Atherosclerosis 150 2000 103 – 111
Effects of combination therapy with estrogen plus simvastatin on lipoprotein metabolism in postmenopausal women with type IIa
hypercholesterolemia
Akihiko Wakatsuki , Yuji Okatani, Nobuo Ikenoue
Department of Obstetrics and Gynecology, Kochi Medical School, Oko cho, Nankoku, Kochi
783
-
8505
, Japan Received 12 March 1999; received in revised form 26 July 1999; accepted 18 August 1999
Abstract
We investigated the effects of estrogen and simvastatin, administered both alone and in combination, on the plasma lipid levels and lipoprotein-related enzymes in 45 postmenopausal women with type IIa hypercholesterolemia. They received 0.625 mg
conjugated equine estrogen n = 15, 5 mg simvastatin n = 15, or the combination n = 15 daily for 3 months. We measured the concentrations of cholesterol and triglyceride in the plasma, and in the very low-density lipoprotein VLDL, intermediate-density
lipoprotein IDL, low-density lipoprotein LDL1 1.019 B d B 1.045 gml and LDL2 1.045 B d B 1.063 gml, and high-density lipoprotein HDL2 1.063 B d B 1.125 gml and HDL3 1.125 B d B 1.210 gml subfractions, and apolipoproteins, and the
activities of lipoprotein-metabolizing enzyme before and after treatment. All three treatments significantly lowered the plasma levels of total cholesterol, LDL1 cholesterol, and apolipoprotein B, C-II, and E. In combination therapy, significantly reduced
levels of VLDL, IDL, and LDL2 cholesterol were also obtained. Combination therapy lowered total and LDL1 cholesterol significantly more than did estrogen alone. Estrogen and combination therapy significantly increased the levels of cholesterol in
the HDL2 subfraction, triglyceride in the HDL2 and HDL3 subfractions, and apolipoprotein A-I and A-II. Estrogen treatment, but not combination therapy, also significantly raised the levels of total and IDL triglyceride. Estrogen and combined therapies
significantly lowered the activities of hepatic triglyceride lipase and lecithin cholesterol acyltransferase. Findings indicate that combination therapy with estrogen plus simvastatin favorably affected lipid metabolism by reducing the concentrations of VLDL
and IDL particles as well as large and small LDL particles, increasing the concentration of HDL particles, and preventing estrogen-induced increases in plasma triglyceride levels. © 2000 Elsevier Science Ireland Ltd. All rights reserved.
Keywords
:
Estrogen; Simvastatin; Combination; Very low-density lipoprotein; Low-density lipoprotein; High-density lipoprotein; Postmenopausal women
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1. Introduction
Low-density lipoprotein LDL, a major cholesterol Ch-carrying lipoprotein in the plasma, is implicated in
the formation of atherosclerotic lesions. In women, the plasma levels of LDL cholesterol LDL-Ch increase
after menopause [1], resulting in age-related increase in the susceptibility to coronary heart disease [2]. We
previously demonstrated that in both postmenopausal and oophorectomized women, the decrease in the
plasma concentration of estrogen leads to an enhanced activity of lipoprotein lipase LPL, which may increase
the plasma LDL concentration [3]. Arca et al. suggested that hypercholesterolemia in postmenopausal women is
due to an impairment of the LDL receptor [4]. High-density lipoprotein HDL is regarded as a
protective factor against coronary heart disease, be- cause HDL particles remove cholesterol from the foam
cells and transport it to the hepatocytes. According to Jensen et al., the plasma level of HDL-cholesterol
HDL-Ch decreased after menopause [5]. However, our previous study demonstrated that the plasma level
of HDL-Ch did not change significantly after either natural or surgically induced menopause [6].
We previously also found that estrogen replacement therapy favorably affects lipid metabolism by reducing
the plasma concentration of LDL particles and increas-
Corresponding author. Tel.: + 81-888-80-2382; fax: + 81-888-80- 2384.
0021-915000 - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 0 2 1 - 9 1 5 0 9 9 0 0 3 5 0 - 0
ing that of HDL particles [6]. Other studies also demonstrated, however, that estrogen stimulates the
hepatic production of very low-density lipoprotein VLDL which, like LDL, is considered an atherogenic
lipoprotein particle [7]. In addition, estrogen induces hypertriglyceridemia, which is associated with an in-
creased incidence of coronary heart disease [8]. Plasma triglyceride TG levels are closely related to the size of
the LDL particles [9]. Thus, the smaller, denser LDL particles are associated with an increased risk of coro-
nary heart disease [10]. We previously reported that estrogen-induced hypertriglyceridemia may lead to a
reduction in the size of LDL particles and an increased prevalence of LDL subclass pattern B [11], which con-
sists of particles having diameters less than 25.5 nm and which is strongly associated with an increased risk for
atherosclerosis [10]. Campos et al. reported [12] that estrogen therapy decreases the proportion of large, but
not of small, LDL particles.
The National Cholesterol Education Program [13] and the Japanese Atherosclerosis Society [14] have
stated the indications and goals of dietary or drug therapy for hypercholesterolemia based on the patients’
plasma levels of total-Ch and LDL-Ch. The estrogen- induced reduction in plasma LDL-Ch is less than 20
[6].
We previously
demonstrated that
in post-
menopausal women with moderate to severe hyperc- holesterolemia, it may be difficult to achieve target
levels of total-Ch or LDL-Ch in the plasma by estrogen therapy alone [15], especially since the estrogen-induced
reduction in LDL-Ch is less than 20.
Simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, effectively reduces the plasma
concentrations of VLDL and intermediate-density lipo- protein IDL, as well as of LDL [16]. Simvastatin has
also been shown to reduce plasma total-TG levels in patients with hypertriglyceridemia [17]. Simvastatin
slightly increases the plasma levels of HDL-Ch [18]. Combination with estrogen plus simvastatin may
provide
additional favorable
effects on
lipid metabolism.
The present study investigated the effects of estrogen and simvastatin, alone and in combination, on the
plasma lipid levels and the activities of enzymes in- volved in lipoprotein metabolism in postmenopausal
women with type IIa hypercholesterolemia.
2. Materials and methods