Effects of atorvastatin on vascular function, inflammation, and androgens in women with polycystic ovary syndrome: a double-blind, randomized, placebo-controlled trial.
ABSTRACT: To determine the effects of statins on vascular function, inflammation, and androgen levels in women with polycystic ovary syndrome (PCOS), we randomized 20 women with PCOS who had low-density lipoprotein cholesterol levels >100 mg/dL to atorvastatin (40 mg/day) or placebo for 6 weeks and found that atorvastatin reduced androgen levels, biomarkers of inflammation, and blood pressure; increased insulin levels and brachial artery conductance during reactive hyperemia; and failed to improve brachial artery flow-mediated dilation. We conclude that until additional studies demonstrate a clear risk-to-benefit ratio favoring statin therapy in PCOS, statins should only be used in women with PCOS who meet current indications for statin treatment.
Project description:In addition to inhibiting cholesterol biosynthesis, statins also inhibit the formation of isoprenoid intermediates, which are required for the activation of the Rho/Rho kinase (ROCK) pathway. Increased ROCK activity has been implicated in causing endothelial dysfunction and atherosclerosis. However, it is not known whether statins, at doses used to lower cholesterol levels, inhibit ROCK activity in humans with atherosclerosis. Furthermore, it is not known whether lipophilic and hydrophilic statins differ in their ability to inhibit ROCK activity. Accordingly, we enrolled 30 men with stable atherosclerosis (low-density lipoprotein [LDL] > or =100 mg/dL) in a randomized, double-blind study comparing equivalent LDL-lowering doses of a hydrophilic statin (rosuvastatin 10 mg once a day) with a lipophilic statin (atorvastatin 40 mg once a day) for 28 days. We assessed the change in lipids, ROCK activity, and flow-mediated dilation (FMD) of the brachial artery before and after statin therapy. Both treatment groups exhibited comparable 30% to 32% and 42% to 45% reductions in total and LDL cholesterol, respectively. Only atorvastatin reduced triglycerides, and neither statin altered high-density lipoprotein cholesterol. Whereas both statins inhibited ROCK activity (p <0.0001), the extent of inhibition was greater with rosuvastatin (18 +/- 2% vs 8 +/- 2%, p = 0.0006). Statins also improved FMD from 7.4 +/- 0.6 to 9.3 +/- 0.4 (p = 0.003) with rosuvastatin being slightly better than atorvastatin. The inhibition of ROCK activity by statins did not correlate with reductions in LDL (p = 0.57) but was associated with improvement in FMD. In conclusion, these findings provide direct clinical evidence that statins, at clinically relevant doses, could differentially inhibit ROCK activity and improve endothelial function by cholesterol-independent mechanism.
Project description:Accumulating evidence from animal and human studies suggests that vitamin D is involved in many functions of the reproductive system in both genders.The aim of this review was to provide an overview on the effects of vitamin D on polycystic ovary syndrome (PCOS) in women and androgen metabolism in men.We performed a systematic literature search in PubMed for relevant English language publications published from January 2012 until September 2017.The vitamin D receptor and vitamin D-metabolizing enzymes are found in reproductive tissues of women and men. In women, vitamin D status has been associated with several features of PCOS. In detail, cross-sectional data suggest a regulatory role of vitamin D in PCOS-related aspects such as ovulatory dysfunction, insulin resistance as well as hyperandrogenism. Moreover, results from randomized controlled trials (RCTs) suggest that vitamin D supplementation may be beneficial for metabolic, endocrine and fertility aspects in PCOS. In men, vitamin D status has been associated with androgen levels and hypogonadism. Further, there is some evidence for a favorable effect of vitamin D supplementation on testosterone concentrations, although others failed to show a significant effect on testosterone levels.In summary, vitamin D deficiency is associated with adverse fertility outcomes including PCOS and hypogonadism, but the evidence is insufficient to establish causality. High-quality RCTs are needed to further evaluate the effects of vitamin D supplementation in PCOS women as well as on androgen levels in men.
