Effect of the Combination of Methyltestosterone and Esterified Estrogens Compared With Esterified Estrogens Alone on Apolipoprotein CIII and Other High-Density Lipoproteins in Surgically Postmenopausal Women

Abstract

High plasma triglycerides are an independent risk factor for coronary heart disease (CHD), and levels are reduced by androgens. Methyltestosterone, when combined with esterified estrogens, reportedly relieves vasomotor symptoms in postmenopausal women and also improves sexual function and quality of life. Triglycerides are carried in plasma on very-low-density (VLDL) and low-density (LDL) lipoprotein. Apolipoprotein CIII (apoCIII), a strong risk factor for CHD, impairs the metabolism of both VLDL and LDL, thereby contributing to elevated triglycerides. This study evaluated a daily oral 2.5-mg dose of methyltestosterone, added to 1.25 mg esterified estrogens daily, on levels of lipoproteins and apolipoproteins, particularly those containing apoCIII. This regimen was compared with esterified estrogens alone, in the same dose, in a 10-week trial following a randomized, double-blind design. Forty surgically postmenopausal women assigned to combination treatment were compared with 39 others given esterified estrogen alone. The groups were similar in age, body mass index, and follicle-stimulating hormone levels at the outset. Women on combined treatment had significant increases in both free and bioavailable testosterone, estradiol, and weakly bound estradiol at 8 weeks and significant decreases in estrone, total estradiol, and sex hormone-binding globulin (SHBG). With combination treatment, changes in weakly bound estradiol correlated inversely with changes in total apoCIII, HDL-apoCIII, and LDL-apoCIII. Changes in estrone and SHBG were positively related to triglyceride levels, and changes in SHBG also correlated with LDL-apoCIII. None of the lipoprotein changes correlated significantly with changes in serum testosterone. Compared with esterified estrogen alone, combination treatment lowered plasma total triglycerides by 11%, total cholesterol by 10%, and HDL cholesterol by 24%. Other effects were significant decreases in apoCI by 13%, in apoCII by 14%, in apoCIII by 14%, and in apolipoprotein E by 13%. Levels of apolipoprotein B did not change significantly. In the combined treatment group, apoCIII decreased significantly by 62%, 35%, and 17% in VLDL, LDL, and HDL, respectively, compared with treatment with esterified estrogen only (Fig. 1). Methyltestosterone plus esterified estrogen did not alter levels of VLDL or LDL that lacked apoCIII. There were no between-group differences in adverse effects such as headache, acne, and breast pain.Fig. 1: ApoCIII concentrations in lipoprotein subfractions: effect of the combination of methyltestosterone and esterified estrogens compared with that of esterified estrogens alone. The mean change from baseline is shown. P values are computed by unpaired t tests of the differences in the 2 groups. ApoCIII concentrations were measured in the VLDL and LDL apoCIII+ particles, ie, those that were retained by anti-apoCIII immunoaffinity chromatography. ApoCIII was measured in the total HDL. Reproduced with permission. J Clin Endocrinol Metab 2004;89:2207–2213. Copyright 2004, Endocrine Society. All rights reserved.It appears that adding methyltestosterone to esterified estrogen in postmenopausal women has favorable effects on lipoprotein-related risk factors, in particular apoCIII concentrations in VLDL and LDL—a predictor of CHD. Methyltestosterone may lower plasma triglycerides through a reduction in apoCIII.