenopausal if more than 12 months had passed since last period.
G. Hall et al. / Maturitas 41 (2002) 177–185 Table 2 Distribution of menopausal status in relation to consecutive visits (V1–V5) Menopausal status
Pre Pen Post HRT Hyst
Visit V1
V2
V3
V4
V5
72 56 9 10 0
56 46 18 26 1
8 56 17 58 6
10 29 22 77 9
4 16 32 82 9
Women using HRT and hysterectomised women (Table 2) formed separate groups.
2.2. Control group The control group consisted of 67 healthy, regularly menstruating non-smoking women 23– 39 years old, they had not used hormones, been pregnant or breastfeeding for at least 6 months prior to inclusion in the study. Blood for lipoproteins was drawn once in the follicular and once in the luteal phase, the mean of the two was used, since the values did not differ significantly. The women were fat fasting and rested sitting for 20 min before blood was drawn. The following lipoproteins were assessed, total chol; HDL; LDL and total TG. Blood was obtained for liver– kidney and thyroid function at the first and fifth visit in the study group.
2.3. Laboratory methods Lipoprotein levels were assessed according to the WHO Method Manual for Lipid, lipoprotein and apolipoprotein C [22]. Liver– kidney and thyroid function tests were performed at Biochemical Central Laboratory of Karolinska Hospital using standard methods.
2.4. Statistical methods Results are presented as arithmetic mean and S.D., when not appointed in the text; differences in distributions between groups were tested with 2-statistics and between means by using Stu-
179
dent’s t-statistics. Survival analysis was applied to menopause status data, where time to menopause was treated in the same way as time to death in ordinary survival analysis. The log rank test was used to test differences between groups. A multivariate stepwise regression model was developed in order to analyse the association between circulating lipoproteins and background variables that were considered important. The study was approved by the Ethics Committee of Karolinska Hospital, Stockholm, Sweden.
3. Results One hundred and sixty-one women were invited, 151 (94%) came to and 147 (91%) attended the first visit, the fifth visit was attended by 143 (89%) women. Six women moved out of town and two did not want to continue. During the study, nine women underwent hysterectomy and bilateral salphingo-oophorectomy, four due to myomas, one to endometriosis, two to endometrial and one to ovarian cancer and one to uterine sarcoma. One woman was treated for mammarian and one for kidney cancer. The women who developed cancer during the study were excluded from analyses. Serum kreatinine was within normal levels in all women (Table 3) abnormal liver enzymes were found in two women, one was treated for endometrial cancer and one was on multimedication for asthma and diabetes. Two women with hypothyreosis were treated with levo thyroxin. Other values outside the normal ranges were found in clinically healthy women. The number of women on HRT increased from ten at visit 1 (6%) to 82 (57%) at visit 5. At the first visit 72 women were premenopausal compared with four at the fifth visit (Table 2). A comparison of body mass index (BMI) between the study and control groups and between visits 1 and 5 in the study group is shown in Table 4. A significantly higher BMI was seen in the study group when compared with the control group (PB 0.0001). BMI increased significantly from visit 1 to 5 during transition to menopause (PB0.0001). In the control group 7.5% of women presented with BMI \ 27,
G. Hall et al. / Maturitas 41 (2002) 177–185
180
Table 3 Thyroid–kidney–liver function in 143 women at visit 5
S-TSH S-T-4 S-kreatinine S-ASAT S-ALAT S-bilirubin S-LP S-GT S-LD
Normal range
Mean
S.D.
