The influence of steroid hormones on plasma lipids and lipoproteins was confirmed by many studies. On the other hand, the effect of plasma lipids on metabolism of steroid hormones has so far not been examined. The objective of this research project was to determine (1) the levels of cortisol, testosterone, estradiol, dehydroepiandrosterone (DHEA), its sulfate (DHEAS), 7-hydroxylated DHEA, and SHBG in men suffering from mixed hyperlipidemia (HPL) (n=23, age 46.1±7.9 years) in comparison with healthy male volunteers (n=17, age 45.1±15.6 years); (2) whether therapy with fenofibrate influences the levels of the above mentioned steroids and SHBG; (3) what are the correlations between lipids and steroids in healthy males and HPL patients before and after therapy. Compared to controls, untreated patients had significantly higher estradiol and free testosterone index (IFT) levels (p<0.0003 and p<0.02, respectively) and significantly lower SHBG (p<0.02). Due to fenofibrate therapy, a significant decrease of TC, TG, and DHEA levels occurred (mean decrease: 14 %, 52 % and 21 %, respectively). Triglycerides correlated negatively with testosterone and SHBG in healthy subjects. HDL-C
correlated positively and consequently, atherogenic index correlated negatively with 7-hydroxylated epimers of DHEAin treated patients. This is the first study dealing with the influence of fenofibrate administration on the steroid levels. Taking together, the most important is the finding of decrease DHEA levels after fenofibrate therapy. It could be explained, at least in part, by the effect of the fenofibrateon on the biosynthesis of DHEA and its regulation.
Fibrate therapy results in elevation of plasma total homocysteine (tHcy), which is known to induce oxidative stress and endothelial dysfunction. We aimed to establish whether fibrate-induced elevation of tHcy has also similar consequences and whether they may be prevented by folate co-administration. Eighteen subjects with hypercholesterolemia were included in an open, prospective, cross-over study. We compared intra-individually the effect of fenofibrate on tHcy, oxidative stress and endothelial dysfunction surrogates, in monotherapy and when combined with 10 mg of folate. These effects were also compared with fluvastatin monotherapy. Fenofibrate in monotherapy significantly decreased LDL cholesterol, increased the tHcy by 39.5 %, while oxidized LDL (oxLDL), malondialdehyde (MDA), von Willebrand factors (vWf) and thrombomodulin (TMD) remained unchanged. When fibrate was co-administered with folate, the tHcy remained on the initial post-diet level, while both the total and oxLDL as well as MDA, vWf and TMD decreased. In contrast to fenofibrate monotherapy, fluvastatin (80 mg) had a similar effect as combined therapy with fenofibrate and folate, while tHcy remained uninfluenced. In conclusion, fenofibrate decreases the LDL cholesterol, but in contrast to fluvastatin, has no significant antioxidative and endothelium-protective potential, probably due to a concomitant increase of tHcy. These effects may be improved by co-administration of folate.
Dyslipidemia and inflammation play an important role in the pathogenesis of cardiovascular and liver disease. Fenofibrate has a well-known efficacy to reduce cholesterol and triglycerides. Combination with statins can ameliorate hypolipidemic and anti-inflammatory effects of fibrates. In the current study, we tested the anti-inflammatory and metabolic effects of fenofibrate alone and incombination with rosuvastatin in a model of inflammation and metabolic syndrome, using spontaneously hypertensive
rats expressing the human C-reactive protein transgene (SHR-CRP transgenic rats). SHR-CRP rats treated with fenofibrate alone (100 mg/kg body weight) or in combination with rosuvastatin (20 mg/kg body weight) vs. SHR-CRP untreated controls showed increased levels of proinflammatory marker IL6, increased concentrations of ALT, AST and ALP, increased oxidative stress in the liver and necrotic changes of the liver. In addition, SHR-CRP rats treated with fenofibrate, or with fenofibrate combined with rosuvastatin vs. untreated controls, exhibited increased serum triglycerides and reduced HDL cholesterol, as well as reduced hepatic triglyceride, cholesterol and glycogen concentrations. These findings suggest that in the presence of high levels of human CRP, fenofibrate can induce liver damage even in combination with rosuvastatin. Accordingly, these results caution against the possible hepatotoxic effects of fenofibrate in patients with high levels of CRP.