title: Stress responses after treatment of hypercholesterolaemia with simvastatin. Efficacy and Safety of Lovastatin Therapy in Adolescent Girls With Heterozygous Familial Hypercholesterolemia Efficacy and safety of lovastatin in adolescent males with heterozygous familial hypercholesterolemia: a randomized controlled trial. Mood changes in response to psychosocial stress in healthy young women: effects of pretreatment with cortisol. Does statin therapy influence steroid hormone synthesis? The Effects of Rosuvastatin on the Serum Cortisol, Serum Lipid, and Serum Mevalonic Acid Levels in the Healthy Indian Male Population Long-term follow-up of the West of Scotland Coronary Prevention Study. Simvastatin Reduces the Expression of Adhesion Molecules in Circulating Monocytes From Hypercholesterolemic Patients Simvastatin Versus Ezetimibe: Pleiotropic and Lipid-Lowering Effects on Endothelial Function in Humans Does simvastatin affect mood and steroid hormone levels in hypercholesterolemic men? A randomized double-blind trial
abstract: In order to determine whether treatment of hyperlipidaemia with simvastatin impairs exercise stress responses and so may contribute to an excess of suicides and violent deaths , the effects of simvastatin 20 mg daily and placebo on exercise physiology were compared in 19 patients . After 6 weeks of treatment there was no evidence of reduced exercise capacity , or of reduced cortisol or catecholamine responses . It is concluded that treatment of hyperlipidaemia with an inhibitor of HMG-CoA reductase does not significantly modify stress responses , and so the explanation for a possible increase in non-cardiac mortality must be sought elsewhere Objective . The present study was design ed to evaluate the lipid-altering efficacy , safety , and tolerability of lovastatin treatment in adolescent girls with heterozygous familial hypercholesterolemia . Methods . A total of 54 postmenarchal girls , aged 10 to 17 years , were enrolled in a 24-week , double-blind , r and omized , placebo-controlled study . After a 4-week diet/placebo run-in period , patients were r and omized to 1 of 2 groups : ( 1 ) treatment with diet plus lovastatin 20 mg/day for 4 weeks , followed by diet plus lovastatin 40 mg/day for 20 weeks , or ( 2 ) diet plus placebo for 24 weeks . Results . Baseline values of lipids , lipoproteins , and apolipoproteins ( apo ) were comparable between treatment groups . Lovastatin treatment was efficacious at reducing low-density lipoprotein cholesterol by 23 % to 27 % , total cholesterol by 17 % to 22 % , and apo B by 20 % to 23 % at weeks 4 and 24 , respectively . Between-treatment group differences were not statistically significant for triglycerides , very-low-density lipoprotein cholesterol , high-density lipoprotein cholesterol , or apo A-I.  Lovastatin was generally safe and well tolerated . There were no clinical ly significant alterations in vital signs ( blood pressure and pulse rate ) , anthropomorphic measurements ( height , weight , and BMI ) , hormone levels ( luteinizing hormone , follicle-stimulating hormone , dehydroepi and rosterone sulfate , estradiol , and cortisol ) , menstrual cycle length , or tests of liver and muscle function . Conclusions . Lovastatin offers an efficacious and well-tolerated treatment option for improving lipid profiles in adolescent girls with familial hypercholesterolemia CONTEXT Heterozygous familial hypercholesterolemia ( HeFH ) is a common disorder associated with early coronary artery disease , especially in men . The age at which drug therapy should be started is still controversial , as is the use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ( statins ) . OBJECTIVE To assess the lipid-lowering efficacy , biochemical safety , and effect on growth and sexual development of lovastatin in adolescent boys with HeFH . DESIGN One-year , double-blind , placebo-controlled , balanced , 2-period , 2-arm r and omized trial . In the first period ( 24 weeks ) , lovastatin was increased at 8 and 16 weeks and the dosage remained stable during the second period ( 24 weeks ) . The study was conducted between 1990 and 1994 . SETTING Fourteen pediatric outpatient clinics in the United States and Finl and . PATIENTS Boys aged 10 to 17 years with HeFH . Of 132 r and omized subjects ( 67 intervention , 65 placebo ) , 122 ( 63 intervention , 59 placebo ) and 110 ( 61 intervention , 49 placebo ) completed the first and second periods , respectively . INTERVENTION Lovastatin , starting at 10 mg/d , with a forced titration