Project description:Treatment with statins improves clinical outcome, but the exact mechanisms of pleiotropic statin effects on vascular function in human atherosclerosis remain unclear. We examined the direct effects of atorvastatin on tetrahydrobiopterin-mediated endothelial nitric oxide (NO) synthase coupling in patients with coronary artery disease.We first examined the association of statin treatment with vascular NO bioavailability and arterial superoxide (O(2)(·-)) in 492 patients undergoing coronary artery bypass graft surgery. Then, 42 statin-naïve patients undergoing elective coronary artery bypass graft surgery were randomized to atorvastatin 40 mg/d or placebo for 3 days before surgery to examine the impact of atorvastatin on endothelial function and O(2)(·-) generation in internal mammary arteries. Finally, segments of internal mammary arteries from 26 patients were used in ex vivo experiments to evaluate the statin-dependent mechanisms regulating the vascular redox state. Statin treatment was associated with improved vascular NO bioavailability and reduced O(2)(·-) generation in internal mammary arteries. Oral atorvastatin increased vascular tetrahydrobiopterin bioavailability and reduced basal and N-nitro-l-arginine methyl ester-inhibitable O(2)(·-) in internal mammary arteries independently of low-density lipoprotein lowering. In ex vivo experiments, atorvastatin rapidly improved vascular tetrahydrobiopterin bioavailability by upregulating GTP-cyclohydrolase I gene expression and activity, resulting in improved endothelial NO synthase coupling and reduced vascular O(2)(·-). These effects were reversed by mevalonate, indicating a direct effect of vascular hydroxymethylglutaryl-coenzyme A reductase inhibition.This study demonstrates for the first time in humans the direct effects of statin treatment on the vascular wall, supporting the notion that this effect is independent of low-density lipoprotein lowering. Atorvastatin directly improves vascular NO bioavailability and reduces vascular O(2)(·-) through tetrahydrobiopterin-mediated endothelial NO synthase coupling. These findings provide new insights into the mechanisms mediating the beneficial vascular effects of statins in humans.URL: http://www.clinicaltrials.gov. Unique identifier: NCT01013103.
Project description:OBJECTIVE: The vascular benefits of statins might be attenuated by inhibition of coenzyme Q(10) (CoQ(10)) synthesis. We investigated whether oral CoQ(10) supplementation improves endothelial dysfunction in statin-treated type 2 diabetic patients. RESEARCH DESIGN AND METHODS: In a double-blind crossover study, 23 statin-treated type 2 diabetic patients with LDL cholesterol <2.5 mmol/l and endothelial dysfunction (brachial artery flow-mediated dilatation [FMD] <5.5%) were randomized to oral CoQ(10) (200 mg/day) or placebo for 12 weeks. We measured brachial artery FMD and nitrate-mediated dilatation (NMD) by ultrasonography. Plasma F(2)-isoprostane and 24-h urinary 20-hydroxyeicosatetraenoic acid (HETE) levels were measured as systemic oxidative stress markers. RESULTS: Compared with placebo, CoQ(10) supplementation increased brachial artery FMD by 1.0 +/- 0.5% (P = 0.04), but did not alter NMD (P = 0.66). CoQ(10) supplementation also did not alter plasma F(2)-isoprostane (P = 0.58) or urinary 20-HETE levels (P = 0.28). CONCLUSIONS: CoQ(10) supplementation improved endothelial dysfunction in statin-treated type 2 diabetic patients, possibly by altering local vascular oxidative stress.
Project description:Cardiovascular disease is the leading cause of mortality in women in the United States. Aggressive treatment of modifiable risk factors (e.g., hypercholesterolemia) is essential in reducing disease burden. Despite guidelines recommending the use of statin treatment in hypercholesterolemic women, this patient group is often undertreated. This subgroup analysis of the Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin (STELLAR) trial examines the effects of statin therapy in hypercholesterolemic women.As part of the STELLAR trial, 1,146 women with elevated low-density lipoprotein cholesterol (LDL-C ≥160 and <250 mg/dL) and triglycerides <400 mg/dL were randomized to rosuvastatin 10-40 mg, atorvastatin 10-80 mg, simvastatin 10-80 mg, or pravastatin 10-40 mg for 6 weeks.LDL-C reduction with rosuvastatin 10 mg, atorvastatin 10 mg, simvastatin 20 mg, and pravastatin 40 mg was 49%, 39%, 37%, and 30%, respectively, after 6 weeks. High-intensity statins (rosuvastatin 20-40 mg and atorvastatin 40-80 mg) reduced LDL-C to the greatest extent: 53% with rosuvastatin 20 mg, 57% with rosuvastatin 40 mg, 47% with atorvastatin 40 mg, and 51% with atorvastatin 80 mg. Similar results were observed for non-high-density lipoprotein cholesterol (non-HDL-C). Increases in HDL-C were greater with rosuvastatin across doses than with other statins. All treatments were well tolerated, with similar safety profiles across dose ranges.Statin therapies in the STELLAR trial led to reductions in LDL-C, non-HDL-C, and triglycerides and increases in HDL-C among hypercholesterolemic women, with rosuvastatin providing the greatest reductions in LDL-C and non-HDL-C.
