The risk of coronary artery disease increases in women after menopause. This increased risk may be associated with alterations in the lipid profile characterized by changes in LDL particle size and buoyancy. Characterization of lipoprotein levels and LDL buoyancy across the stages of the menopausal transition has yet to be reported.
Methods
Plasma lipoprotein concentrations, LDL buoyancy, and body mass index (BMI) were studied cross-sectionally in five groups of women: premenopausal women (n=42), women in early menopausal transition (n=35), middle menopausal transition (n=19), late menopausal transition (n=20), and postmenopausal women (n=14). No women were taking estrogen.
Results
The postmenopausal women had significantly higher low-density lipoprotein cholesterol (LDL-C) and total cholesterol than premenopausal women (P<0.05). LDL-C and Apo B was significantly higher in women in the late menopausal transition compared to premenopausal women (P<0.05). All women in the menopausal transition and postmenopause had significantly more dense LDL than premenopausal women (P<0.05). Multiple regression analysis revealed that the change in LDL buoyancy associated with the menopausal transition period could be explained by changes in triglyceride and HDL-C, related to changes in body mass index.
Conclusions
These data suggest that the menopausal transition is associated with more dense LDL and higher LDL-C levels in comparison to premenopausal women. It appears that whereas LDL-C may change late in the menopausal transition, the production of denser LDL particles appears early in the menopausal transition, both acting to worsen the lipoprotein profile. Increased triglyceride and decreased HDL appeared to account for the shift toward small, dense LDL, presumably related to increased BMI. The change in LDL density may contribute to the higher incidence of atherosclerosis in postmenopausal women.
KannelWB, HjortlandMC, McNamaraPM, GordonT.Menopause and risk of cardiovascular disease: the Framingham study. Ann Intern Med1976;85:447–452.
2.
HjortlandMC, McNamaraPM, KannelWB.Some atherogenic concomitants of menopause: the Framingham Study. Am J Epidemiol1976;103:304–311.
3.
GardnerCD, FortmannSP, KraussRM.Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women. JAMA1996;276:875–881.
4.
CamposH, McNamaraJR, WilsonPW, OrdovasJM, SchaeferEJ.Differences in low density lipoprotein subfractions and apolipoproteins in premenopausal and postmenopausal women. J Clin Endocrinol Metab1988;67:30–35.
5.
MatthewsKA, MeilahnE, KullerLH, KelseySF, CaggiulaAW, WingRR.Menopause and risk factors for coronary heart disease. N Engl J Med1989;321:641–646.
6.
LiZ, McNamaraJR, FruchartJC, LucG, BardJM, OrdovasJM, WilsonPW, SchaeferEJ.Effects of gender and menopausal status on plasma lipoprotein subspecies and particle sizes. J Lipid Res1996;37: 1886–1896.
7.
AustinM, BreslowJ, HennekensC, BuringJ, WillettW, KraussR.Low-density lipoprotein subclass patterns and risk of myocardial infarction. JAMA1988;260:1917–1921.
8.
CapellWH, ZambonA, AustinMA, BrunzellJD, HokansonJE.Compositional differences of LDL particles in normal subjects with LDL subclass phenotype A and LDL subclass phenotype B. Arterioscler Thromb Vasc Biol1996;16:1040–1046.
9.
AustinMA, KingMC, VranizanKM, KraussRM.Atherogenic lipoprotein phenotype. A proposed genetic marker for coronary heart disease risk. Circulation1990:82:495–506.
10.
CrouseJ, ParksJ, ScheyH, KahlF.Studies of low density lipoprotein molecular weight in human beings with coronary artery disease. J Lipid Res1985;26:566–574.
11.
CamposH, GenestJJ, BlijlevensE, McNamaraJR, JennerJL, OrdovasJM, WilsonPW, SchaeferEJ.Low density lipoprotein particle size and coronary artery disease. Arterioscler Thromb1992;12:187–195.
12.
CoreshJ, KwiterovichPJ, SmithH, BachorikP.Association of plasma triglyceride and LDL particle diameter, density and chemical composition with premature coronary artery disease in men and women. J Lipid Res1993;34:1687–1697.
13.
GriffinBA, FreemanDJ, TaitGW, ThomsonJ, CaslakeMJ, PackardCJ, ShepherdJ.Role of plasma triglyceride in the regulation of plasma low density lipoprotein (LDL) subfractions: relative contribution of small, dense LDL to coronary heart disease risk. Atherosclerosis1994;106:241–253.
14.
AustinM, KingM-C, VranizanK, NewmanB, KraussR.Inheritance of low density lipoprotein subclass patterns: results of complex segregation analysis. Am J Hum Genet1988;43:838–846.
15.
AustinM.Genetics of LDL subclass phenotypes. Curr Opin Lipidol1993;4:125–131.
16.
SchaeferEJ, Lamon-FavaS, CohnSD, SchaeferMM, OrdovasJM, CastelliWP, WilsonPW.Effects of age, gender, and menopausal status on plasma low density lipoprotein cholesterol and apolipoprotein B levels in the Framingham Offspring Study. J Lipid Res1994;35: 779–792.
17.
MitchellES, WoodsNF.Symptom experiences of midlife women: observations from the Seattle Midlife Women's Health Study. Maturitas1996;25:1–10.
18.
ChungBH, WilkinsonT, GeerJC, SegrestJP.Preparative and quantitative isolation of plasma lipoproteins: rapid, single discontinuous density gradient ultracentrifugation in a vertical rotor. J Lipid Res1980; 21:284–291.
19.
