Medicine, Faculty of
Anesthesiology, Pharmacology and Therapeutics, Department of
DSpace
UBCV
Shawish, MHD Ismail
Master of Science - MSc
University of British Columbia
Background: Statins are one of the most prescribed classes of drugs worldwide. Atorvastatin, the most prescribed statin, is currently used to treat conditions such as hypercholesterolemia and dyslipidemia. Testosterone and other androgens play important roles in biological functions. A potential reduction in androgens levels caused by atorvastatin might cause negative effects except for conditions such as polycystic ovary syndrome (PCOS), where reduction of excessive levels of androgens is potentially beneficial. Objectives: To quantify the magnitude of the effects of atorvastatin as compared to placebo or no treatment on total testosterone, free testosterone, sex hormone binding globin (SHBG), androstenedione, dehydroepiandrosterone sulfate (DHEAS) concentrations, free androgen index (FAI), and withdrawal due to adverse effects (WDAEs). Methods: We searched major databases (CENTRAL, MEDLINE, EMBASE) and other sources for randomized controlled trials (RCTs) comparing atorvastatin with placebo or no treatment on testosterone levels in males and females. Two authors independently screened the citations, extracted the data and assessed the quality of the included studies. We used mean difference with 95% confidence interval to report effect size of continuous outcomes and a fixed effect model to combine the effect sizes across studies, and risk ratio to report effect size of the dichotomous outcome (WDAEs). iv Results: We included six RCTs involving 265 participants. Participants in two of the studies were male with normal or mild dyslipidemia (N=140). Participants in four of the studies were female with PCOS (N=125). Compared to placebo, atorvastatin had no significant effect on total testosterone levels (MD -0.20 [-0.77, 0.37] nmol/L in males. Atorvastatin may reduce total testosterone, FAI, androstenedione, and DHEAS in females by -0.27 (-0.50, -0.04) nmol/L, -2.59 (-3.62, -1.57), -1.37 nmol/L (-2.26, -0.49), and -0.64 μmol/l (-1.12, -0.16), respectively. Furthermore, atorvastatin increased SHBG concentrations in females by 3.11 nmol/L [0.23, 5.99] compared to placebo. Conclusions: Compared to placebo atorvastatin had no significant effect on the levels of total testosterone in males. In females with PCOS, atorvastatin lowered the total testosterone, FAI, androstenedione, and DHEAS. The certainty of evidence ranged from low to very low for both comparisons. More RCTs studying the effect of atorvastatin on testosterone are needed.
The Effects of Atorvastatin on Testosterone Levels in Males and Females: A Systematic Review and Meta-analysis by MHD Ismail Shawish B. Pharm, Damascus University, 2012 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF Master of Science in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Pharmacology and Therapeutics) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) September 2020 © MHD Ismail Shawish, 2020 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, a thesis entitled: The Effects of Atorvastatin on Testosterone Levels in Males and Females: A Systematic Review and Meta-analysis submitted by MHD Ismail Shawish in partial fulfillment of the requirements for the degree of Master of Science in Pharmacology and Therapeutics Examining Committee: Prof. James M. Wright, Anesthesiology, Pharmacology & Therapeutics Supervisor Assistant Prof. Vijaya Musini, Anesthesiology, Pharmacology & TherapeuticsSupervisory Committee Member Prof. Ismail Laher, Anesthesiology, Pharmacology & TherapeuticsSupervisory Committee Member iii Abstract Background: Statins are one of the most prescribed classes of drugs worldwide. Atorvastatin, the most prescribed statin, is currently used to treat conditions such as hypercholesterolemia and dyslipidemia. Testosterone and other androgens play important roles in biological functions. A potential reduction in androgens levels caused by atorvastatin might cause negative effects except for conditions such as polycystic ovary syndrome (PCOS), where reduction of excessive levels of androgens is potentially beneficial. Objectives: To quantify the magnitude of the effects of atorvastatin as compared to placebo or no treatment on total testosterone, free testosterone, sex hormone binding globin (SHBG), androstenedione, dehydroepiandrosterone sulfate (DHEAS) concentrations, free androgen index (FAI), and withdrawal due to adverse effects (WDAEs). Methods: We searched major databases (CENTRAL, MEDLINE, EMBASE) and other sources for randomized controlled trials (RCTs) comparing atorvastatin with placebo or no treatment on testosterone levels in males and females. Two authors independently screened the citations, extracted the data and assessed the quality of the included studies. We used mean difference with 95% confidence interval to report effect size of continuous outcomes and a fixed effect model to combine the effect sizes across studies, and risk ratio to report effect size of the dichotomous outcome (WDAEs). iv Results: We included six RCTs involving 265 participants. Participants in two of the studies were male with normal or mild dyslipidemia (N=140). Participants in four of the studies were female with PCOS (N=125). Compared to placebo, atorvastatin had no significant effect on total testosterone levels (MD -0.20 [-0.77, 0.37] nmol/L in males. Atorvastatin may reduce total testosterone, FAI, androstenedione, and DHEAS in females by -0.27 (-0.50, -0.04) nmol/L, -2.59 (-3.62, -1.57), -1.37 nmol/L (-2.26, -0.49), and -0.64 µmol/l (-1.12, -0.16), respectively. Furthermore, atorvastatin increased SHBG concentrations in females by 3.11 nmol/L [0.23, 5.99] compared to placebo. Conclusions: Compared to placebo atorvastatin had no significant effect on the levels of total testosterone in males. In females with PCOS, atorvastatin lowered the total testosterone, FAI, androstenedione, and DHEAS. The certainty of evidence ranged from low to very low for both comparisons. More RCTs studying the effect of atorvastatin on testosterone are needed. v Lay Summary Statins are one of the most prescribed classes of drugs, and atorvastatin is the most used drug in that class. We wanted to quantify the effect of atorvastatin on testosterone and other androgens which are important hormones that play crucial functions in male and female health and development. We reviewed the available evidence about the effect of daily dose of different doses of atorvastatin compared to placebo or no treatment on testosterone and other androgens in males and females. We found six studies involving 265 participants. We found that atorvastatin has a potential beneficial effect on females with PCOS since it decreased total testosterone and the other androgens, while it had no significant effect on the total testosterone in males. However, the certainty of the evidence for these different comparisons ranged from low to very low, and more studies are needed to reach a definitive answer. vi Preface The methodology of this review (Chapter 2) has been published as a Cochrane protocol in the Cochrane library: Shawish, M. I., Bagheri, B., Musini, V. M., Adams, S. P., & Wright, J. M. (2018). Effect of atorvastatin on testosterone levels. Cochrane Database of Systematic Reviews, (12). https://doi.org/10.1002/14651858.cd013211 Dr. James M. Wright formulated the idea and developed the basis of the protocol. Bagheri B and Stephen Adams are co-authors. They confirmed that the included studies met the pre specified inclusion criteria and extracted data independently. Dr. Musini contributed throughout this systematic review, and offered expertise and secondary supervision. Chapters 3,4,5 and 6 of this thesis are original and unpublished works of MHD Ismail Shawish under the supervision of Dr. James M. Wright. MHD Ismail Shawish contributed to all steps of this systematic review. No patient or animal contact occurred for the purpose of this thesis therefore ethical approval was not required. vii Table of Contents Abstract ......................................................................................................................................... iii Lay Summary .................................................................................................................................v Preface ........................................................................................................................................... vi Table of Contents ........................................................................................................................ vii List of Tables .............................................................................................................................. xiv List of Figures ...............................................................................................................................xv List of Abbreviations ................................................................................................................ xvii Acknowledgements .................................................................................................................... xix Dedication .....................................................................................................................................xx Background information .............................................................................................1 1.1 Androgens ............................................................................................................................. 1 1.1.1 Steroidogenesis pathway ............................................................................................. 1 1.1.2 Testosterone ................................................................................................................ 3 1.1.3 DHEA and DHEAS .................................................................................................... 6 1.1.4 Androstenedione (A4) ................................................................................................. 9 Sex Hormone Binding Globulin ..................................................................................... 9 Polycystic Ovary Syndrome ........................................................................................... 9 Statins ............................................................................................................................ 10 1.4.1 Statin Indications ...................................................................................................... 11 1.4.2 Mechanism of action ................................................................................................. 12 1.4.3 Safety of statins ......................................................................................................... 14 viii Atorvastatin ................................................................................................................... 16 1.5.1 Atorvastatin Pharmacokinetics ................................................................................. 16 1.5.1.1 Absorption and distribution .............................................................................. 16 1.5.1.2 Metabolism ....................................................................................................... 17 1.5.1.3 Excretion and Elimination ................................................................................ 17 1.5.1.4 Onset ................................................................................................................. 17 1.5.2 Atorvastatin Pharmacodynamics .............................................................................. 17 1.5.2.1 Atorvastatin Efficacy ........................................................................................ 17 1.5.2.2 Drug Interactions .............................................................................................. 18 Rationale ....................................................................................................................... 18 Methods .......................................................................................................................20 Criteria for considering studies for this review............................................................. 20 2.1.1 Types of studies ........................................................................................................ 20 2.1.2 Types of participants ................................................................................................. 20 2.1.3 Types of interventions............................................................................................... 20 2.1.4 Types of outcome measures ...................................................................................... 21 2.1.4.1 Primary outcome ............................................................................................... 21 2.1.4.2 Secondary outcomes ......................................................................................... 21 Search methods for identification of studies ................................................................. 21 2.2.1 Electronic searches.................................................................................................... 21 2.2.2 Searching other resources ......................................................................................... 