Project description:BACKGROUND:Polycystic ovary syndrome (PCOS) is an endocrine disorder affecting about 10% of women in reproductive age and associated with a variety of hormonal abnormalities, including hyperandrogenemia and infertility, all of which could lead to PCOS. Statins were previously introduced as a therapeutic option for reducing testosterone levels in women with PCOS, either alone or in combination. The aim of this study is to evaluate the effectiveness of different statins alone or in combination with metformin in reducing testosterone levels in women with PCOS. METHODS:Medline, Embase, and clinicaltrials.gov were searched for studies that investigated the efficacy of statins, metformin, spironolactone, or combined oral contraceptives (COCs), individually or in combination, in reducing the testosterone level in patients with PCOS. The search was limited to randomized clinical trials and conducted according to the preferred reporting items for systematic reviews and meta-analyses - extension statement for network meta-analyses (PRISMA-NMA). The quality of included studies was assessed using the Cochrane Collaboration risk of bias (RoB) assessment tool. A frequentist network meta-analysis using random-effects models was used to assess the efficacy in reducing testosterone level and were expressed as odds ratios (OR) and 95% credible interval (95%Crl). All statistical analyses were performed using netmeta Version 1.0 on R statistical package. RESULT:Nine RCTs involving 613 patients were included. Atorvastatin showed greater reduction in testosterone level compared to COC (MD -2.78, 95%CrI -3.60, -1.97), spironolactone plus metformin (MD -2.83, 95%CrI -3.80, -1.87), simvastatin (MD -2.88, 95%CrI -3.85, -1.92), spironolactone (MD -2.90, 95%CI -3.77, -2.02), simvastatin plus metformin (MD -2.93, 95%CrI -3.79, -2.06), metformin (MD -2.97, 95%CrI -3.69, -2.25), lifestyle modification (MD -3.02, 95%CrI -3.87, -2.18), and placebo (MD -3.04, 95%CrI -3.56, -2.53). CONCLUSION:Atorvastatin was found to be more effective than the other management strategies in reducing the total testosterone level for patients with PCOS. Future studies should focus on the optimal dose.
Project description:Low-density lipoprotein cholesterol (LDL-C) reductions with the PCSK9 monoclonal antibody alirocumab may be affected by background statin dose due to increased PCSK9 levels with higher statin doses. Data from 8 Phase 3 trials conducted with background statin (n = 4629) were pooled by alirocumab dose (75 or 150 mg every 2 weeks) and control (placebo/ezetimibe), and analyzed by background statin type/dose. Overall, 58.4% received high-dose statins (atorvastatin 40-80 mg, rosuvastatin 20-40 mg, simvastatin 80 mg), 28.6% moderate-dose statins (atorvastatin 20-<40 mg, rosuvastatin 10-<20 mg, simvastatin 40-<80 mg), and 12.9% low-dose statins (atorvastatin <20 mg, rosuvastatin <10 mg, simvastatin <40 mg). Mean baseline PCSK9 levels were higher with high versus moderate and low statin doses (318.5 vs 280.6 ng/mL). Baseline LDL-C levels were similar across pools, regardless of statin intensity. No associations were observed between statin type/dose and LDL-C % change from baseline or % of patients achieving LDL-C goals at Week 24 for alirocumab versus control (interaction P-values non-significant). Incidence of adverse events was similar for alirocumab versus control, except for a higher rate of injection-site reactions with alirocumab. In summary, alirocumab provided consistent LDL-C reductions and was generally well tolerated independent of background statin type/dose.
