Thiazide-induced hypercholesterolemia: sex differences

Thiazide diuretics are used commonly to treat hypertension. Unfortunately, they also are known to elevate serum cholesterol levels. Because serum lipid fraction levels differ between the sexes, possible sex-related differences in thiazide-induced changes in serum total cholesterol (TC), triglycerides (TG) and high density lipoprotein cholesterol (HDL-C) levels were examined. Four groups of male and female hamsters were treated for a minimum of 3 months with hydrochlorothiazide (HCTZ) at zero, 1, 2 or 4 mg/kg/day. At zero dose, there was no difference in TG levels between the sexes; however, females had significantly higher TG concentrations than did males at 1, 2 and 4 mg HCTZ (all p less than 0.05). Females demonstrate a significant dose response with HCL-C levels increasing with increasing doses of HCTZ, (r = 0.983; p less than 0.02); in contrast males had a similar increase in HDL-C at all dose levels (all p less than 0.05) thus there was no demonstrable dose response (r = 0.539). Total cholesterol concentrations were significantly higher in the females than in males (p less than 0.05) at all 3 dose levels as well as at zero dose. Further, the females demonstrated a direct dose response in TC levels (r = 0.986; p less than 0.02) while the males showed no such dose response (r = 0.824; p less than 0.01). Based on these findings we conclude that: 1) HCTZ increases TG, TC and HDL-C levels in both male and female hamsters; 2) TC levels are higher in females than in males regardless of HCTZ dose; 3) only females show a dose-dependent increase in HCL-C and TC in response to HCTZ. These sex-related changes in lipid fractions occurring with HCTZ treatment, if they occur in humans, may contribute to sex-related differences in rates and severity of atherosclerosis in HCTZ-treated populations.