Range
N-abnormal value
0.1–5.0 mE per l 60–150 mmol/l B120 mmol/l B0.60 ukat per l B0.60 ukat per l 4–22 mmol/l B4.6 ukat per l 0.80 ukat per l 3.9–8.0 ukat per l
1.90 114.95 72.24 0.51 0.48 11.25 2.53 0.48 6.40
1.45 19.21 9.29 0.17 0.21 9.07 0.71 0.58 1.18
0.01–10.00 75–204 54.00–107.00 0.29–2.13 0.23–2.26 2.30–99.00 0.90–5.30 0.20–6.60 0.00–9.90
11 2 0 19 21 5 2 8 13
compared with 21% at visit 1 and 32% at visit 5. Circulating levels of lipoproteins at visit 1– 5 in the study group and in the controls are shown in Figs. 1–4. Chol was significantly higher in the study group when compared with the controls (PB 0.0001) and at visit 4 compared with visit 1 (PB 0.0001). LDL was significantly higher in the study group, when compared with the controls (PB 0.000l). In the study group the levels were higher at visit 2 when compared with 5 (PB 0.005). HDL was significantly lower in the study group at visits 1–3 and 5 when compared with the controls. (P B0.0001), and higher at visits 3 and 4, when compared with 1, 2, and 5 (P B 0.0001). TG was significantly higher in the older women (PB 0.0001), and increased significantly during the study (PB 0.0001). When a multiple stepwise regression analyses was performed at visit 5 on chol, LDL, HDL, TG, using education, postmenopausal status, and the use of HRT, BMI and smoking as predictor variables, postmenopausal status was significantly associated with LDL, being higher in the postmenopausal women compared with pre and perimenopausal women (PB 0.3). For chol no variable had a significant role. HDL and TG was significantly predicted by BMI, heavier women having lower HDL and higher TG levels. Smoking was not significantly associated with the lipid levels. When a comparison was performed between the controls and the older (49 years) women, who were premenopausal at visit 1, the older women presented with significantly higher levels of chol, LDL and TG and lower HDL (Table 5). When
the women taking HRT were compared with postmenopausal women without HRT at the last visit no significant differences in lipoprotein patterns were observed.
4. Discussion Only a few prospective longitudinal studies have been performed in healthy women during transition to menopause [4,15–21]. The present study was population based and included 143 women from the Stockholm area who were followed for 5 years during transition to menopause from 49 to 54 years. Their BMI and lipoprotein patterns were compared with a control group of healthy normally menstruating women who were 23–39 years old. The older women were heavier at baseline than the controls and their BMI increased significantly during the study period of 5 years. Chol, LDL, and TG were higher and HDL was lower in the perimenopausal, older women. Menopausal status significantly predicted LDL with higher levels in postmenopausal women comTable 4 BMI* at visit 1 and 5 in 143 women and in 67 controls
Visit 1 Visit 5 Controls
Mean
S.D.
Range
24.2 25.8** 22.6***
93.7 94.3 90.3
17.0–38.0 18.0–39.0 19.0–30.0
*, Calculated as weight (kg), height2 (m); **, controls vs. visit 1 PB0.0001; ***, visit 1 vs. visit 5 PB0.0001.
G. Hall et al. / Maturitas 41 (2002) 177–185
181
Fig. 1. Total cholesterol serum levels at visits 1 – 5 and controls (nmol/l).
pared with pre and perimenopausal women. The lipoprotein pattern changed with increasing BMI and age. BMI was significantly associated with HDL and TG, the heavier women presented with lower HDL and higher TG. When the older regularly menstruating women at visit 1 were compared with the controls, the lipoprotein patterns differed significantly. HDL was lower, chol, LDL and TG were higher in the older women. When the postmenopausal women on HRT at visit 5 were compared with those without HRT no differences in lipoprotein pattern were found. The present study illustrates the changes in the use of HRT, which have occurred during the 90s in Sweden, an increase from approximately 30 to 86 daily doses per 1000 women, from 1987 to 1998 [23]. This made it impossible to follow the transition to menopause in all women, since HRT was prescribed to women, who were still menstruating, thus the HRT group represents a mixture of menopausal status. The lack of differences in lipoproteins between postmenopausal women
with and without HRT is in contrast to other investigators, who report a positive effect of HRT on the lipoprotein pattern [11–13,18]. This may be explained by the possible source of bias seen in earlier studies [14,24] showing that women using HRT differ in many aspects from non-users. They exercised more, were leaner and generally more concerned about their health. The findings in the present study indicate that age and BMI may be as important for the lipoprotein pattern and thus also for the risk of coronary heart disease as menopausal status, at least in women during transition to and immediately after menopause. These results are partly in agreement with those of Poehlman et al. [7] and Do et al. [21] who found that the only risk factor which changed as a consequence of menopause was HDL, in contrast to our findings that both HDL and LDL levels were related to on menopausal status. It should be pointed out, that the women were only followed for 5 years and it may be necessary to have a longer follow up. We could not find any
182
G. Hall et al. / Maturitas 41 (2002) 177–185
Fig. 2. Low density lipoproteins (LDL) levels at visit 1 – 5 and controls (nmol/l).