at 8 and 16 weeks to 20 and 40 mg/d , respectively , or placebo . MAIN OUTCOME MEASURES The primary efficacy outcome measure was low-density lipoprotein cholesterol ( LDL-C ) . Primary safety measures were growth and sexual development . RESULTS Compared with placebo , LDL-C levels of patients receiving lovastatin decreased significantly ( P<.001 ) by 17 % , 24 % , and 27 % receiving dosages of 10 , 20 , and 40 mg/d , respectively , and remained 25 % lower than baseline at 48 weeks . Growth and sexual maturation assessed by Tanner staging and testicular volume were not significantly different between the lovastatin and placebo groups at 24 weeks ( P = .85 ) and 48 weeks ( P = .33 ) ; neither were serum hormone levels or biochemical parameters of nutrition . However , the study was underpowered to detect significant differences in safety parameters . Serum vitamin E levels were reduced with lovastatin treatment consistent with reductions in LDL-C , the major carrier of vitamin E in the circulation . CONCLUSIONS This study in adolescent boys with HeFH confirmed the LDL-C-reducing effectiveness of lovastatin . Comprehensive clinical and biochemical data on growth , hormonal , and nutritional status indicated no significant differences between lovastatin and placebo over 48 weeks , although further study is required Effects of cortisol on human mood during stress situations are still incompletely understood , although this topic has important clinical implication s. In this experiment , the mood of 44 healthy young women ( all oral contraceptive users ) was examined . A double-blind , r and omized , placebo-controlled time series paradigm was used . Subjects were treated with either 30-mg cortisol or placebo orally . Forty-five minutes later , subjects attended a psychosocial stress procedure ( Trier Social Stress Test ; TSST ; C. Kirschbaum , K. M. Pirke , & D. H. Hellhammer , 1993 ) . The course of the subjects ' mood as well as salivary cortisol and alpha-amylase levels were measured before and after the TSST . With regard to mood , it was found that the groups did not differ in mood before the TSST . After stress exposure , the subjective ratings of current mood state of cortisol-treated women were significantly less negative than that of placebo-treated subjects . These findings show that raising cortisol levels prior to acute stress has a protective effect on mood during stress situations . Results are discussed with regard to the context of specific adaptive effects of cortisol and the role of cortisol in posttraumatic stress disorder Statine reduzieren die Cholesterin- und Isoprenoid-de-novo-Biosynthese , darüber hinaus die rezeptorvermittelte Aufnahme von Cholesterin für die Steroidhormonsynthese . In der vorgelegten r and omisierten , placebo-kontrollierten Studie wurde der Effekt von Pravastatin ( 40 mg/Tag ) auf die Plasmakonzentrationen von Steroidhormonen und Gonadotropinen untersucht . Die Patienten ( n = 22 ; 15 Männer , 7 Frauen ) wurden mit Pravastatin 40 mg/Tag oder Placebo beh and elt . Die Konzentrationen des Gesamtcholesterins sowie des LDL-Cholesterins und der Steroidhormone Östradiol , Testosteron , Cortisol und Dehydroepi and rosteron-Sulfat ( DHEAS ) sowie der Gonadotropine FSH und LH wurden untersucht . Pravastatin führte zu einer signifikanten Reduktion der Serumkonzentration des Gesamtcholesterins und des LDL-Cholesterins . Signifikante Veränderungen von Östradiol , Testosteron , Cortisol oder DHEAS wurden nicht beobachtet . Kompensatorische Veränderungen von FSH oder LH f and en sich nicht . Es wird schlussgefolgert , dass die Pravastatin-Therapie , die zu einer signifikanten Reduktion des Gesamtcholesterins und des LDL-Cholesterins führte , in therapeutisch verwendeten Dosierungen keinen Einfluss auf die Steroidhormon- Synthese oder die Freisetzung von Gonadotropinen hat . Statins reduce cholesterol and isoprenoid de novo bio synthesis as well as receptormediated uptake of cholesterol for steroidogenesis . The present r and omized placebo-controlled trial investigated whether pravastatin ( 40 mg/day ) reduces the plasma concentrations of steroid hormones as well as of gonadotropins .  