In view of the role of both the de novo biosynthesis and receptor-mediated uptake of
cholesterol for normal steroidogenesis, we evaluated whether extending the therapeutic dose of the hepatic hydroxymethyl
glutaryl coenzyme A (
HMG-CoA) reductase inhibitor,
simvastatin, to 80 mg/d would affect adrenal and gonadal
steroid synthesis in men with
hypercholesterolemia. To evaluate this question, we enrolled men into a multicenter randomized, placebo-controlled study lasting 12 weeks. Men with serum
low-density lipoprotein cholesterol (
LDL-C) more than 145 mg/dL after 6 weeks of a
lipid-lowering diet were randomized to 80 mg
simvastatin or placebo. Half of the subjects were asked to undergo a 6-hour infusion of
corticotropin (
ACTH) to evaluate
cortisol synthesis, and the entire cohort received a
human chorionic gonadotropin (hCG) stimulation test to assess
gonadal hormone secretion using pooled serum samples taken 15 minutes apart. A total of 81 men (age, 45 +/- 11 years; 93% Caucasian) with baseline serum
LDL-C of 197 mg/dL (placebo, n = 39) and 184 mg/dL (
simvastatin 80 mg, n = 42) completed the study. After 12 weeks, serum
LDL-C,
triglycerides, and
high-density lipoprotein cholesterol (HDL-C) in the
simvastatin group changed by -43%, -25%, and 8%, respectively (all P < .001). The basal
cortisol level and the peak serum
cortisol and area under the curve response to the 6-hour
ACTH infusion were comparable between the two treatment groups at baseline and after 12 weeks. The pooled total
testosterone level at baseline was 541 and 513 ng/dL in the placebo and
simvastatin-treated groups, respectively, which declined to 536 +/- 20.5 ng/dL (-1.5%) and 474 +/- 30.4 ng/dL (-13.6%, P = .09)
after treatment (mean +/- SD). The pooled free
testosterone declined by 6.3% in the
simvastatin group, versus a 4.9% increase in the placebo group (P = .588), while pooled bioavailable
testosterone declined 10.2% in the
simvastatin group and increased 1.4% in the placebo group (P = .035). There were no changes in serum
gonadotropin levels or
sex hormone-binding globulin (SHBG). After administration of hCG, there were no differences in the peak total pooled
testosterone level before or after 12 weeks of treatment.
Simvastatin 80 mg was well tolerated compared with placebo. In conclusion, basal and stimulated
cortisol production was unaffected by the use of
simvastatin 80 mg versus placebo. As reported with other
statins and
cholestyramine, there were small declines in the
simvastatin-treated group for pooled total, free, and bioavailable
testosterone after 12 weeks, although there was no compensatory increase in serum
follicle-stimulating hormone (FSH) or
luteinizing hormone (LH) levels.