Project description:Randomized trials suggest that statin treatment may lower blood pressure and influence cardiovascular autonomic function (CVAF), but the impact of duration of usage, discontinuation, and adherence to this therapy is unknown. We examined these issues with regard to blood pressure (BP)-related variables in a large, population-based study. Participants were 4942 adults (58% male; aged 50-84 years): 2179 on statin treatment and 2763 untreated. Days of utilization, adherence (proportion of days covered ?0.8), and discontinuation (non-use for ?30 days immediately prior to BP measurement) of three statins (atorvastatin, pravastatin, and simvastatin) over a period of up to 2 years was monitored retrospectively from electronic databases. Systolic BP (SBP), diastolic BP (DBP), augmentation index, excess pressure, reservoir pressure, and CVAF (pulse rate and BP variability) parameters were calculated from aortic pressure waveforms derived from suprasystolic brachial measurement. Days of statin treatment had inverse relationships with pulse rate variability parameters in cardiac arrhythmic participants (20-25% lower than in statin non-users) and with most arterial function parameters in everyone. For example, compared to untreated participants, those treated for ?659 days had 3.0 mmHg lower aortic SBP (<i>P</i> < 0.01). Discontinuation was associated with higher brachial DBP and aortic DBP (for both, <i>?</i> = 2.0 mmHg, <i>P</i> = 0.008). Compared to non-adherent statin users, adherent users had lower levels of brachial SBP, brachial DBP, aortic DBP, aortic SBP, and peak reservoir pressure (<i>?</i> = -1.4 to -2.6 mmHg). In conclusion, in a real-world setting, statin-therapy duration, non-discontinuation and adherence associate inversely with BP variables and, in cardiac arrhythmias, CVAF parameters.
Project description:CONTEXT:Polycystic ovary syndrome (PCOS) is a prevalent disorder in reproductive aged women associated with a number of endocrine and metabolic complications, including increased risk of endometrial cancer. OBJECTIVE:To study the effect of the characteristic increased androgen levels in PCOS on the endometrium, a novel scaffold-free multicellular endometrial organoid was established. DESIGN:Human endometrial organoids were constructed using primary endometrial epithelial and stromal cells from endometrial tissues. Organoids were treated for 14 days with physiologic levels of estradiol and testosterone to mimic a normal follicular phase or PCOS hormone profiles. Organoids were harvested for immunostaining and ribonucleic acid sequencing. SETTING:Academic institution. PATIENTS:Endometrial tissues from 10 premenopausal women undergoing hysterectomy for benign pathologies were obtained following written consent. MAIN OUTCOME MEASURES:Organoid architecture, cell specific markers, functional markers, proliferation, and gene expression were measured. RESULTS:A method to generate scaffold-free endometrial organoids containing epithelial and stromal cells was established. These organoids exhibited distinct organization with epithelial cells lining the outer surface and stromal cells in the center of the organoids. Epithelial cells were polarized, organoids expressed cell type specific and functional markers, as well as androgen, estrogen, and progesterone receptors. Treatment with PCOS hormones increased cell proliferation and dysregulated genes in endometrial organoids. CONCLUSIONS:A new multicellular, scaffold-free endometrial organoid system was established that resembled physiology of the native endometrium. Excess androgens in PCOS promoted cell proliferation in endometrial organoids, revealing new mechanisms of PCOS-associated with risk of endometrial neoplasia.
Project description:The relationship between statin-induced increases in HDL cholesterol (HDL-C) concentration and statin-induced decreases in LDL cholesterol (LDL-C) is unknown. The effects of different statins on HDL-C levels, relationships between changes in HDL-C and changes in LDL-C, and predictors of statin-induced increases in HDL-C have been investigated in an individual patient meta-analysis of 32,258 dyslipidemic patients included in 37 randomized studies using rosuvastatin, atorvastatin, and simvastatin. The HDL-C raising ability of rosuvastatin, and simvastatin was comparable, with both being superior to atorvastatin. Increases in HDL-C were positively related to statin dose with rosuvastatin and simvastatin but inversely related to dose with atorvastatin. There was no apparent relationship between reduction in LDL-C and increase in HDL-C, whether analyzed overall for all statins (correlation coefficient = 0.005) or for each statin individually. Percentage increase in apolipoprotein A-I was virtually identical to that of HDL-C at all doses of the three statins. Baseline concentrations of HDL-C and triglyceride (TG) and presence of diabetes were strong, independent predictors of statin-induced elevations of HDL-C. Statins vary in their HDL-C raising ability. The HDL-C increase achieved by all three statins was independent of LDL-C decrease. However, baseline HDL-C and TGs and the presence of diabetes were predictors of statin-induced increases in HDL-C.