22 Data collection and analysis.......................................................................................... 23 2.3.1 Selection of studies ................................................................................................... 23 ix 2.3.2 Data extraction and management .............................................................................. 24 Assessment of risk of bias in included studies.............................................................. 25 Measures of treatment effect ......................................................................................... 26 Unit of analysis issues ................................................................................................... 26 Dealing with missing data ............................................................................................. 26 2.7.1 Missing statistics ....................................................................................................... 27 Assessment of heterogeneity......................................................................................... 27 Assessment of reporting biases ..................................................................................... 27 Data synthesis ............................................................................................................... 28 Subgroup analysis and investigation of heterogeneity.................................................. 28 Sensitivity analysis........................................................................................................ 28 Overall grading of certainty of evidence - 'Summary of findings' tables ..................... 29 Results .........................................................................................................................30 Description of studies ................................................................................................... 30 3.1.1 Results of the search ................................................................................................. 30 3.1.2 Included studies ........................................................................................................ 30 3.1.3 Excluded studies ....................................................................................................... 31 Risk of bias in included studies .................................................................................... 32 3.2.1 Allocation (selection bias) ........................................................................................ 32 3.2.2 Blinding (performance bias and detection bias) ....................................................... 33 3.2.3 Incomplete outcome data (attrition bias) .................................................................. 33 3.2.4 Selective reporting (reporting bias) .......................................................................... 34 3.2.5 Other potential sources of bias .................................................................................. 35 x 3.2.6 Publication bias ......................................................................................................... 35 Effects of interventions ................................................................................................. 38 3.3.1 The potential adverse effect of atorvastatin on androgens........................................ 38 3.3.1.1 Effect of atorvastatin on total testosterone level (TT)(males) .......................... 38 3.3.1.2 Effect of atorvastatin on free testosterone levels (males) ................................. 39 3.3.1.3 3.3.1.3 Effect of atorvastatin on WDAEs in males and females ....................... 39 3.3.2 The possible beneficial effects of atorvastatin for the treatment of PCOS ............... 39 3.3.2.1 Effect of atorvastatin on total testosterone level ............................................... 39 3.3.2.2 Effect of atorvastatin on free testosterone levels .............................................. 40 3.3.2.3 Effect of atorvastatin on FAI ............................................................................ 40 3.3.2.4 Effect of atorvastatin on SHBG ........................................................................ 41 3.3.2.5 Effect of atorvastatin on androstenedione ......................................................... 41 3.3.2.6 Effect of atorvastatin on DHEAS ..................................................................... 42 Subgroup analysis and exploring heterogeneity ........................................................... 42 Sensitivity analysis........................................................................................................ 42 Discussion ....................................................................................................................44 Summary of the results of the possible adverse effect of atorvastatin on androgens ... 44 4.1.1 Effect of atorvastatin on total testosterone................................................................ 44 4.1.2 Effect of atorvastatin on free testosterone and other androgens. .............................. 45 Summary of the results of the possible beneficial effects of atorvastatin for the treatment of PCOS .................................................................................................................... 45 4.2.1 Effect of atorvastatin on total testosterone................................................................ 45 4.2.2 Effects of atorvastatin on SHBG and FAI: ............................................................... 46 xi 4.2.3 4.1.4 Effect of atorvastatin on DHEAS and androstenedione: ................................. 46 Effect of Atorvastatin on WDAEs ................................................................................ 46 Overall completeness and applicability of evidence ..................................................... 47 Certainty of the evidence .............................................................................................. 52 Potential biases and limitations in the review ............................................................... 53 Agreements and disagreements with other studies or reviews ..................................... 54 Conclusion ...................................................................................................................56 Implications for practice ............................................................................................... 56 Implications for research............................................................................................... 57 The effects of atorvastatin on androgen levels in males (a parallel group, triple-blinded, randomized controlled trial protocol) .........................................................................58 Introduction: .................................................................................................................. 58 6.1.1 Background ............................................................................................................... 58 6.1.2 How the intervention might work ............................................................................. 62 6.1.3 Study rational ............................................................................................................ 63 Research question ......................................................................................................... 63 The hypothesis .............................................................................................................. 63 Objectives ..................................................................................................................... 64 6.4.1 Primary objectives .................................................................................................... 64 6.4.2 Secondary objectives ................................................................................................ 64 Study Design ................................................................................................................. 64 6.5.1 Type of trial............................................................................................................... 64 6.5.2 Study duration: .......................................................................................................... 64 xii 6.5.3 Methods of randomisation ........................................................................................ 65 6.5.4 Blinding..................................................................................................................... 65 6.5.5 Study endpoints ......................................................................................................... 66 6.5.5.1 Primary endpoints ............................................................................................. 66 6.5.5.2 Secondary Endpoints ........................................................................................ 66 Patient selection ............................................................................................................ 66 6.6.1 Inclusion criteria ....................................................................................................... 67 6.6.2 Exclusion criteria ...................................................................................................... 67 Patient recruitment ........................................................................................................ 68 6.7.1 Target population ...................................................................................................... 68 6.7.2 Sample selection ....................................................................................................... 68 6.7.3 Sampling method ...................................................................................................... 68 6.7.4 Proportion expected to participate ............................................................................ 69 Screening and baseline evaluation ................................................................................ 69 Conduct of study ........................................................................................................... 69 Investigations to be conducted ...................................................................................... 70 Breaking of blinded codes ............................................................................................ 70 Evaluation of compliance ............................................................................................. 71 Follow-up evaluation .................................................................................................... 71 Biostatistical considerations and analysis ..................................................................... 71 6.14.1 Sample size calculation ............................................................................................. 71 6.14.2 Data analysis. ............................................................................................................ 72 Ethics............................................................................................................................. 72 xiii 6.15.1 Informed consent ...................................................................................................... 73 Study monitoring .......................................................................................................... 73 Organization .................................................................................................................. 73 Coordinating center ....................................................................................................... 73 Data monitoring board .................................................................................................. 74 Data management.......................................................................................................... 74 Authorship..................................................................................................................... 74 Limitations of the Study................................................................................................ 75 Bibliography .................................................................................................................................76 Appendices ....................................................................................................................................88 Appendix A Search strategy ..................................................................................................... 88 Appendix B Data extraction form ............................................................................................. 93 Appendix C Furukawa data ...................................................................................................... 98 Appendix D Characteristics of included studies and their risk of bias assessment ................ 102 AKBARI 2016 .................................................................................................................... 102 Chen 2014 ........................................................................................................................... 107 Gokce 2012 ......................................................................................................................... 114 Puurunen 2013 .................................................................................................................... 