HokansonJ, AustinM, BrunzellJ.Measurement and clinical significance of low-density lipoprotein subclasses. In: RifaiN, WarnickG, DominiczakM, eds. Handbook of lipoprotein testing. Vol. 1. Washington, DC: AACC Press; 1997:267–282.
20.
ZambonA, AustinMA, BrownBG, HokansonJE, BrunzellJD.Effect of hepatic lipase on LDL in normal men and those with coronary artery disease. Arterioscler Thromb1993;13:147–153.
21.
WarnickGR.Enzymatic methods for quantification of lipoprotein lipids. Methods Enzymol1986;129:101–123.
22.
MarcovinaSM, AlbersJJ, DatiF, LedueTB, RitchieRF.International Federation of Clinical Chemistry standardization project for measurements of apolipoproteins A-I and B. Clin Chem1991;37: 1676–1682.
23.
CamposH, SacksFM, WalshBW, SchiffI, O'HanesianMA, KraussRM.Differential effects of estrogen on low-density lipoprotein subclasses in healthy postmenopausal women. Metabolism1993;42: 1153–1158.
24.
PEPI. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI Trial. [published correction appears in JAMA 1995 Dec 6;274: 1676]. JAMA1995;273:199–208.
25.
SantamarinaF-S, HaudenschildC, AmarM.The role of hepatic lipase in lipoprotein metabolism and atherosclerosis. Curr Opin Lipidol1998;9:211–219.
26.
Applebaum-BowdenD, HaffnerSM, WahlPW, HooverJJ, WarnickGR, AlbersJJ, HazzardWR.Postheparin plasma triglyceride lipases. Relationships with very low density lipoprotein triglyceride and high density lipoprotein cholesterol. Arteriosclerosis1985;5:273–282.
27.
ColvinPLJr, AuerbachBJ, CaseLD, HazzardWR, Applebaum-BowdenD.A dose-response relationship between sex hormone-induced change in hepatic triglyceride lipase and high-density lipoprotein cholesterol in postmenopausal women. Metabolism1991;40:1052–1056.
28.
TikkanenMJ, KuusiT, NikkilaEA, StenmanUH.Variation of postheparin plasma hepatic lipase by menstrual cycle. Metabolism1986; 35:99–104.
29.
Tilly-KiesiM, PuolakkaM, LuotolaJ, PyoralaH, TaskinenT, MR. Different effects of continuous oestrogen-progestin and transdermal oestrogen with cyclic progestin regimens on low-density lipoprotein subclasses. Eur J Clin Invest1996;26:1125–1133.
30.
TikkanenMJ, NikkilaEA, VartiainenE.Natural oestrogen as an effective treatment for type-II hyperlipoproteinaemia in postmenopausal women. Lancet1978;2:490–491.
31.
TikkanenMJ, NikkilaEA, KuusiT, SipinenSU.High density lipoprotein-2 and hepatic lipase: reciprocal changes produced by estrogen and norgestrel. J Clin Endocrinol Metab1982;54:1113–1117.
32.
HokansonJE, ZambonA, CapellWC, BrunzellJD.Small, dense LDL is associated with low lipoprotein lipase and high hepatic lipase activities, and alterations in IDL and VLDL composition. Atherosclerosis1997;134:25. Abstract.
33.
ZambonA, HokansonJE, BrownBG, BrunzellJD.Evidence for a new pathophysiological mechanism for coronary artery disease regression: hepatic lipase-mediated changes in LDL density. Circulation1999;99:1959–1964.
34.
CarrMC, HokansonJE, DeebSS, PurnellJQ, MitchellES, BrunzellJD.A hepatic lipase gene promoter polymorphism attenuates the increase in hepatic lipase activity with increasing intra-abdominal fat in women. Arterioscler Thromb Vasc Biol1999;19:2701–2707.
35.
PoehlmanET, TothMJ, GardnerAW.Changes in energy balance and body composition at menopause: a controlled longitudinal study. Ann Intern Med1995;123:673–675.
36.
LeyCJ, LeesB, StevensonJC.Sex- and menopause-associated changes in body-fat distribution. Am J Clin Nutr1992;55:950–954.
37.
Despr´esJP, FerlandM, MoorjaniS, NadeauA, TremblayA, LupienPJ, Th´eriaultG, BouchardC.Role of hepatic-triglyceride lipase activity in the association between intra-abdominal fat and plasma HDL cholesterol in obese women. Arteriosclerosis1989;9:485–492.
38.
SelbyJV, AustinMA, NewmanB, ZhangD, QuesenberryCPJr, MayerEJ, KraussRM.LDL subclass phenotypes and the insulin resistance syndrome in women. Circulation1993;88:381–387.
GambertP, Bouzerand-GambertC, AthiasA, FarnierM, LallemantC.Human low density lipoprotein subfractions separated by gradient gel electrophoresis: composition, distribution, and alterations induced by cholesteryl ester transfer protein. J Lipid Res1990;31: 1199–1210.
41.
BagdadeJD, RitterMC, SubbaiahPV.Accelerated cholesteryl ester transfer in plasma of patients with hypercholesterolemia. J Clin Invest1991;87:1259–1265.
42.
HulleyS, GradyD, BushT, FurbergC, HerringtonD, RiggsB, VittinghoffE.Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) research group. JAMA1998;280:605–613.
43.
StampferMJ, WillettWC, ColditzGA, RosnerB, SpeizerFE, HennekensCH.A prospective study of postmenopausal estrogen therapy and coronary heart disease. N Engl J Med1985;313:1044–1049.
44.
BushTL, Barrett-ConnorE, CowanLD, CriquiMH, WallaceRB, SuchindranCM, TyrolerHA, RifkindBM.Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the Lipid Research Clinics Program Follow-up Study. Circulation1987;75: 1102–1109.
