HYPERCHOLESTEROLEMIA IN POSTMENOPAUSAL WOMEN - METABOLIC DEFECTS AND RESPONSE TO LOW-DOSE LOVASTATIN

Objective.-To determine the metabolic mechanisms underlying hypercholesterolemia in postmenopausal women and to determine whether a low dose of lovastatin will correct this abnormality. Design.-In the first part of the study, turnover rates of autologous low-density lipoprotein (LDL) were measured in hypercholesterolemic and control women. In the second part, hypercholesterolemic women participated in a placebo-controlled, randomized, double-blind study using lovastatin as the therapeutic agent. Setting.-The General Clinical Research Center of the University of Texas Southwestern Medical Center, Dallas, utilizing inpatient and outpatient facilities, and the Veterans Affairs Medical Center, Dallas, Tex. Patients.-For the LDL turnover study, 26 postmenopausal women with moderate hypercholesterolemia (mean+/-SD LDL cholesterol, 4.78+/-0.59 mmol/L [185 +/-23 mg/dL]) and 13 postmenopausal women with normal levels of plasma lipids and lipoproteins (mean+/-SD LDL cholesterol, 3.31+/-0.39 mmol/L [128+/-15 mg/dL]) were studied. Sixteen postmenopausal women participated in the drug study. Interventions.-In the drug study, patients received blindly both lovastatin (10 mg/d) and placebo. Main Outcome Measures.-In the first study, kinetic parameters of LDL metabolism; in the second study, response in lipids and lipoproteins to lovastatin therapy. Results.-In the LDL turnover study, mean (+/-SD) input (production) rates for LDL apolipoprotein B (apo B) were similar for hypercholesterolemic women and control women (12.4 [+/-3.2] mg/kg per day and 11.1 [+/-2.21 mg/kg per clay, respectively). In contrast, mean (+/-SD) fractional catabolic rates for LDL apo B in hypercholesterolemic women (0.29 [+/-0.04]pools per day) were significantly lower than those in normolipidemic women (0.35 [+/-0.03] pools per day). In the drug trial, lovastatin therapy reduced mean (+/-SD) total cholesterol and LDL cholesterol from 7.03 (+/-1.16) mmol/L (272 [+/-45] mg/dL) and 4.42 (+/-0.80) mmol/L (171 [+/-31] mg/dL, respectively, to 5.70 (+/-1.03) mmol/L (221 [+/-40] mg/dL) and 3.46 (+/-0.85) mmol/L (134 [+/-33] mg/dL). Conclusions.-The turnover data suggest that hypercholesterolemia in postmenopausal women is primarily attributable to a reduced activity of LDL receptors. In accord, the hypercholesterolemia in these women was effectively lowered by low doses of lovastatin. Thus, a low dose of lovastatin appears highly effective for treatment of moderate hypercholesterolemia in most postmenopausal women, presumably because it reverses the reduction in LDL receptor activity associated with menopause.