120 Raja-khan 2011 ................................................................................................................... 129 Sathyapalan 2009 ................................................................................................................ 136 Sathyapalan 2012 (associated with Sathyapalan 2009) ...................................................... 145 Appendix E List of excluded studies ...................................................................................... 153 Appendix F Sensitivity analysis using random effects model (forest plots) .......................... 203 xiv List of Tables Table 1-1 The normal range of free testosterone and total testosterone in males and females stratified by age (adapted from 10). ................................................................................................. 6 Table 1-2 The normal range of DHEA and DHEAS in males and females stratified by age (Adapted from14) ............................................................................................................................. 8 Table 4-1 Summary of findings table for the effects of atorvastatin on males ............................. 50 Table 4-2 Summary of findings table for the effects of atorvastatin on females .......................... 52 xv List of Figures Figure 1-1 Schematic outline of the steroidogenic pathway from cholesterol or biosynthesis of steroid hormones from cholesterol (adapted from 5) ...................................................................... 3 Figure 1-2 Statin pathway (adapted from 43) ................................................................................ 14 Figure 1-3 Chemical structures of atorvastatin (adapted from 48) ................................................. 16 Figure 3-1 PRISMA diagram for included studies ....................................................................... 31 Figure 3-2 Risk of bias summary of the included studies ............................................................. 36 Figure 3-3 Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies .................................................................................... 37 Figure 3-4 Forest plot of comparison: Atorvastatin versus control (fixed-effect model), outcome: Total testosterone in males ............................................................................................................ 38 Figure 3-5 forest plot of comparison: Atorvastatin versus control (fixed-effect model), outcome: Withdrawal due to adverse effects (WDAEs) ............................................................................... 39 Figure 3-6 Forest plot of comparison: Atorvastatin versus control (fixed-effect model), outcome: Total testosterone (females) .......................................................................................................... 40 Figure 3-7 Forest plot of comparison: Atorvastatin versus control (fixed-effect model), outcome: Free androgen index (FAI) in females. ......................................................................................... 40 Figure 3-8 Forest plot of comparison: Atorvastatin versus control (fixed-effect model), outcome: Sex hormone binding globulin (SHBG) in females ...................................................................... 41 Figure 3-9 Forest plot of comparison: Atorvastatin versus control (fixed-effect model), outcome: Androstenedione in females. ......................................................................................................... 41 Figure 3-10 Forest plot of comparison: Atorvastatin versus control (fixed-effect model), outcome: Dehydroepiandrosterone sulfate (DHEAS) in females ................................................. 42 xvi Figure 6-1 steroidogenic pathway(adapted from 82). .................................................................... 61 xvii List of Abbreviations A4 Androstenedione A5 Androstenediol ALT Alanine aminotransferase Apo B Apolipoprotein AST Aspartate aminotransferase AUC Area under the curve BMI Body mass index CENTRAL Cochrane Central Register of Controlled Trials CI Confidence interval CK Creatine Kinase CYP Cytochrome P450 CYP11A1 Cytochrome P450 Family 11 Subfamily A Member 1 DHEA Dehydroepiandrosterone DHEA-S Dehydroepiandrosterone sulfate DHT Dihydrotestosterone EqD Equilibrium dialysis HDL High-density lipoprotein HMG-COA 3-hydroxy-3methylglutary1-coenzyme A HSD Hydroxysteroid dehydrogenase IDL Intermediate-density lipoprotein LCMS Liquid-chromatography/mass spectroscopy LDL Low-density lipoprotein xviii LH Luteinizing Hormone MD Mean difference MI Myocardial infraction MOA Mechanism of action OATP Organic anion transport polypeptide PCOS Polycystic ovary syndrome PICO Population, intervention, comparison, outcome PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses RCTs Randomized controlled trials RR Risk ratio SAEs Serious adverse events SD Standard deviation SE Standard error SHBG Sex hormone binding globulin SoF Summary of findings SREBPs Sterol regulatory element binding proteins TG Triglycerides TT Total testosterone VLDL Very low-density lipoprotein WDAEs Withdrawals due to adverse effects xix Acknowledgements My sincere gratitude goes to my supervisor, Professor James Wright, for his continuous support. He has shown great patience and guidance in the course of my work on writing the thesis. I wish to express my deepest gratitude to Professor Wright for all his insightful comments and helpful suggestions which he has provided during his supervision. I wish to extend my thanks and appreciation to the distinguished committee members for their valuable remarks. Special thanks are owed to my mentor, Dr. Vijaya Musini, for the support and guidance she showed from the very beginning of my journey. I also owe particular thanks to Professor Ismail Laher for his constructive feedback. I have great appreciation for my co-authors, for all the contribution which they have provided throughout my work. I would also like to thank my colleagues in the Therapeutics Initiative and Cochrane Hypertension Review Group, Vancouver, Canada. I extend my enduring gratitude to World University Service of Canada WUSC for giving me the opportunity to pursue my studies. xx Dedication To my loving father and mother, To my two lovely sisters, With all my love. 1 Background information 1.1 Androgens Androgens are a group of sex steroid hormones which are mainly responsible for the development and maintenance of the male sex organs, and secondary male sex traits. Androgens also impact libido and sexual behavior in both males and females. Circulating androgens include testosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), androstenedione (A4), androstenediol (A5), and dihydrotestosterone (DHT). Androgens are mainly produced by the testicles, adrenal cortex, and ovaries1. 1.1.1 Steroidogenesis pathway All androgens and other steroid hormones including glucocorticoids, mineralocorticoids, estrogens, and progestogens are synthesized from cholesterol. The main source of steroid synthesis is derived from the cholesterol-containing lipoproteins in the blood plasma including LDL, and HDL. The cholesterol precursor can also come from cholesterol synthesized within the cell from acetate via the 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-COA) reductase pathway. Cholesterol can also be obtained from cholesterol ester stores in intracellular lipid droplets2. Under control of the pituitary gonadotropin luteinizing hormone (LH), the testicular Leydig cells synthesize testosterone from the cholesterol stored in them. Leydig cells can de novo synthesize cholesterol. To ensure steroidogenesis function, they can use stored cholesterol ester as well2, 3 The synthesis of steroid hormones occurs within the mitochondria and the endoplasmic reticulum, since the group of required oxidative enzymes exists only within these two intracellular organelles. The transport of free cholesterol from the cytoplasm into the mitochondria is the rate-limiting step. 2 Within the mitochondria cholesterol is converted to pregnenolone, the immediate precursor, by cytochrome P450 family 11 subfamily A member 1 (CYP11A1). Organs that contain this enzyme, such as the testicles, adrenal cortex, ovaries, and placenta, are the only ones that participate in the synthesis of steroids. The following steps of steroidogenesis are catalyzed by several enzymes that are categorized into two different groups, the cytochrome P450 (CYP) enzymes (oxidative enzymes) and the hydroxysteroid dehydrogenase (HSD) enzymes4. The ability of the organ to produce the various types of steroids is controlled by the expression of enzymes. The following figure illustrates the steroidogenesis pathway (Figure 1-1) 3 Figure 1-1 Schematic outline of the steroidogenic pathway from cholesterol or biosynthesis of steroid hormones from cholesterol (adapted from 5) 1.1.2 Testosterone Testosterone, C19 H28 O2, is the main male sex hormone that plays a crucial role in several biological processes in males such as regulating sex drive and the production of sperm. Testosterone is also involved in regulating other functions in both males and females, for instance, bone mass, muscle mass and strength, fat distribution, and erythropoiesis6. Testosterone circulates 4 in the blood in three different forms: testosterone firmly attached to sex hormone binding globulin (SHBG) (roughly 45% of total testosterone), which is biologically inactive; free testosterone (approximately 2 to 3% of total testosterone); and testosterone weakly bound to other proteins, mainly albumin (approximately 50% of total testosterone). Both free testosterone and testosterone attached to albumin are bioavailable for use by tissues7. Bioavailable testosterone are better measures than total serum testosterone to diagnose abnormal androgen status and their clinical sequelae. However, compared to tests measuring total testosterone (TT) level, bioavailable testosterone tests are time-consuming, expensive, and are not always accessible. Therefore, tests measuring TT level are commonly used to diagnose overt male hypogonadism. A limitation of measuring TT is its inability to be a reliable marker in patients who have total testosterone levels just below the normal range or in the low-normal range. To overcome this limitation and provide a more reliable indicator, some researchers use the SHBG and total testosterone in a formula to calculate an approximate estimate of bioavailable testosterone 8. The normal range of the serum total testosterone is significantly higher in adult men than adult women and varies widely depending on various factors, including the laboratory methods used and age. There is a significant increase in total testosterone in males after puberty and approximately 1% reduction in total testosterone per year in males over thirty years old 9,10,11; refer to Table 1-1). 5 Tests of blood: normal findings Free testosterone pg/mL Age/Tanner stage Male Female Postmenopausal 0.6-3.8 7 months-9 years (Tanner stage I) ≤ 3.7 < 2.2 10-13 years (Tanner stage II) 0.3-21 0.4-4.5 14-15 years (Tanner stage III) 1.0-98 1.3-7.5 16-17 years (Tanner stage IV) 35.0-196 1.1-15.5 18-19 years (Tanner stage V) 41.0-239 0.8-9.2 Free testosterone % of total testosterone Adult male 1.6-2.9 Adult female 0.1-0.3 Total testosterone ng/dL Male Female 7 months-9 years (Tanner stage I) < 30 < 30 10-13 years (Tanner stage II) < 300 < 40 14-15 years (Tanner stage III) 170-540 < 60 16-19 years (Tanner stage IV, V) 250-910 < 70 20 years and over 280-1080 < 70 6 Dihydrotestosterone pg/mL Adult male 240-650 Adult female ≤ 300 Table 1-1 The normal range of free testosterone and total testosterone in males and females stratified by age (adapted from 10). Studies and reports suggest that low serum testosterone in men is associated with health problems, such as reduced fertility and decreased libido12 . Low serum testosterone in both males and females can lead to an abnormal increase in body fat and an increase in the risk of depression. Furthermore, it can also decrease the mass and strength of skeletal muscles, reduce body hair, increase the risk of anemia by reducing the production of red cells and decrease bone density13. On the other hand, abnormally high serum testosterone in females is associated with a number of negative manifestations, such as: frontal balding, hirsutism, acne, infertility, increased muscle mass, and irregularities in menstrual cycles. 1.1.3 DHEA and DHEAS Dehydroepiandrosterone (DHEA) and DHEAS, sulfated form dehydroepiandrosterone sulfate, are considered weak androgens and they are the most bioavailable circulating steroid hormones in humans14. The adrenal synthesis is the major source of the circulating levels of DHEA and DHEAS. In addition, male and female gonads and some types of brain cells produce the remaining amount of DHEAS. DHEA is an intermediate steroid within the testosterone and estrogen pathways15. Less than 5% of TT level is from peripheral metabolism of DHEA16. However, DHEA 7 is one of the major circulating sex hormones in women by percentage. High levels of DHEAS are associated in females with hirsutism, acne and infertility, which are signs and symptoms in women with polycystic ovary syndrome (PCOS)17. The following table displays the normal range of DHEA and DHEAS in males and females (Table 1-2). 