Mechanisms Regulating LDL Metabolism in Subjects on Peroral and Transdermal Estrogen Replacement Therapy

Abstract

Abstract-To study the mechanisms of low density lipoprotein (LDL) cholesterol lowering by peroral and transdermal estrogen replacement therapy (ERT), 79 hysterectomized postmenopausal women aged 48 to 62 years were randomized in a double-blind double-dummy trial to receive either peroral estradiol valerate (2 mg/d) or transdermal estradiol gel (1 mg/d) for 6 months. Plasma LDL cholesterol decreased from 4.19Ϯ0.83 (meanϮSD) to 3.39Ϯ0.78 mmol/L (PϽ0.001) in the peroral group and from 4.11Ϯ0.86 to 3.72Ϯ0.78 mmol/L (PϽ0.001) in the transdermal estrogen group. Peroral estrogen did, but transdermal treatment did not, enhance the fractional catabolic rate (FCR) and production of LDL apolipoprotein B (apoB). However, the decrease of LDL cholesterol was related to an increase in FCR for LDL apoB on both peroral and transdermal ERT (rϭϪ0.645, PϽ0.001 and rϭϪ0.627, PϽ0.001, respectively). These changes were associated with changes in the serum estrogen level. Both therapies reduced absorption of dietary cholesterol by 6% to 10% (PϽ0.05). The effects of estrogen were not modified by the polymorphisms of apoE and apoB or cholesterol 7␣-hydroxylase. In conclusion, the ERT-induced LDL cholesterollowering effect is related to changes in estrogen level, which presumably enhance LDL receptor activity, which is manifested as an increase in FCR for LDL apoB. The small decrease in the absorption efficiency of dietary cholesterol does not seem to contribute largely to the cholesterol lowering on either transdermal or peroral ERT. Key Words: estrogen replacement therapy Ⅲ LDL cholesterol Ⅲ menopause Ⅲ lipids A ccording to observational studies, up to 50% of cardiovascular mortality in postmenopausal women could be prevented by postmenopausal hormone replacement therapy (HRT). 1,2 However, a recent randomized secondary prevention study was not able to confirm these results. 3 At any rate, menopause is related to unfavorable alterations in lipids and lipoproteins. 4,5 The beneficial changes in lipids and lipoproteins observed during HRT in several previous studies have been assumed to explain 25% to 50% of the reduced cardiovascular risk. 1 Peroral estrogens decrease total and LDL cholesterol and Lp(a) and increase HDL cholesterol but also triglycerides, whereas less marked reduction in total and LDL cholesterol and no change in Lp(a), HDL cholesterol, and triglyceride levels have been observed during transdermal estrogen treatments. 6,7 The underlying mechanisms of action of estrogen administered via various routes are poorly known. The serum estrogen level is varied by the estrogen regimen and the route of estrogen administration. 8,9 After peroral administration, high levels of estradiol are catabolized into estrone, which induces protein synthesis in the liver. 10 When the transdermal route is used, induction of hepatic first-pass metabolism can be avoided, and a more physiological estrone/estradiol ratio is achieved. 11 Mainly based on animal studies 12,13 or the use of pharmacological doses of estrogen in prostate cancer, 14 the ...

Characterization of metabolic interrelationships and in silico phenotyping of lipoprotein particles using self-organizing maps

“…Here, we focus on an extensive set of UCF-based lipoprotein data in which the apoB particles were isolated as VLDL, IDL, and LDL fractions and the HDL particles separated to HDL 2 and HDL 3 (18)(19)(20). The use of UCF is tedious and expensive and thus, most often only the total HDL fraction is physically isolated and the IDL fraction might not be separately spun.…”

“…2 ; for example, the samples with highest concentrations of VLDL lipids are clustion at 1200-1500 g for 10-15 min at 4°C. The lipoprotein fractions were isolated from plasma by sequential UCF using density ranges of <1.006 g/ml for VLDL, 1.006-1.019 g/ml for IDL, 1.019-1.063 g/ml for LDL, 1.063-1.125 g/ml for HDL 2 , and 1.125-1.210 g/ml for HDL 3 (18)(19)(20). The lipoprotein fractions were isolated from fresh plasma samples and the lipid and protein analyses were commenced immediately after isolation of each fraction.…”

“…, using gradient gel electrophoresis or nuclear magnetic resonance spectroscopy) and therefore, the chemical composition of the particles remains unknown ( 7,36 ). In analytical lipid biochemistry, sequential ultracentrifugation is the gold standard for physical lipoprotein isolation allowing for subsequent analyses of the molecular composition of the particles (18)(19)(20). However, the UCFbased lipoprotein work is most often restricted regarding the analyzed subfractions.…”

“…For some individuals, more than one sample was included from separate blood collections with a typical time interval of 6 months. The study population consisted of heavy alcohol drinkers (40%) ( 19 ), hysterectomised postmenopausal women on estrogen replacement therapy (41%) ( 20 ), and apparently healthy control individuals (19%) ( 19 ), thereby representing a wide range of plasma lipoprotein lipid values. The phenotypic characteristics of the study population are discussed in supplementary information I.…”

“…However, the molecular composition as well as the metabolic and structural interrelationships between lipoprotein particles are often hampered due to limited measurement data available and the molecular complexity of lipoprotein metabolism. Physical isolation of lipoproteins by sequential ultracentrifugation (UCF) is common to measure plasma lipoprotein concentrations ( 17 ) but most studies are restricted regarding the analyzed subpopulations and detailed attention is rarely paid to the molecular composition of the isolated particles.Here, we focus on an extensive set of UCF-based lipoprotein data in which the apoB particles were isolated as VLDL, IDL, and LDL fractions and the HDL particles separated to HDL 2 and HDL 3 (18)(19)(20). The use of UCF is tedious and expensive and thus, most often only the total HDL fraction is physically isolated and the IDL fraction might not be separately spun.…”