Patients ( n = 22 ; 15 males , 7 females ) were treated with pravastatin ( 40 mg/day ) or placebo . Levels of total and LDL cholesterol , the steroid hormones estradiol , testosterone , cortisol and dehydroepi and rosterone sulphate ( DHEAS ) as well as FSH and LH were studied . Pravastatin led to a significant reduction of total cholesterol and LDL cholesterol . There was no significant change in estradiol , testosterone , cortisol or DHEAS plasma concentrations . There was no compensatory change in FSH or LH . It is concluded that pravastatin does not alter steroid hormones or gonadotropins in a clinical ly applicable dose , which significantly reduces total and LDL cholesterol In this open-label , balanced , r and omized , placebo-controlled , parallel study , healthy male volunteers were r and omly divided into two groups . Each group received either a single oral dose of rosuvastatin 20 mg or placebo . Estimations were done at predose on day 1 of dosing ( baseline ) and 24 h postdose after days 7 and 14 . Serum cortisol and serum lipid levels were estimated using enzyme-linked immunosorbent assay kits and serum mevalonic acid ( MVA ) levels were measured using vali date d liquid chromatography – t and em mass spectrometry method . Rosuvastatin produced a statistically significant ( P < 0.05 ) decrease in total cholesterol , low-density lipoprotein cholesterol , very low-density lipoprotein cholesterol , and triglycerides . However , the increase in high-density lipoprotein cholesterol and decrease in cortisol and MVA were not statistically significant when compared to the placebo-treated group . The study showed that rosuvastatin at a dose of 20 mg/day for a period of 14 days was very potent as cholesterol-lowering agent , without any significant change in serum cortisol level in the healthy Indian male population BACKGROUND The West of Scotl and Coronary Prevention Study was a r and omized clinical trial comparing pravastatin with placebo in men with hypercholesterolemia who did not have a history of myocardial infa rct ion , with an average follow-up of approximately 5 years . The combined outcome of death from definite coronary heart disease or definite nonfatal myocardial infa rct ion was reduced from 7.9 to 5.5 % ( P<0.001 ) in the treatment group . Extended follow-up data were obtained for approximately 10 years after completion of the trial . METHODS For the survivors of the trial , all deaths , hospitalizations and deaths due to coronary events and stroke , and incident cancers and deaths from cancer were tracked with the use of a national computerized record-linkage system . The results were analyzed with time-to-event analyses and use of Cox proportional-hazards models . RESULTS Five years after the trial ended , 38.7 % of the original statin group and 35.2 % of the original placebo group were being treated with a statin . In the period approximately 10 years after completion of the trial , the risk of death from coronary heart disease or nonfatal myocardial infa rct ion was 10.3 % in the placebo group and 8.6 % in the pravastatin group ( P=0.02 ) ; over the entire follow-up period , the rate was 15.5 % in the placebo group and 11.8 % in the pravastatin group ( P<0.001 ) . Similar percentage reductions were seen in the combined rate of death from coronary heart disease and hospitalization for coronary events for both periods . The rate of death from cardiovascular causes was reduced ( P=0.01 ) , as was the rate of death from any cause ( P=0.03 ) , over the entire follow-up period . There were no excess deaths from noncardiovascular causes or excess fatal or incident cancers . CONCLUSIONS In this analysis , 5 years of treatment with pravastatin was associated with a significant reduction in coronary events for a subsequent 10 years in men with hypercholesterolemia who did not have a history of myocardial infa rct ion Objective —The intercellular adhesion molecule-1 ( ICAM-1/CD54 ) and its lig and , CD11a/CD18 , mediate endothelial adhesion of leukocytes and their consecutive transmigration . Anti-inflammatory effects of statins are considered to be exerted in part through inhibition of leukocyte – endothelial interactions . We investigated the in vivo effects of simvastatin treatment in hypercholesterolemic patients and the influence of various statins on expression of cellular adhesion molecules in vitro . Methods and Results —A total number of 107 hypercholesterolemic patients were treated with 20 mg ( n=52 ) or 40 mg ( n=55 ) of simvastatin daily . After 6 weeks of treatment , peripheral blood mononuclear cells ( P BMC s ) expressed lower amounts of CD54- , CD18- , and CD11a-mRNA compared with pretreatment values . Surface expression of CD54 and CD18/CD11a on CD14 + -monocytes also decreased significantly in both groups of patients . Moreover , simvastatin , atorvastatin , and cerivastatin were found to downregulate tumor