8 Table 1-2 The normal range of DHEA and DHEAS in males and females stratified by age (Adapted from14) 9 1.1.4 Androstenedione (A4) Androstenedione is a weak androgen steroid hormone, which is an intermediate in the converting process of dehydroepiandrosterone (DHEA) to estrone and testosterone18. Androstenedione plays a vital role in the development and regulation of sexual attraction. Furthermore, it affects the levels of testosterone. The normal levels of Androstenedione range from 65-210 ng/dL (2.27-7.33 nmol/L) in adult males; and 80-240 ng/dL (2.79-8.38 nmol/L) (adult females). High levels of A4 are associated with PCOS19. Sex Hormone Binding Globulin Sex hormone binding globulin, SHBG, a protein that is mainly produced in the liver, and has the ability to bind with a few hormones, including: testosterone, and dihydrotestosterone. SHBG allows sex hormones to move around the body through the bloodstream in an inactive biological form20. High SHBG means that there is less available free testosterone for cells to use, which is clinically translated into hypoandrogenism. According to an observational study, the use of statins reduces SHBG concentrations in diabetic patients,21 however, the mechanism of action is not clear, and more investigation is needed. Polycystic Ovary Syndrome Although androgens play important roles in females, abnormally high androgen levels are associated with health issues and manifestations which are traditionally diagnosed as PCOS. Females with PCOS suffer from symptoms such as hirsutism, irregular to no menstrual periods, heavy menstrual periods, acne, pelvic pain, infertility and patches of thick, darker, velvety skin21. The treatment of PCOS may include several medications to control and manage the symptoms 10 specific to each individual patient, including combination birth control pills (estrogen and progesterone) which decreases androgen levels; spironolactone which reduces hair growth by blocking the effects of androgen on the skin; metformin, clomiphene, and letrozole which help to stimulate ovulation22. Furthermore, some studies suggested that statins can help with managing some of the manifestations of PCOS that were mentioned previously by reducing excess androgen levels23. These studies were funded by pharmaceutical industry thus represent an attempt to find another indication for statins. These studies represent an indication that the drug industry is aware that statins are likely to reduce androgen levels. Statins Statins are 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase inhibitors, a class of drugs mainly prescribed to lower blood cholesterol. Statins are the most prescribed class of drugs in Canada and in the world 24 25; in Canada, approximately 3 million people aged 20 to 79 (12%) have taken a statin during the period 2007 to 2011 and one in four Canadians are potentially eligible for statin treatment 26. There are seven approved statins in Canada: atorvastatin (Lipitor), fluvastatin (Lescol, Lescol XL), lovastatin (Mevacor, Altoprev), pravastatin (Pravachol), rosuvastatin (Crestor), simvastatin (Zocor), and pitavastatin (Livalo). One statin, cerivastatin, was marketed and withdrawn from the market due to a higher incidence of severe rhabdomyolysis27. Statins can be classified based on the source: some are derived from fungal metabolites such as pravastatin and simvastatin and some are entirely artificial compounds like rosuvastatin and atorvastatin28. These agents have different chemical structures which lead to differences in water solubility and half-life. The half-life of statins ranges widely from 1 hour to 19 hours for fluvastatin and rosuvastatin, respectively29. Pravastatin and rosuvastatin are relatively hydrophilic which 11 means they are not substantially metabolized by CYP450 enzymes. On the other hand, all other statins are lipophilic, and are metabolized by CYP450 enzymes28. The main difference among statins is their efficacy in reducing LDL cholesterol. Rosuvastatin and atorvastatin have the greatest ability to reduce LDL for recommended doses, 55%-60% reduction of LDL 30while fluvastatin has the least ability to reduce LDL for the recommended doses, 28% reduction.31 1.4.1 Statin Indications Statins are highly effective in reducing low-density lipoprotein (LDL) cholesterol32 . They can also reduce triglycerides (TG), and apolipoprotein B (apo B). In addition, they slightly increase high-density lipoprotein (HDL). The approved indications for atorvastatin are to treat a wide range of dyslipidemia and hypercholesteremia including primary hypercholesterolemia; combined hyperlipidemia; dysbetalipoproteinemia; hypertriglyceridemia; and homozygous and heterozygous familial hypercholesterolemia33. They are commonly recommended for use as an adjunct to diet, if the diet fails to reduce LDL to less than 190 mg/dL (4.9 mmol/L) for example in children 10 to 17 years of age with heterozygous familial hypercholesterolemia32,34. Statins are prescribed to prevent cardiovascular disease. Statins are widely used in adult patients for primary and secondary prevention of adverse cardiovascular events35. While the effectiveness of statins in reducing the risk of myocardial infraction (MI) and stroke in secondary prevention is well established 36, their effectiveness in primary prevention is controversial. A Cochrane review on the question in 2011 concluded that caution should be taken before prescribing statins for primary prevention patients37. When this review was updated in 201338, the interpretation was changed to no longer discourage prescribing for primary prevention. In contrast, the Therapeutic 12 Initiative systematic reviews concluded that the observed decrease in mortality was most likely due to bias and since there was no effect on total serious adverse events (SAEs), there is no net health benefit of statins in a primary prevention population39,40. Furthermore, the effectiveness of statins has not been well-studied in subgroups like older people (especially females). While there are some studies supporting the use of statins as part of the treatment for PCOS, as statins can have anti-hyperandrogenism and anti-inflammatory properties; the use of statins for PCOS remains controversial, and there are no guidelines that recommend statins for PCOS. 1.4.2 Mechanism of action Atorvastatin inhibits the enzyme that converts HMG-CoA into a cholesterol precursor called mevalonic acid in hepatocytes and other cells. Atorvastatin molecules bind reversibly, and competitively to the active site, change the conformation of the enzyme, which leads to preventing the enzyme from acquiring a functional structure. Inhibition of HMG–CoA reductase, leads to a decline in intracellular cholesterol, resulting in the activation of a protease that cleaves the sterol regulatory element binding proteins (SREBPs) from the endoplasmic reticulum. SREBPs are translocated into the nucleus and increase the gene expression for LDL receptors in hepatocytes. This leads to a reduction of the circulating LDL and both intermediate-density lipoprotein (IDL) and very low-density lipoprotein (VLDL), precursors for LDL41. (Figure 1-2) 13 In terms of its potential effect on testosterone, atorvastatin likely decreases the availability of cholesterol, which is a crucial substrate for testosterone production, leading to a decline in serum testosterone42. The reduction of androgen levels can be potentially harmful and an adverse side effect in males and females with normal or below normal testosterone levels. However, women with PCOS (hyperandrogenism) may reap benefits from reduced androgen levels. Distinguishing between these two clinical settings is crucial when the effect of statins on androgen levels are being evaluated. 14 Figure 1-2 Statin pathway (adapted from 43) 1.4.3 Safety of statins Statins are associated with a number of potential adverse effects. Such adverse effects can be divided into two groups, common and serious adverse effects. Common adverse effects include 15 headache; nausea; vomiting; constipation; diarrhea; rash; insomnia; myalgia; dyspepsia; pain in extremities; upper respiratory infection; arthralgia; creatine kinase (CK) elevated; alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevated; cognitive impairment; and gynecomastia. Serious adverse effects include muscle symptoms; ranging from muscle pain and weakness to rhabdomyolysis; tendon rupture; acute renal failure; hepatotoxicity; pancreatitis; hypersensitivity reaction; anaphylaxis; photosensitivity; toxic epidermal necrolysis; erythema multiforme; Stevens-Johnson syndrome; thrombocytopenia; leukopenia; hemolytic anemia; diabetes mellitus; and interstitial lung disease44. The most relevant adverse effect in terms of this thesis is gynecomastia. This is listed as a common side effect of statins, which means it occurs in >1% of patients. It is a condition clinically defined by an enlargement of male breast tissue along with other histopathological characteristics including benign proliferation of glandular male breast tissue45. While the mechanism of action is unclear, statins could lead to gynecomastia via an increased production of estrogen, decreased production of androgens, or a combination of both. According to a recent case control study based on 6147 cases, the use of statins is associated with an increased risk of gynecomastia46. The occurrence of gynecomastia among male patients receiving statins most likely reflects an effect of to reduce androgen serum levels and coincides with the thesis hypothesis. A Therapeutic letter summarized the evidence on the potential side effects of statins provided by meta-analysis, randomized controlled trials (RCTs), observational studies, and case studies. This letter concluded that there is uncertainty about the magnitude of most statin side effects which are usually dose related and sometimes are serious47. 16 All statins share the same mechanism of action in which the inhibition of HMG-COA reductase happens at an early stage of the mevalonate pathway leading to a decline in a number of other important products including vitamin D; coenzyme Q10, heme A; isoprenylated proteins, sex steroids, and corticosteroids. In this systematic review, we only focus on the effect of atorvastatin on testosterone and other androgens. Atorvastatin Atorvastatin is the most prescribed member of the statin class which is why we selected it as the intervention for this systematic review. (Figure 1-3) Figure 1-3 Chemical structures of atorvastatin (adapted from 48) 1.5.1 Atorvastatin Pharmacokinetics 1.5.1.1 Absorption and distribution After oral administration, atorvastatin is rapidly absorbed; reaching peak plasma concentration within one to two hours34. 17 1.5.1.2 Metabolism Cytochromes P-450 3A4 and P-450 3A5 extensively metabolize atorvastatin to two active metabolites ortho and para hydroxylated derivatives. Those metabolites increase the half-life of inhibitory activity for HMG-CoA reductase (about 20 to 30 hours) and are responsible for roughly 70% of the inhibitory activity of HMG-CoA reductase. Atorvastatin and its metabolites undergo a complex metabolic pathway which involves several enzymes including, CYP3A4. that mediates different reactions such as oxidations, β-oxidation, lactonization, and hydrolysis, as well as, uridine-diphospho-glucuronyltransferases (UGTs) which mediates glucuronidation28, 34,49. 1.5.1.3 Excretion and Elimination The liver and gut wall are the main organs which contribute to the elimination of atorvastatin and its metabolites. While the biliary route is the major route of elimination, the urinary route is only responsible for 1% - 2% 34. 1.5.1.4 Onset The maximal lipid lowering effect of atorvastatin is seen after 3 weeks of daily intake34. 1.5.2 Atorvastatin Pharmacodynamics 1.5.2.1 Atorvastatin Efficacy A Cochrane Review showed that atorvastatin 2.5 mg/day to 80 mg/day reduces total blood LDL-cholesterol by 27.3% to 52%, respectively50,49. 18 1.5.2.2 Drug Interactions Since atorvastatin is metabolized by CYP3A4, inhibitors of CYP3A4 increase atorvastatin concentrations in plasma increasing atorvastatin’s effects and likely increasing the risk of myopathy or rhabdomyolysis. Inducers of CYP3A4 may cause variable reductions in plasma atorvastatin concentrations. Another potential interaction can occur with inhibitors of organic anion transport polypeptide (OATP) 1B1, which increases the bioavailability of atorvastatin34. Drugs such as antifungals, azoles, cyclosporine, and macrolides (i.e., clarithromycin, erythromycin) inhibit CYP3A4 and increase atorvastatin peak plasma concentration and area under the curve (AUC)34. By a different mechanism combining atorvastatin with other lipid lowering agents such as niacin (antilipemic dosages [≥1 g daily]) and fibric acid derivatives (e.g., fenofibrate, gemfibrozil), can inhibit the glucuronidation of atorvastatin and its metabolites and therefore reducing atorvastatin elimination and leading to increased levels and effects of atorvastatin51. Rationale Based on the mechanism of action (MOA) of atorvastatin; a decline in the levels of testosterone and other androgens will likely occur in patients taking atorvastatin as atorvastatin decreases the availability of cholesterol a crucial precursor for androgen production. Due to the widely increasing use of atorvastatin and the important role of testosterone in both men and women, concerns have been raised about the effect of atorvastatin on serum testosterone in men and women. A non-Cochrane systematic review, conducted by Schooling (2013)42, attempted 19 to address the effect of statins on testosterone. However, this review has a number of limitations. Firstly, it is out of date (searched until the end of 2011) with a limited search strategy that included MEDLINE and ISI web only and only looked at English publications. Secondly, the review was limited to adults, thus excluding adolescents and children who are potentially particularly vulnerable to reduced serum testosterone levels during their growing years. Thirdly, no protocol was pre-published and there are errors in the data they included. Finally, the systematic review was potentially biased as it was funded by Medimmune Inc., one of the manufacturers of Rosuvastatin. At present, there is no Cochrane Review that addresses the question: what is the effect of atorvastatin on serum testosterone? 