Fig. 3. High density lipoproteins (HDL) levels at visit 1 – 5 and controls (nmol/l).
G. Hall et al. / Maturitas 41 (2002) 177–185
183
Fig. 4. Total triglycerides (Tot. TG) levels at visit 1 – 5 and controls (nmol/l). Table 5 Lipoprotein levels in younger (23–39 years) controls and premenopausal regularly menstruating women (49 years, nmol/l, mean9 S.D.) at visit 1 and in postmenopausal women at visit 5 (54 years) without and with HRT (nmol/l, mean 9S.D.) Lipoproteins
Total chol LDL RDL TG
Controls N = 67
Visit 1 premenopausal N =70
Visit 5 postmenopausal N =32
HRT N =82
Mean
S.D.
Mean
S.D.
P-values
Mean
S.D.
Mean
S.D.
P-values
4.93 2.92 1.65 0.81
90.81 90.78 90.31 90.24
5.44 3.74 1.42 1.00
90.80 9l.02 90.30 90.39
B0.0003 B0.0001 B0.0001 B0.0007
6.18 4.10 1.50 1.26
9l.28 9l.35 90.34 90.57
5.77 3.59 1.55 1.20
90.82 90.99 90.37 90.58
n.s. n.s. n.s. n.s.
possible explanation for the higher HDL levels at visit 4 as compared with the other occasions. Our findings are also in agreement with those of Matthews et al. [4] who followed a cohort of healthy middle-aged premenopausal women through to menopause and Fukami et al. [19] who reported a follow up study of 7 years. However, the study involved only 16 women. Andersson et al. [16] measured lipoproteins twice in 8 years and only found an increase in HDL, however, the definition of menopause was inadequate. Smoking did not play a significant role for the lipids. We
are carrying out further analyses of the relationship between life style factors and weight changes in this sample. Previous reports on TG have been inconsistent, some reporting an increase [15,25] and others no change [16,17], which may be explained by the study designs and definitions of menopause. Stevenson et al. [26] found that menopause, independent of age, was associated with adverse changes in lipids and lipoproteins. However, the study was cross sectional and involved women with a wide age range (18– 70 years).
184
G. Hall et al. / Maturitas 41 (2002) 177–185
In our study, it seems that age and menstrual status are the main cause for changes in lipoproteins. There is ample evidence that HRT has a positive effect on vasomotor symptoms and osteoporosis. The studies on prevention of coronary heart disease are inconclusive as well as the studies on Alzheimers disease and until further proof is shown on these issues it does not seem adequate to recommend HRT on those indications. Ageing itself is a great risk factor for different illnesses as well as hereditary factors, smoking, alcohol intake, diet and exercise. We should not withhold HRT from women who wish to use HRT for different reasons but we should not try to convince an otherwise healthy woman to use HRT for reasons we still have incomplete knowledge about. In summary the results of the present study indicate that BMI and menopausal status are important for the lipoprotein pattern in middle aged women.
Acknowledgements The study was funded by a grant from Riksbankens Jubileumsfond.
References [1] Tre´ mollie`res FA, Pouilles J-M, Cauneille C, Ribot C. Coronary heart disease risk factors and menopause: a study in 1684 French women. Atheriosclerosis 1999;142:415 – 23. [2] Mosinger BJ. Human low-density lipoproteins: oxidative modification and its relation to age, gender, menopausal status and cholesterol concentrations. Eur J Clin Chem Clin Biochem 1997;35:207 –14. [3] Lindquist O, Bengtsson C, Lapidus L. Relationships between the menopause and risk factors for ischaemic heart disease. Acta Obstet Gynecol Scand Suppl 1985;130:43 –7. [4] Matthews KA, Meilahn E, Kuller LH, Kelsey SF, Caggiula AW, Wing RR. Menopause and risk factors for coronary heart disease. New Engl J Med 1989;10:641 – 6. [5] Schaefer EJ, Lamon-Fava S, Cohn SD, Schaefer MM, Ordovas JM, Castelli WP, Wilson PWF. 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;35:779 – 92.
