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 ...