20 Methods Criteria for considering studies for this review 2.1.1 Types of studies All randomized controlled trials (RCTs) with a minimum duration of 3 weeks that compared Atorvastatin to placebo or no treatment and measured one or more of the androgenic outcomes were included in this review. 2.1.2 Types of participants Participants of both sexes may be of any age with normal lipid parameters or any type of hyperlipidemia or dyslipidemia. We included participants with various comorbid conditions: diabetes mellitus, hypertension, metabolic syndrome, chronic renal failure, polycystic ovary syndrome, or cardiovascular diseases. 2.1.3 Types of interventions For the intervention arm, we included Atorvastatin doses that ranged from 2.5 mg/day to 80 mg/day and administered daily for at least three weeks. We have chosen a three-week time window in order to allow for a steady-state effect of Atorvastatin to occur. 21 2.1.4 Types of outcome measures 2.1.4.1 Primary outcome The primary outcome in this study is the absolute change in total testosterone concentrations. When the absolute change was reported at different time periods, we chose the absolute change at the longest time period. 2.1.4.2 Secondary outcomes • Absolute change in free testosterone. • Absolute change in FAI. • Absolute change in DHEAS. • Absolute change in A4. • Absolute change in SHBG. (When the absolute change was reported at different periods for these outcomes, we chose the absolute change at the longest period). • Patient withdrawals due to adverse drug effects. Search methods for identification of studies 2.2.1 Electronic searches The Cochrane Hypertension Information Specialist searched the following databases without language, publication year or publication status restrictions: • the Cochrane Hypertension Specialised Register via the Cochrane Register of Studies (CRS-Web) (searched 14 September 2019); 22 • the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies (CRS-Web) (searched 14 September 2019); • MEDLINE Ovid (from 1946 onwards), MEDLINE Ovid Epub Ahead of Print, and MEDLINE Ovid In-Process & Other Non-Indexed Citations (searched 14 September 2019); • Embase Ovid (from 1974 onwards) (searched 14 September 2019); • ClinicalTrials.gov (www.clinicaltrials.gov) (searched 14 September 2019); • World Health Organization International Clinical Trials Registry Platform (www.who.it.trialsearch) (searched 14 September 2019). The Information Specialist modelled subject strategies for databases on the search strategy designed for MEDLINE. Where appropriate, they were combined with subject strategy adaptations of the highly sensitive search strategy designed by Cochrane for identifying randomized controlled studies (as described in the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0, Box 6.4.c52. The MEDLINE search strategy was translated into the other databases using the appropriate controlled vocabulary, as applicable. We present search strategies for major databases in (Appendix A). 2.2.2 Searching other resources The Cochrane Hypertension Information Specialist searched the Hypertension Specialised Register segment (which includes searches of MEDLINE, Embase, and Epistemonikos for 23 systematic reviews) to retrieve existing reviews relevant to this systematic review, so that we can scan their reference lists for additional trials. The Specialised Register also includes searches of CAB Abstracts & Global Health, CINAHL, ProQuest Dissertations & Theses and Web of Science for controlled trials. We checked the bibliographies of included studies and any relevant systematic reviews identified for further references to relevant trials. Where necessary, we contacted authors of key papers and abstracts to request additional information about their trials, or clarification and further data if trial reports are unclear. We also searched the following resources for additional information. ▪ Pfizer website (www.pfizer.ca/en/our_products). ▪ US Food and Drug Administration website (www.fda.gov). ▪ European Patent Office website (worldwide.espacenet.com). Data collection and analysis 2.3.1 Selection of studies Two review authors independently, in duplicate, screened the title and the abstract records which were retrieved by the search results. We used the Covidence software to code the title and abstract records as ‘yes,’ ‘no’ or ‘maybe’ by applying the eligibility criteria. We excluded articles if the citation appeared completely irrelevant after reading the title and abstract. We resolved disagreements in the coding by discussion to reach consensus. We obtained the full-text papers for all records coded as ‘included' and 'maybe' at the title and abstract screening stage. Two review 24 authors independently screened the full-text papers in duplicate to decide which studies meet the inclusion criteria. We resolved disagreements by discussion, with adjudication by a third review author (JMW) in the event of non-consensus. We provided the reasons for exclusion and bibliographic details for all excluded articles (full-text level). We identified multiple full-text papers of the same study, which we linked and treated as a single study. We also checked the list of references in the included studies and the articles that cited the included studies in Google Scholar to identify relevant articles. We provided a PRISMA chart diagram to document and report the flow of records and studies through a systematic review process 53.(See figure 1-3) 2.3.2 Data extraction and management We used an electronic data extraction form based on the Cochrane Public Health template 54, modified to allow extraction of all data required for this review (appendix B). Two authors independently performed the extraction form and followed by a cross-check. We described the characteristics of each included study in the Characteristics of Included Studies table. We included in the data extraction form details on study design, type of masking, PICO (population, intervention, comparison, outcome) elements: primary and secondary outcomes, effect estimates, mean differences, confidence intervals, standard deviation for each group and main differences, details of intervention and comparator, duration of intervention, baseline characteristics of the participants, statistical analysis, the follow-up duration, number of participants lost to follow-up, and funding source. We resolved discrepancies by rechecking the data, discussion and consensus between the two review authors. When we are not able to reach an agreement, a third reviewer (JMW) acted as arbiter. When necessary, we contacted the authors of the studies to provide 25 clarification on ambiguous information. All extracted data was entered and double-checked in RevMan 5.3 software. Assessment of risk of bias in included studies We independently assessed the risk of bias of the included studies using the Cochrane risk of bias tool (version 1) following chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions for the following domains55: • Sequence generation (selection bias); • Allocation sequence concealment (selection bias); • Blinding of participants (performance bias); • Blinding of outcome assessors (detection bias); • Incomplete outcome data (attrition bias); • Selective outcome reporting (reporting bias); and • Other potential sources of bias (conflict of interest, funding source) We produced 'Risk of bias ' tables as outlined in the Cochrane Handbook for Systematic Reviews of Interventions, Chapter 8. We reported this information in the 'Risk of bias' tables associated with each included trial. 26 We included all studies regardless of the assessment of the risk of bias in the meta-analysis. We performed a sensitivity analysis excluding studies with a high risk of bias to explore their impact on the treatment effect estimate. This risk of bias across studies informed the GRADE assessment of the certainty of evidence as one of the features of the GRADE framework. Measures of treatment effect For continuous outcomes, we calculated the mean difference (MD) by using mean values, corresponding standard deviations, and treatment arm sizes. Moreover, we analyzed the data using 95% CIs. We summarized categorical data (withdrawals due to adverse effects) as risk ratios with 95% CIs. We used an intention-to-treat analysis. Unit of analysis issues Since there is no cross-over trial included we did not have any unit of analysis issues for cross-over trials. For multi-arm trials, if a study reported more than one intervention arm (different drugs), we identified the relevant intervention arm (atorvastatin in any dose) and included that in the review. Dealing with missing data We sought missing or unclear data from reports of included studies by contacting the study authors using the contact information provided in the respective articles. 27 2.7.1 Missing statistics The most common type of value that is not reported is the standard deviation (SD) of the change. If a standard error (SE) was given instead of a standard deviation (SD), we used the formula SD = SE x square root of n (number of participants) to calculate the SD. We also calculated SD if 95% CI, P-value, t value, was reported in the included studies according to chapter 7 of the Cochrane Handbook. If we were not able to obtain the SD from the study authors or calculate from the values mentioned above, we imputed SD using the following hierarchy (listed from highest to lowest): • SD of the end of treatment value. • SD of the baseline treatment value • Average weighted standard deviation of the change from other trials in the review (Furukawa 2006)56. Appendix C. Assessment of heterogeneity We assessed statistical heterogeneity in results by inspection of a graphical display of the estimated treatment effects from included studies along with their 95% CIs and by formal statistical tests of measures of inconsistency (I2 statistic)57. If the I2 statistic value is greater than 50%, we investigated the reasons behind the heterogeneity by looking for clinical and methodological differences between trials. Assessment of reporting biases Funnel plot was not used as planned in the protocol since there were less than 10 studies that contributed to a meta-analysis in order to detect the extent of risk of reporting bias based on the 28 symmetry of the plot. However, the other types of reporting bias have been discussed, for example multiple publication bias, outcome reporting bias, and language bias.58 Data synthesis We used Review Manager 5.3 to perform data synthesis and meta-analyzed the results of clinically and statically homogeneous studies (Review Manager 2014)59 analysis for these groups (males, females and overall) separately. We performed meta-analyses using the Mantel-Haenszel method for dichotomous outcomes (risk ratio (RR)) with 95% CI using a fixed-effect model, and the inverse variance method for continuous outcomes as MD with 95% CI using fixed-effect model. Subgroup analysis and investigation of heterogeneity We planned on performing subgroup analysis based on the following: • According to various doses. • Males vs females. • Age ≥ 60 years versus < 60 years. • Children (age < 18 years) versus adult (≥ 18 years). It was not possible to conduct a subgroup analysis based on the age since we do not have enough data. Sensitivity analysis The following sensitivity analyses were performed: • We checked if high risk of bias trials affected the effect estimate of total testosterone, DHEAS, and A4 29 • To check for the difference between the effect estimates of the outcomes derived by using the fixed-effect model and the random-effects model, we conducted sensitivity analysis. • To explore the impact of data that we imputed due to missing data. Overall grading of certainty of evidence - 'Summary of findings' tables We used GRADEpro software (GRADEpro GDT)60 (Grading of Recommendations, Assessment, Development and Evaluation) to produce an evidence profile table and used that to generate the 'Summary of Findings' table61. We considered the following domains in assessing the overall certainty of evidence: limitations in study design and implementation (risk of bias), indirectness of evidence, unexplained heterogeneity or inconsistency of results, imprecision in results and high probability of publication bias. The certainty of the body of evidence was assessed as high, moderate, low or very low and review authors' comments were provided to support the judgements as outlined in the Cochrane Handbook of systematic Reviews. RCTs started at a high level of certainty and were downgraded by one level for each domain judged to have a high risk of bias57,62. 