necrosis factor (TNF)-&agr ;– induced expression of CD54 and CD18/CD11a in isolated P BMC s obtained from normal donors as well as TNF-&agr ;– dependent expression of these CAMs in cultured human umbilical vein endothelial cells ( HUVECs ) . Furthermore , all three statins were found to reduce the binding of P BMC s to TNF-&agr ;– stimulated HUVECs in vitro . Conclusions —Statin-induced inhibition of expression of CD54 and CD18/CD11a in P BMC s and HUVECs with consecutive loss of adhesive function may contribute to the anti-inflammatory effects of these drugs and some of their beneficial clinical activities Background —Statins may exert important pleiotropic effects , ie , improve endothelial function , independently of their impact on LDL cholesterol . In humans , however , pleiotropic effects of statins have never been unequivocally demonstrated because prolonged statin treatment always results in reduced LDL cholesterol levels . We therefore tested the hypothesis that similar reductions in LDL cholesterol with simvastatin and ezetimibe , a novel cholesterol absorption inhibitor , result in different effects on endothelial function . Methods and Results —Twenty patients with chronic heart failure were r and omized to 4 weeks of simvastatin ( 10 mg/d ) or ezetimibe ( 10 mg/d ) treatment . Flow-dependent dilation ( FDD ) of the radial artery was determined by high-resolution ultrasound before and after intra-arterial vitamin C to determine the portion of FDD inhibited by radicals ( ΔFDD-VC ) . Activity of extracellular superoxide dismutase , a major vascular antioxidant enzyme system , was determined after release from the endothelium by a heparin bolus injection . Endothelial progenitor cells were analyzed with an in vitro assay . Simvastatin and ezetimibe treatment reduced LDL cholesterol to a similar extent ( 15.6 % versus 15.4 % ; P = NS ) , whereas changes in mevalonate , the product of HMG-CoA-reductase , differed between groups ( Δmevalonate-simvastatin , −1.04±0.62 versus Δmevalonate-ezetimibe , 1.79±0.94 ng/mL ; P<0.05 between groups ) . Importantly , FDD was markedly improved after simvastatin ( 10.5±0.6 % versus 5.1±0.7 % ; P<0.01 ) but not after ezetimibe treatment ( 5.6±0.5 % versus 5.8±0.6 % ; P = NS ) . ΔFDD-VC was substantially reduced after simvastatin but not after ezetimibe treatment . Extracellular superoxide dismutase activity was increased by > 100 % ( P<0.05 ) after simvastatin but not ezetimibe treatment . Simvastatin treatment increased the number of functionally active endothelial progenitor cells , whereas ezetimibe had no effect . Conclusions —Four weeks of simvastatin treatment improves endothelial function independently of LDL cholesterol lowering , at least in part by reducing oxidant stress . Simvastatin may thereby exert important pleiotropic effects in humans Epidemiological and clinical studies have suggested that powerful cholesterol lowering may have adverse effects on mood and psychological well-being . Inhibition of cholesterol bio synthesis by simvastatin ( a hydroxymethyl glutaryl coenzyme A reductase inhibitor ) may also reduce steroid hormone bio synthesis . To explore if mood changes are related with steroid hormone levels , we design ed a r and omized double-blind placebo-controlled crossover trial . The separate and combined effects of a Mediterranean-type diet intervention and treatment with simvastatin 20 mg/day PO for 12 weeks were studied in 120 hypercholesterolemic but otherwise healthy middle-aged men .  Psychological functioning was assessed with question naires , and steroid hormone levels in blood were assayed radioimmunologically before and after the treatments . Simvastatin result ed in a statistically significant increase of depression and somatization without changes in the anxiety , hostility or aggression scores . Mood changes seemed to be unrelated with the statistically significant but clinical ly insignificant decline in serum testosterone levels and unrelated with the increase in serum dehydroepi and rosterone levels
target: In the meta-regression analysis , changes in plasma cortisol concentrations following statin therapy were found to be independent of treatment duration .
  Results of this meta- analysis of RCTs suggest a significant elevation in plasma cortisol levels following statin therapy
background: This study aim ed to perform a systematic review and meta- analysis of r and omized controlled trials ( RCTs ) in order to calculate the effect size of statin therapy in changing plasma cortisol concentrations .