Archief Roodbont

Question

To what extent does statin therapy for lowering cholesterol levels also hinder appropriate hormone production and function? Cholesterol is the starting point for various needed compounds, including testosterone. If the substrate levels are too low, don't we interfere with hormone production?

Response from Darrell T. Hulisz, PharmD Associate Professor, Department of Family Medicine, Case Western Reserve University School of Medicine, University Hospitals, Case Medical Center, Cleveland, Ohio

Recent consensus guidelines recommend increasingly aggressive treatment of low-density lipoprotein cholesterol (LDL-C) to targets lower than previous values to improve patient outcomes.^[1] For example, in very high-risk patients, such as those with established cardiovascular disease plus multiple risk factors (eg, diabetes, smoking, metabolic syndrome), an LDL-C goal of <>[1] Recent evidence from clinical trials, such as Treating to New Targets (TNT), also suggests that using higher doses of atorvastatin to achieve lower LDL-C targets can decrease subsequent coronary interventions and revascularization procedures.^[2] However, there is concern that lowering LDL-C to very low thresholds may decrease hormone synthesis, as free intracellular cholesterol is necessary for adequate gonadal and adrenal steroid hormonal production.

Various studies have examined the effects of lipid-lowering agents on endogenous steroid synthesis.^[3-10] These studies have focused mainly on hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, also known as statins. Statins decrease hepatic cholesterol synthesis by competitive inhibition of HMG-CoA.

An early study of 26 men was conducted to determine the long-term effects of pravastatin or simvastatin on steroidogenesis under basal and maximal adrenal and testicular stimulation.^[3] Subjects were followed up to 36 months with no adverse changes observed in adrenocortical and testicular steroidogenesis, even under glandular stimulation. Similarly, a 1-year controlled study showed that up to 80 mg/day of atorvastatin yielded an average of 57% decrease in LDL-C but was not associated with any adverse effects on adrenal function under basal and maximal stimulation.^[4]

Dobs and colleagues^[5] studied simvastatin 80 mg/day vs placebo in 81 men over 12 weeks to determine drug effect on adrenal and gonadal steroidogenesis. There were small but nonsignificant declines in pooled total, free, and bioavailable testosterone associated with simvastatin, relative to placebo. However, there was no compensatory increase in follicle-stimulating hormone (FSH) or luteinizing hormone (LH) levels. Likewise, basal and stimulated cortisol production was unaffected by simvastatin.

To address whether reproductive hormonal changes are seen in women receiving lipid-lowering drugs, a cross-sectional analysis of the Women's Ischemia Syndrome Evaluation (WISE) was conducted.^[6] The WISE trial enrolled 453 women with coronary risk factors undergoing coronary angiography for suspected ischemia. While the majority of women were postmenopausal, premenopausal and perimenopausal women were also enrolled. Only 27% (n = 121) received a statin. Levels of total estradiol, progesterone, estrone, FSH, LH, and bioavailable estradiol were measured and compared between statin and nonstatin users. Overall, the use of statins was not associated with lower reproductive hormone levels. Even in women with very low LDL-C targets <>

A small study of atorvastatin treatment in both men (n = 16) and postmenopausal women (n = 8) with type 2 diabetes examined drug effect on gonadal and adrenal hormone levels.^[7] All patients had mild-to-moderate dyslipidemia and received atorvastatin 20 mg/day for 3 months. Measurements of cortisol and various sex hormone levels were compared at baseline and at the end of the 3-month trial. Use of atorvastatin resulted in no clinically significant difference in adrenal or gonadal hormone production. However, no placebo group was used.

A more recent study of 74 men with dyslipidemia evaluated the effects of statins on sex steroids, autonomic function, libido, and erectile function.^[8] All subjects received atorvastatin 40 mg/day over a 12-month period. Mean LDL-C level at 12 months of treatment was 95.6 mg/dL. Hormone levels for prolactin, testosterone, LH, estradiol, and dehydroepiandrosterone-sulfate (DHEA-S) were obtained at baseline and at 6 and 12 months, as were parameters to assess autonomic and erectile function. With the exception of a statistically significant decrease in DHEA-S levels, no hormonal changes were associated with statin use. Autonomic changes were not significant, and erectile function improved on statin therapy, relative to baseline. The clinical implications of the decreased DHEA-S levels observed from baseline are unknown.

One cross-sectional study of 355 men with type 2 diabetes receiving a variety of statins showed an association with statin use and lower total testosterone levels, but not bioavailable or free testosterone levels.^[9]

Most of the aforementioned trials did not focus specifically on the effect of lower LDL-C targets (<>[10] studied 160 men with coronary heart disease who received either high-dose atorvastatin (up to 80 mg/day) to a target LDL-C <> 100 mg/dL. Patients were stratified according to cardiac risk factors. At the end of 12 weeks, mean LDL-C in the high-dose group was 77 mg/dL. There were no significant alterations in free and total testosterone, sex hormone-binding globulin, FSH, or LH. The authors concluded that high-dose atorvastatin, given to achieve lower LDL targets, appears to be as safe as conventional doses with respect to gonadal steroidogenesis. However, this study was not placebo controlled for ethical reasons and was of short duration.

In conclusion, there remains a theoretical concern that HMG-CoA inhibitors -- and perhaps other lipid-lowering drugs -- may slightly blunt adrenal and/or gonadal steroid production. The balance of studies that examined this hypothesis have shown little or no effect, however, although most studies have not treated patients to targets <>