30 Results Description of studies 3.1.1 Results of the search Database searching identified 6964 citations. After duplicates were removed, 6942 records remained. After irrelevant citations were removed, 297 records remained. The remaining 297 records were obtained as full-text articles and assessed for eligibility. Fifteen citations to six studies63,64,65,66,67,68,69 met the inclusion criteria (Figure 3-1). 3.1.2 Included studies We have summarized each included study in the Characteristics of Included Studies (See Appendix D). All the six studies were published in English. They included 265 participants and all of them had a parallel-group design. Among the six studies included, one was single-blind, 4 were double-blind, and one was open-label. Two of the studies included only male participants (N=140), with a mean age of 68 years. One of them included exclusively healthy participants while the other study included participants with mild dyslipidemia and osteopenia. Four of the studies included female participants (N=125) and the mean age was 32 years. All the participants in the four female studies had polycystic ovary syndrome (PCOS). The dose of Atorvastatin, in the two male studies, was 10 mg. The dose of Atorvastatin was 20 mg in two of the female studies, and 40 mg in the remaining two studies. 31 Figure 3-1 PRISMA diagram for included studies 3.1.3 Excluded studies We excluded 282 articles after reviewing the full-text articles; the reasons for exclusion were recorded (Appendix E). The majority of articles were excluded for not measuring and reporting the outcomes of this review (264 articles). We excluded 7 articles due to incorrect study design. In addition, one 32 study was excluded because it measured the testosterone levels but did not report them (see figure 3-1 for more reasons). Risk of bias in included studies We independently assessed the risk of bias following the methodology described in the Cochrane Handbook for Systematic Reviews of Interventions chapter 8 version 1.00. We assessed the risk of bias based on 14 domains: random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias) for each outcome (total testosterone, free testosterone, FAI, SHBG, DHEAS, androstenedione), selective reporting (reporting bias) for WDAEs, selective reporting (reporting bias) for all other outcomes, and other biases (conflict of interest, industry sponsorship). We classified each domain as being at a low, high or uncertain risk of bias. In the case of disagreement, JMW was involved in order to discuss and resolve the disagreement. The expected direction of risk of bias would be to exaggerate the anti-androgen effect in the case of PCOS (potential treatment), and to underestimate the reduction in androgens when it is was studied and measured as a potential adverse effect of atorvastatin. 3.2.1 Allocation (selection bias) We assessed selection bias based on two categories: random sequence generation and allocation concealment. 33 For random sequence generation, of the six included studies, five studies were classified as low risk of bias since they used and described a true randomization method. One study (Akbari 2016)63 was classified as uncertain risk of bias, since the method of randomization was not described. For allocation concealment, three included studies (Akbari 201663, Chen 201467, and Gokce 201268) were classified as uncertain risk of bias because the method of allocation concealment was not reported. The remaining three studies were classified as low risk of bias due to the application of appropriate methods such as central allocation (pharmacy-controlled randomization and sequentially numbered drug containers) in the Puurunen 2013 trial, or allocation by external personnel who were not involved in the trial. 3.2.2 Blinding (performance bias and detection bias) All the six studies were classified as low risk of performance and detection bias as we consider the individuals measuring laboratory outcomes were not aware of the treatment allocation. For withdrawals due to adverse effects (WDAEs), a lack of blinding could have had an effect. Four studies (Akbari 201658, Puurunen 2013 70, Sathyapalan 200965, and Raja-khan 201171) were classified as uncertain risk of bias, since the blinding was not described. Two studies (Chen 2014, and Gokce 2012) were classified as high risk of bias, since they were open label and single-blind, respectively. 3.2.3 Incomplete outcome data (attrition bias) We assessed the attrition reporting bias based on six outcomes: total testosterone, free testosterone, free Androgen Index, Androstenedione, SHBG, and DHEAS. For total testosterone, three studies 34 (Akbari 2016, Chen 2014, and Sathyapalan 2009) were classified as a low risk given that either all participants were included in the final analysis, or missing data were balanced across intervention and control groups with a similar reason for missing data across groups. Two studies (Gokce 2012, and Raja-khan 2011) were classified as uncertain risk of bias since 10% of participants did not complete the trial but the authors included all the data of all participants in the analysis. One study (Puurunen 2013) was classified as high risk of bias, since 21.1% of participants were not included in the analysis for the Atorvastatin group, and 31.6% of participants were not included in the analysis for the placebo group. For Androstenedione and DHEAS, only four studies measured these outcomes. Two studies (Akbari 2016, and Sathyapalan 2009) were classified as low risk of bias, the Puurunen 2013 study was classified as high risk of bias, and the Raja-khan 2011 study was assessed as uncertain risk of bias. (see the risk of bias table in appendix D) 3.2.4 Selective reporting (reporting bias) We assessed this separately for WDAEs and for all other outcomes. For WDAEs, four studies were classified as low risk of bias (Akbari 2016, Chen 2014, Gokce 2012, and Puurunen 213) because they recorded and reported the WDAEs in the result section. Two studies (Raja-khan 2011, and Sathyapalan 2009) were classified as high risk of bias since the WDAEs were not reported separately from withdrawals due to other reasons. For all other outcomes, three studies (Akbari 2016, Chen 2014, and Gokce 2012) were classified as uncertain risk of bias since no protocol was published and there was insufficient information to evaluate if it was low or high risk of bias. Two studies (Puurunen 2013, and Raja-khan 2011) were classified as low risk of bias since all the study’s prespecified outcomes were reported. One study 35 (Sathyapalan 2009) was classified as a high risk of bias since one reported primary outcome (HS-CRP) was not prespecified in the ISRCTN24474824 registry. 3.2.5 Other potential sources of bias The other potential sources of bias assessed include industry sponsorship. Two studies [Chen 2014, and Puurunen] were classified as low risk of bias because they were funded by government grants. Two studies (Akbari 2016, and Gokce 2012) were classified as uncertain risk of bias since the funding source was not reported. Two studies (Raja-khan 2011, and Sathyapalan 2009) were classified as high risk of bias because they were funded partially or fully by Pfizer. 3.2.6 Publication bias There were not enough studies to construct a funnel plot for all the outcomes. However, all the studies were published in English. Only six studies from more than 268 placebo controlled RCTs of Atorvastatin have reported the total testosterone, and only two studies have reported this outcome in males. There are no studies on healthy females or children (less than 18). This suggests that there are likely RCTs measuring and demonstrating an effect of atorvastatin to reduce testosterone and other androgens that were not published, because the results of such RCTs might adversely impact the marketing of atorvastatin. 36 Low risk of bias Unclear risk of bias High risk of bias Not applicable since the trial did not report on that particular outcome Figure 3-2 Risk of bias summary of the included studies 37 Figure 3-3 Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies 38 Effects of interventions While in the general patient population, the reduction of testosterone levels caused by the administration of lipid-reducing interventions including Atorvastatin is considered an adverse side effect, this reduction is potentially beneficial in trials in which Atorvastatin is administrated as a treatment for polycystic ovary syndrome (PCOS). Because the risk of bias is in the opposite direction in these two clinical settings, we presented and pooled these two clinical settings separately. 3.3.1 The potential adverse effect of atorvastatin on androgens 3.3.1.1 Effect of atorvastatin on total testosterone level (TT)(males) Based on two studies [Chen 2014, and Gokce 2012], in 140 male participants, the mean change in TT using a fixed-effect model was -0.20 nmol/L [95% CI (-0.77, 0.37), P value = 0.49]. There was no heterogeneity, (I2=0%). Figure (3-4) Figure 3-4 Forest plot of comparison: Atorvastatin versus control (fixed-effect model), outcome: Total testosterone in males 39 3.3.1.2 Effect of atorvastatin on free testosterone levels (males) None of the included studies reported data for this outcome. 3.3.1.3 3.3.1.3 Effect of atorvastatin on WDAEs in males and females Based on five studies (Akbari 2016, Chen 2014, Gokce 2012, Puurunen 2013, and Sathyapalan 2009) in 272 participants, the risk ratio for WDAEs using the fixed-effect model was 1.00 [95% CI (0.15, 6.84), P value=1.00]. There was no heterogeneity, (I2=0%). Figure 3-5 forest plot of comparison: Atorvastatin versus control (fixed-effect model), outcome: Withdrawal due to adverse effects (WDAEs) 3.3.2 The possible beneficial effects of atorvastatin for the treatment of PCOS 3.3.2.1 Effect of atorvastatin on total testosterone level Based on four studies (Akbari 2016, Puurunen 2013, Raja-khan 2011, and Sathyapalan 2009) in 125 participants, atorvastatin decreased TT, mean decrease using a fixed-effect model was -0.27 nmol/L [95% CI (-0.50, -0.04), P value=0.02]. There was substantial heterogeneity, (I2 = 84%). 40 Figure 3-6 Forest plot of comparison: Atorvastatin versus control (fixed-effect model), outcome: Total testosterone (females) 3.3.2.2 Effect of atorvastatin on free testosterone levels None of the included studies reported data for this outcome. Only one study (Raja-khan 2011) reported free testosterone levels before the treatment and did not report it after the treatment. 3.3.2.3 Effect of atorvastatin on FAI Only two studies in females (Puurunen 2013, and Sathyapalan 2009) reported FAI in 65 participants. Atorvastatin decreased FAI; mean decrease using a fixed-effect model was -2.59 [95% CI (-3.62, -1.57), P-value <0.00001]. There was substantial heterogeneity, (I2=94%). Figure 3-7 Forest plot of comparison: Atorvastatin versus control (fixed-effect model), outcome: Free androgen index (FAI) in females. 41 3.3.2.4 Effect of atorvastatin on SHBG Only two studies in females (Puurunen 2013, and Sathyapalan 2009) reported SHBG in 65 participants. Atorvastatin increased SHBG; mean increase using a fixed-effect model was 3.11 nmol/L [95% CI (0.23, 5.99), P-value<0.03]. There was no heterogeneity, (I2=0%). Figure 3-8 Forest plot of comparison: Atorvastatin versus control (fixed-effect model), outcome: Sex hormone binding globulin (SHBG) in females 3.3.2.5 Effect of atorvastatin on androstenedione The four studies in females (Akbari 2016, Raja-khan 2011, Puurunen 2013, and Sathyapalan 2009) reported androstenedione in 125 participants. Atorvastatin decreased androstenedione; mean decrease using a fixed-effect model was -1.37 nmol/L [95% CI (-2.26, -0.49) P-value = 0.002]. There was substantial heterogeneity, (I2=68%). Figure 3-9 Forest plot of comparison: Atorvastatin versus control (fixed-effect model), outcome: Androstenedione in females. 42 3.3.2.6 Effect of atorvastatin on DHEAS Four studies in females (Akbari 2016, Raja-khan 2011, Puurunen 2013, and Sathyapalan 2009) reported DHEAS in 125 participants. Atorvastatin decreased DHEAS; mean decrease using a fixed-effect model was -0.63 μmol/L [95% CI (-1.12, -0.15) P-value=0.01]. There was no significant heterogeneity, (I2=9%). Figure 3-10 Forest plot of comparison: Atorvastatin versus control (fixed-effect model), outcome: Dehydroepiandrosterone sulfate (DHEAS) in females Subgroup analysis and exploring heterogeneity We planned to conduct several subgroup analyses according to dosage and age. Due to the small number of studies, we were not able to conduct subgroup analyses since it is recommended that there should be at least 10 studies in each of the subgroups. Sensitivity analysis As planned, we conducted a sensitivity analysis to compare the results using the random-effects model and the fixed-effect model. While the reduction in total testosterone, FAI, and androstenedione was statistically significant when the fixed-effects model was used, the reduction in all outcomes mentioned 43 above was not significant when the random-effects model was applied (see the forest plots in Appendix F).We planned on conducting sensitivity analysis on the studies based on their level of risk of bias. Most of the included studies had a similar risk of bias across all the domains except for industry sponsorship bias and incomplete data for total testosterone. Due to the inadequate number of studies, we were not able to conduct a sensitivity analysis on the included studies based on industry sponsorship. 