[6] Razay G, Heaton KW, Bolton CH. Coronary heart disease risk factors in relation to the menopause. Quart J Med New Ser 1992;85:307 – 8, 889 – 96. [7] Poehlman ET, Toth MF, Ades PA, Rosen CJ. Menopause-associated changes in plasma lipids, insulin like growth factor I and blood pressure: a longitudinal study. Eur J Clin Invest 1997;4:322 – 6. [8] Brochier ML, Arwidson P. Coronary heart disease risk factors in women. Eur Heart J 1998;19(Suppl. A):A45 – 52. [9] Bush TL, Fried LP, Barrett-Connor E. Cholesterol, lipoproteins and coronary heart disease in women. Clin Chem 1988;34B:B60 – 70. [10] Kannel WB. Metabolic risk factors for coronary heart disease in women: perspective from the Framingham study. Am Heart J 1987;114:413 – 9. [11] Barrett-Connor E, Grady D. Hormone replacement therapy, heart disease and other considerations. Ann Rev Public Health 1998;19:55 – 72. [12] Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992;117:1016 – 37. [13] Stampfer MJ, Colditz GA. Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev Med 1991;20:47 – 63. [14] Mattews KA, Kuller LH, Wing RR, Meilahn EN, Plantinga P. Prior to use of estrogen replacement therapy, are users healthier than nonusers. Am J Epidemiol 1996;143:971 – 8. [15] Lindquist O. Intravidual changes of blood pressure, serum lipids and body weight in relation to menstrual status: results from a prospective population study of women in Goteborg, Sweden. Prev Med 1982;11:162 – 72. [16] Anderson KM, Wilson PWF, Garrison RJ, Castelli WP. Longitudinal and secular trends in lipoprotein cholesterol measurements in a general population sample. The Framingham Offspring Study. Atherosclerosis 1987;68:59 – 66. [17] Van Beresteijn ECH, Korevaar JC, Huijbregts PCW, Schouten EG, Burema JM, Kok FJ. Perimenopausal increase in serum cholesterol: a 10-year longitudinal study. Am J Epidemiol 1993;137:383 – 92. [18] Matthews KA, Wing RR, Kuller LH, Meilahn EN, Plantinga P. Influence of the perimenopause on cardiovascular risk factors and symptoms of middle-aged healthy women. Arch Intern Med 1994;154:2349 – 55. [19] Fukami K, Koike K, Hirota K, Yoshikawa H, Miyake A. Perimenopausal changes in serum lipids and lipoproteins: a 7-year longitudinal study. Maturitas 1995;22:193 – 7. [20] Collins A, Landgren B-M. Psychosocial factors associated with the use of hormonal replacement therapy in a longitudinal follow-up of Swedish women. Maturitas 1999;28:1 – 9. [21] Do K-A, 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;151:584 – 93.
G. Hall et al. / Maturitas 41 (2002) 177–185 [22] Cooper GR, De Keersgleter W, Ezurra EJ, Rosseneu M, Shephered J, d’Arcangues C. Method Manual for Lipid, Lipoprotein and Apolipoprotein Determinations, 1989. [23] ACS, Apoteket AB. 0006 30. [24] Moorhead T, Hannaford P, Warskyj M. Prevalence and characteristics associated with use of hormone replacement therapy in Britain. Br J Obstet Gynaecol 1997;104:290 –7.
185
[25] Jensen J, Nilas L, Christiansen C. Influence of menopause on serum lipids and lipoproteins. Maturitas 1990;12:321 – 31. [26] Stevenson JC, Crook D, Godsland IF. Influence of age and menopause on serum lipids and lipoproteins in healthy women. Atheriosclerosis 1993;98:83 – 90.