Combined hormone replacement therapy improves lipids but may increase leucocytes

Abstract

Dear Sir, Recent clinical trial data have cast doubt on the efficacy of oral hormone replacement therapy (HRT) for decreasing cardiovascular events. One of the postulated mechanisms is the upregulation of inflammation leading to accelerated atherosclerosis, plaque instability or thrombosis. Thus, plasma C-reactive protein levels increase during HRT, an effect that is attenuated with statin therapy [1]. On the other hand, some markers of inflammation may be reduced with HRT therapy, including levels of cell adhesion molecules [2], whilst other markers seem not to be influenced by HRT [3]. In a randomized, double-blind, controlled study, we evaluated the efficacy of continuous combined HRT with 1 mg oestradiol and 0.5 mg norethisterone acetate (Activelle®, Novo Nordisk A/S, Bagsvaerd, Denmark) compared with placebo in lowering total and LDL cholesterol levels in women at high risk for cardiovascular disease (CVD). The subjects were postmenopausal women aged 40–75 years (mean 64 years) with LDL cholesterol levels ≥4.1 mmol L−1. All had at least one other CVD risk factor. Major exclusions were the standard ones for the use of HRT. All provided written informed consent and the study was approved by the regional ethics committee. Subjects (n = 113) were treated with a cholesterol-lowering diet for 14 weeks and continued the diet throughout. If LDL cholesterol levels remained ≥4.1 mmol L−1 at week 5, they started therapy with cerivastatin 300 μg at week 6. At week 14, subjects were randomized to HRT or matching placebo. Combined oestrogen and progestin was provided in one daily tablet containing oestradiol 1 mg and norethisterone acetate 0.5 mg. HRT or placebo was planned to continue for 36 weeks. However, due to withdrawal of cerivastatin in August 2000, the study was stopped prematurely. At that time 23 subjects had received HRT or placebo for 12 weeks or more. Laboratory samples were obtained after an overnight fast. Total cholesterol and triglyceride concentrations were measured using automated analyser equipments (Hitachi 911; Hitachi Limited, Tokyo, Japan) and reagents from Boehringer Mannheim (Mannheim, Germany). HDL cholesterol concentrations were measured on a Hitachi 911 analyzer using the direct, enzymatic inhibition assay of Boehringer Mannheim. LDL cholesterol was calculated using the Friedewald formula. Standard methods were used to determine liver transaminase, creatinine, erythrocyte, platelet and leucocyte counts. Analyses were performed at the Department of Clinical Chemistry, Ullevål University Hospital, Oslo, Norway. For statistical analyses, an analysis of covariance model was used with the change from randomization to week 12 as response, group as fixed factor and the values at randomization as covariate. The mean difference between groups over the randomized period, P-values for the between-group comparison and 95% confidence intervals were calculated using the Statistical Analysis System version 6.12 (SASTM; SAS, Cary, NC, USA). Continuous combined HRT reduced total cholesterol by 0.7 mmol L−1 (95% CI, −1.1, −0.3) or 14% and LDL cholesterol levels by 0.6 mmol L−1 (95% CI, −1.0, −0.1) or 20% (Table 1). Levels of HDL cholesterol were also reduced by 0.3 mmol L−1 (95% CI, −0.4, −0.1) or 14%. Levels of glucose, liver transaminases, creatinine, erythrocytes and platelets did not differ between the groups (data not shown). However, levels of leucocytes increased in the HRT group compared with placebo after adjustment for baseline levels (mean difference 0.7 × 109 L−1, 95% CI, 0.3–1.2). In this study HRT resulted in a further reduction in total and LDL cholesterol levels, in addition to the reduction due to the combination of diet and cerivastatin. However, HDL cholesterol levels were reduced and the leucocyte count increased. The effects of HRT on lipid levels are in accordance with earlier data. Whilst therapy with oestrogen alone reduces total and LDL cholesterol and increases HDL cholesterol, the addition of a gestagen, in particular when the gestagen is taken continuously, has a deleterious effect on HDL cholesterol. However, the leucocyte count increased. In a previous study conducted amongst women with diabetes, the leucocyte count did not change during treatment with conjugated equine oestrogen plus medroxyprogesterone acetate for 6 months [2]. Differences between trials may be due to the type of HRT that is used, subject characteristics or other variables. Our finding may be the result of chance as the number of participants was low. However, the relationship between HRT use and leucocyte count warrants further investigation. No conflict of interest was declared. This study was supported by a research grant from Novo Nordisk.