44 Discussion This review summarizes the effects of atorvastatin on total testosterone, androstenedione, DHEAS, FAI, and SHBG serum levels in males and females. The primary focus of the review was to document the effect of atorvastatin on these outcomes as a potential adverse effect. However, in conducting the review we identified RCTs meeting the inclusion criteria in which patients with polycystic ovary syndrome (PCOS) were given atorvastatin with the goal of reducing androgens as a potential treatment. For trials studying the possible adverse effect of atorvastatin to decrease androgens, there is a potential bias towards not showing this effect or not reporting RCTs that found this adverse effect. The knowledge that atorvastatin decreased testosterone, could result in a negative impact on sales of atorvastatin. Summary of the results of the possible adverse effect of atorvastatin on androgens 4.1.1 Effect of atorvastatin on total testosterone In this review, we only found two trials investigating the effects of atorvastatin on androgen levels among males and no studies reporting the effect of atorvastatin on androgens in normal females. This was a surprising and shocking finding, as we anticipated a much larger number of studies looking at the effects of atorvastatin on androgen levels given the widespread use of atorvastatin. The dearth of studies, the small sample size and the fact that other androgens were not reported resulted in the pooled effect atorvastatin in males being a statistically insignificant reduction of total testosterone levels. In addition, the two studies we found used a relatively low dose of atorvastatin, 10 mg/day, when we know that atorvastatin daily doses of 80 mg/day are common. We highly suspect that the companies 45 marketing atorvastatin have successfully suppressed the conduct and/or publication of trials showing the reduction of testosterone and other androgens. Additionally, it is important to mention that atorvastatin is given as a treatment for children and adolescents with familial hypercholesterolemia. In this population, where reduction of androgens is more likely to be problematic, we again found no RCTs reporting the effects of atorvastatin on testosterone or other androgens. 4.1.2 Effect of atorvastatin on free testosterone and other androgens. Although free testosterone is a better indicator of the androgen status than total testosterone, no study reported the free testosterone levels. Summary of the results of the possible beneficial effects of atorvastatin for the treatment of PCOS 4.2.1 Effect of atorvastatin on total testosterone For the possible beneficial reduction of total testosterone levels among females with PCOS, the direction of the potential risk of bias is towards a reduction, as the trials are designed to demonstrate that atorvastatin can be used to treat women with PCOS. In this review, we found that atorvastatin decreased total testosterone levels in females by -0.27 nmol/l. This finding was based on four studies in females with PCOS. 46 4.2.2 Effects of atorvastatin on SHBG and FAI: Atorvastatin increased SHBG by 3.11 nmol/l in females, while it decreased FAI by 2.95 (units). These results were based on only two studies in females with PCOS. The increase in SHBG level suggests that more testosterone is bound and that there is less bioavailable free testosterone for tissues. The decrease in FAI corresponds with an increase in SHBG and a decline in TT. 4.2.3 4.1.4 Effect of atorvastatin on DHEAS and androstenedione: Atorvastatin decreased DHEAS concentration in females by 0.63 μmol/L, and androstenedione by 1.37 nmol/L. These results were based on four studies in females with PCOS. These results can be explained by the steroidogenesis pathway; the reduction in DHEAS levels would have led to a reduction in both androstenedione and testosterone levels. It is important to appreciate that the decline in androstenedione concentration may be an overestimate, since the heterogeneity in the meta-analysis was substantial and the reduction comes mostly from the Raja-khan 2011 study, which was sponsored by the pharmaceutical industry. Effect of Atorvastatin on WDAEs In the five trials that reported impact of atorvastatin on WDAEs levels, drug therapy had no significant effect on withdrawals due to adverse effects compared to placebo or no treatment. However, these were small and short-term trials and do not represent a good opportunity to determine whether atorvastatin leads to adverse effects. 47 Overall completeness and applicability of evidence Surprisingly, there is very little available published data to evaluate the effect of atorvastatin on testosterone and other androgens. Given that we have presented evidence that atorvastatin decreases testosterone and other androgens in women with PCOS, we suspect that atorvastatin also reduces testosterone in other settings. There are likely trials meeting our inclusion criteria that show this effect of atorvastatin that have not been published. It is very likely that atorvastatin reduces testosterone as a result of its mechanism of action to reduce cholesterol levels. Further strong evidence that this is occurring is the fact that gynecomastia is being recognized as an adverse effect of atorvastatin. The two studies in males, represented a range in terms of age and health condition. The participant populations were (old males with normal libido in Gokce 2012 and elder men with mild dyslipidemia in Chen 2014). The overall evidence generated in this review is insufficient to answer the question in the populations studied and cannot be extrapolated to men and women of all ages or to adults with sexual dysfunction. Regarding the studies on females, the participant population was women with PCOS predominantly in premenopausal age (younger than 40). We unfortunately do not have any trials studying the effect on females at any age without PCOS. It is, however, likely that atorvastatin does decrease androgen levels in women without PCOS and that this could have adverse consequences. There was substantial heterogeneity in the meta-analysis of the effect of atorvastatin on testosterone in females with PCOS due to the presence of one study (Sathyapalan2009). This study was funded by Pfizer. The mean reduction of total testosterone was greater in this study compared to other studies. Thus, we suspect that this reduction may be an overestimate. 48 There was substantial heterogeneity in the meta-analysis of the effect of atorvastatin on androstenedione in females due to the presence of one study (Raja-khan 2011). This study was funded by the pharmaceutical industry. The mean reduction of total testosterone was greater in this study compared to other studies. The unbalanced baseline between the comparison groups in Puurunen 2013 may explain the substantial heterogeneity between the two studies in FAI meta-analysis. 49 Summary of findings table Population: Male participants Intervention: Atorvastatin Comparison: Placebo or no treatment Outcomes Number of participants (RCTs) Mean difference of atorvastatin compared to placebo [95% CI] Certainty of evidence (GRADE) Total testosterone 140 (2) -0.20 nmol/L [-0.77 to 0.37] Very Low 1 2 3 Acronyms and grades * The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect Footnotes 1 Unclear risk of selection bias 50 2 95% confidence interval around the best effect estimate includes both negligible effect and appreciable benefit. 3 evidence was derived from only two studies which had several limitations Table 4-1 Summary of findings table for the effects of atorvastatin on males 51 Summary of findings table Population : Adult female participants with PCOS Intervention : Atorvastatin Comparison: Placebo Outcomes Number of participants (RCTs) Mean difference of atorvastatin compared to placebo [95% CI] Certainty of evidence (GRADE) Total testosterone 125 (4) -0.27 nmol/L [-0.50, -0.04] Very low 1 2 3 FAI 65 (2) -2.59 [-3.62, -1.57] Very low 1 2 3 SHBG 65 (2) 3.11 nmol/L [0.23, 5.99] low 1 3 Androstenedione 125 (4) -1.37 nmol/L [-2.26, -0.49] Very low 1 2 3 DHEAS 125 (4) -0.64 μmol/L [-1.12, -0.16] low 1 3 Acronyms and grades * The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval 52 Table 4-2 Summary of findings table for the effects of atorvastatin on females Certainty of the evidence We graded the overall certainty of evidence using the GRADE approach via the GRADEpro GDT software 60and formulated a summary of findings (SoF) table as outlined in the protocol. We constructed two SoF tables to show the certainty of evidence and summary of the effects on the outcomes of interest (total testosterone, androstenedione, DHEAS, FAI, SHBG, and WDAEs) in females (table 4.1), and the total testosterone in males (table 4.2). In this review, the certainty of evidence ranged from low to very low which suggests that the estimated effect of atorvastatin may be substantially different from the true effect. Regarding the effect of GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect Footnotes 1 High risk of bias in source of funding and sponsorship bias in more than one study 2 Significant heterogeneity 3 Small sample size 53 atorvastatin on total testosterone levels in males, the certainty of evidence was downgraded to very low due to the small size of the studies, wide confidence intervals, and the high risk of bias. Regarding the effect of Atorvastatin on total testosterone, androstenedione, and FAI in females, the certainty of evidence was downgraded to very low due to the small size of the studies, significant inconsistency, and the high risk of bias in some domains. The certainty of evidence for DHEAS, and SHBG, in studies on females was downgraded to low due to small sample size and the high risk of bias in some of the studies. Potential biases and limitations in the review We employed a robust methodology to assess biases and used comprehensive search strategies to minimize potential for bias by the authors in the selection process of included studies. A few amendments have been implemented on the protocol which were explicitly mentioned and justified. We have identified several limitations within this review, which are related to the studies that were included. We highly suspect that there are more studies which meet the inclusion criteria and were not published (publication bias) despite our efforts to search the grey literature. The included studies and its data are only applicable to specific population groups, and therefore, should not be generalized. The overall sample size of the studies was not sufficiently large to answer our question. Finally, the reporting of outcomes in some of the included studies tended to be poor in nature. The reporting of the standard deviation (SD) of the change was the main problem. In one of the male studies (Gokce 2012), the authors did not report the SD of the change or the SD of the 54 means either before or after the intervention. Thus, we imputed the SD of the change from other studies using Furukawa. In female studies, SD of change was missing, and we had to calculate it from the reported p-values and in some studies (Puurunen, and Akbari 2016) we imputed SD of change using the SD of final values. Accordingly, the results should be interpreted with caution. Another major problem related to data reporting, was the units of measurements. In one of the included studies (Gokce 2012), the units were reported incorrectly (testosterone unit was reported as ng/ml instead of ng/dl). Additionally, units were essentially missing, and the author did not report reasons for not including units (Akbari 2016). Furthermore, withdrawal due to adverse effects was not explicitly reported in some of the studies. To overcome limitations mentioned above, we have written a detailed protocol (See chapter 6) with robust methodology to conduct a well-designed statistically powered trial that we propose be conducted in the future. Agreements and disagreements with other studies or reviews One published review, Schooling 2013, examined the effect of atorvastatin on total testosterone. As discussed earlier in this review, Schooling 2013, pooled the effect of all statin agents on testosterone by assuming that they all had similar effects. We limited the focus of this review to atorvastatin only. Schooling concluded that statins reduce testosterone in both males and females. However, there are a number of limitations of the Schooling review that we have listed in the background. 55 Another published review, Yang 2019, examined the effect of atorvastatin on DHEAS. Yang 201972, pooled the effect of all statin agents on DHEAS and conducted a subgroup which analyzed that effect of atorvastatin and simvastatin separately. According to Yang 2019, atorvastatin significantly reduced DHEAS compared to simvastatin. The Yang 2019 conclusion which was based on three of the studies that were included in this review (Puurunen 2013, Raja-khan 2011, and Sathyapalan 2009), aligns with the conclusion of this review. Statin-induced gynecomastia was reported by several studies and case reports as a potential adverse effect among male patients 73,74,75.Although our review failed to show significant reduction in androgens among male patients taking statins, this could be due to publication bias and the limitations of studies included. This review did not detect a significant difference in WDAEs between the atorvastatin and the placebo groups since only two studies reported WDAEs events. A previous review50 with 43 short-term RCTs reporting WDAEs, also showed no effect of atorvastatin on WDAEs. 56 Conclusion Implications for practice This review provides the most up-to-date clinical evidence on the effects of atorvastatin on testosterone and other androgens in males and females. The studies on females were limited by trialists to women with PCOS. In adult females with PCOS, very low certainty of evidence shows that atorvastatin (20 to 40 mg daily) reduced the following androgens: total testosterone by a mean of -0.27 nmol/L, FAI by -2.59, androstenedione by -1.37 nmol/L, and DHEAS by -0.64 µmol /L, and increased SHBG by a mean 3.11 nmol/L. The indicated change in the level of androgens illustrates that through lowering cholesterol levels, atorvastatin can lower all the downstream androgens in the steroidogenic pathway. We have judged this evidence to be low to very low and it is unknown whether a reduction of androgens by atorvastatin in women with PCOS would have any beneficial clinical effects. The studies on males were limited by trialists to men with normal libido. In this specific population, using 10 mg of atorvastatin did not have a significant effect on total testosterone levels with very low certainty of evidence. It is impossible to know with the limited data available whether atorvastatin reduces androgens but given the mechanism of action, the fact that atorvastatin reduces androgens in women with PCOS and can be associated with gynecomastia, we have a high index of suspicion that it does reduce androgens in most if not all settings. Therefore, healthcare providers should be aware of the potential reduction in androgens by atorvastatin and inform patients of this potential adverse effect. 57 Implications for research This review provides better understanding of the available evidence on the effects of atorvastatin on androgens and sheds light on the absence of high-quality evidence in certain patient populations. Based on our findings, we recommend the following: 1. More RCTs are needed to evaluate the effects of atorvastatin on androgens in females with PCOS. 2. More RCTs are needed to evaluate the effects of atorvastatin on androgens in males using higher doses of atorvastatin. 3. The review did not find any eligible RCTs that report the effects of atorvastatin on children, healthy females, or males with abnormal libido. Future RCTs in these populations are needed. 4. The procedure of randomization and blinding must be described in detail within published reports. 5. Trials should report the SD of the change and the unit of measurement used. 6. Reporting of withdrawal due to adverse effects should be mandatory for all trials. 7. Free testosterone should be measured and reported as it provides a better indication of androgen status. 58 The effects of atorvastatin on androgen levels in males (a parallel group, triple-blinded, randomized controlled trial protocol) Introduction: 6.1.1 Background Androgens are defined as steroid hormones, whether they are natural or synthetic compounds, which play a role in regulating the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. There are several types of androgens in males: testosterone, dehydroepiandrosterone sulfate (DHEA-S), androstenedione (A4), and dihydrotestosterone (DHT). Testosterone, C19 H28 O2, is the main male sex hormone and plays a crucial role in several biological processes, particularly, in males such as regulating sex drive and the production of sperm. Testosterone is also involved in regulating some other functions in males, for example, bone mass, muscle mass and strength, fat distribution, and the production of red cells6. Testosterone circulates in the blood in three different forms: as testosterone firmly attached to sex hormone binding globulin (SHBG) (roughly 45% of total testosterone), which is biologically inactive; as free testosterone (approximately 2% to 3% of total testosterone); and as testosterone weakly bound to other proteins, mainly albumin (approximately 50% of total testosterone). Both free testosterone and testosterone attached to albumin are bioavailable for use by tissues 7. Bioavailable and free testosterone are better measures than total serum testosterone to diagnose abnormal androgen status and their clinical sequelae. However, bioavailable and free testosterone tests are time-consuming, expensive and not always available. Therefore, determining total 59 testosterone level, which is easy and relatively cheap, is commonly used to diagnose overt male hypogonadism. However, it is an unreliable marker in patients who have total testosterone levels just below the normal range or in the low-normal range. To overcome this issue and provide a more reliable indicator, some researchers use the SHBG and total testosterone with a formula to calculate an approximate estimate of bioavailable or free testosterone 76. The normal ranges of the serum total testosterone in adult males vary widely depending on various factors, including the age and the laboratory methods used. There is a significant increase in total testosterone in males after puberty and approximately 1% reduction in total testosterone per year in males over thirty years old9 Studies and reports suggest that low serum testosterone in men is associated with health problems, such as reduction in fertility and decreased libido. Low testosterone in males can also increase body fat and the incidence of depression. It can also decrease mass and strength of muscles, decrease body hair, decrease the production of red cells leading to anaemia, and decrease bone density77 . Statins are 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase inhibitors, a class of drugs mainly prescribed to lower blood cholesterol. They are widely used in adult patients for primary and secondary prevention of cardiovascular events35. They are also used to lower cholesterol in people of all ages with heterozygous familial hypercholesterolaemia and mixed dyslipidemia78. They are considered to be a highly effective class of drugs in reducing low-density lipoprotein (LDL) cholesterol78. 60 Dehydroepiandrosterone (DHEA) is a major steroid hormone produced in the adrenal cortex from cholesterol. It is considered the primary precursor of natural estrogens in women79. Dehydroepiandrosterone sulfate (DHEAS), the sulfated form of DHEA, an androgen which exists in both men and women. It plays a role in developing male secondary sexual characteristics at puberty and can be converted by the body into testosterone and androstenedione or estrogen79. Androstenedione (A4) is 19 carbon (C19) steroid produced by the testes, adrenal cortex, and ovaries. Androstenediones are metabolized to testosterone and other androgens or can be converted to estrone80. Testosterone is converted by 5α-reductase catalyzes to Dihydrotestosterone in certain tissues including the prostate gland, seminal vesicles, and skin. DHT is 2.5 time more potent androgen than testosterone, since it binds more strongly to the androgen receptor. The concentration of DHT is almost 1/10 the testosterone levels. Excessive DHT concentration is associated with hirsutism, benign prostatic hyperplasia (BPH) and prostate cancer81. 61 Figure 6-1 steroidogenic pathway(adapted from 82). Atorvastatin is the most prescribed member of the statin class, which are amongst the most commonly prescribed medications worldwide83,84 . In Canada, approximately 3 million people aged 20 to 79 (12%) have taken a statin during the period 2007 to 2011 and one in four Canadians are potentially eligible for statin treatment 85. Studies illustrate that long-term statin therapy in secondary prevention significantly reduces all-cause mortality and major adverse cardiovascular 62 events (myocardial infarction (MI), and stroke). However, it remains controversial whether they reduce mortality in primary prevention patients86. Atorvastatin is rapidly absorbed after oral administration; reaching peak plasma concentration within one to two hours. Atorvastatin is extensively metabolised by cytochromes P-450 3A4 and P-450 3A5 to two active metabolites ortho- and para hydroxylated derivatives, which contribute to approximately 70% of the inhibitory activity for HMG-CoA reductase. These two active metabolites also increase the half-life of inhibitory activity for HMG-CoA reductase (about 20 to 30 hours)28. A Cochrane Review shows that 2.5 mg/day to 80 mg/day of atorvastatin reduces total blood LDL-cholesterol by between 27.3% and 52%, respectively30. Although atorvastatin is generally well tolerated, it is associated with potential adverse effects. Such adverse effects can be divided into two groups: minor adverse effects, such as headache, nausea, vomiting, constipation, diarrhea, and rash, and more serious adverse effects, such as statin-associated muscle symptoms, ranging from muscle pain and weakness to rhabdomyolysis, new onset diabetes mellitus, and an increase in hepatic transaminases87. 6.1.2 How the intervention might work Atorvastatin inhibits the enzyme that converts HMG-CoA into a cholesterol precursor called mevalonic acid in hepatocytes. Atorvastatin molecules bind reversibly to the active site, change the conformation of the enzyme, which leads to preventing the enzyme from acquiring a functional structure. Inhibition of HMG–CoA reductase, leads to a decline in the intracellular cholesterol, resulting in the activation of a protease which cleaves the sterol regulatory element binding proteins (SREBPs) from the endoplasmic reticulum. SREBPs, in their turn, are translocated in the 63 nucleus and increase the gene expression for LDL receptors in hepatocytes, which leads to a reduction of the circulating LDL and both intermediate-density lipoprotein (IDL) and very low-density lipoprotein (VLDL), precursors for LDL88. Atorvastatin decreases the availability of cholesterol, which is a crucial substrate for testosterone production, and may lead to a decline in serum testosterone and other androgens. 6.1.3 Study rational Due to the widely increase in usage of atorvastatin and the important role of serum testosterone in males, concerns have been raised about its influence on serum testosterone in men. We conducted a Cochrane systematic review to address the effect of atorvastatin therapy on testosterone. However, our conclusion was not definitive, and the certainty of evidence was very low, since only two small studies, which were assessed as high risk of bias studies, in males met our inclusion criteria. Thus, this study aims to assess the effect of atorvastatin on androgens in adult males compared to placebo. Research question Does atorvastatin therapy decrease the levels of androgens in adult male patients, as compared to placebo? The hypothesis Atorvastatin therapy reduces androgen levels, including (testosterone level, A4, DHT, DHEAS) as compared to placebo. 64 Objectives 6.4.1 Primary objectives To measure the effect of atorvastatin on free testosterone, and total testosterone, as compared to placebo. 6.4.2 Secondary objectives 1. To measure the effect of atorvastatin on DHT levels as compared to placebo. 2. To measure the effect of atorvastatin on DHEAS levels as compared to placebo. 3. To measure the effect of atorvastatin on A4 levels as compared to placebo. 4. To assess the effect of atorvastatin on Withdrawal due to adverse effects (WDAEs). Study Design 6.5.1 Type of trial This is a prospective, triple blinded (researchers, patients and assessors), multi-centre, randomized controlled trial. Male adult patients between the 30 to 60 years old with normal libido and mild dyslipidemia who meet the inclusion criteria will be randomized to receive either atorvastatin 40 mg once daily or placebo once daily for a minimum period of three months. 6.5.2 Study duration: Three months to recruit all patients. A minimum follow-up period of 3 months per patient 65 The study recruitment will start at(x). The estimated Study Completion Date(x). 6.5.3 Methods of randomisation After eligibility is confirmed and written informed consent obtained, participants will be randomised to either atorvastatin 40 mg (group A) once daily or placebo (group B) in a 1:1 ratio stratified by site. Prior to study commencement, an independent statistician not associated with the study will develop a randomisation scheme using SPSS software 89 and input into a password-protected web-based randomisation system. Variable block sizes of 2 and 4 will be used. Participants will be assigned to either group A or group B based on the predesignated allocation code provided by an independent statistician to an independent pharmacy which will prepare coded drug containers of identical appearance. 6.5.4 Blinding Site investigators will all be blinded to the treatment allocation. Eligible patients will be blinded to the intervention and receive identical drug containers of atorvastatin 40mg tablet which will be taken orally once daily or identical in appearance (same colour, shape, size) placebo tablet once daily. The assessors of the outcomes will also be blinded to the treatment allocation. It is likely that the lack of the blinding will not have an effect on the primary outcomes (laboratory outcomes). The blinding in the study aims to minimize the dropout rate and loss to follow up, which may happen if the patients in the control group are aware of their allocation. Additionally, blinding is important to minimize detection bias caused by the knowledge of the allocated interventions by outcome assessors of subjective outcomes. 66 6.5.5 Study endpoints 6.5.5.1 Primary endpoints The primary endpoints are 1. Free testosterone level [12 weeks from the start of the treatment] which will be determined by equilibrium dialysis (EqD), (the gold standard) (pg /mL). 2. The total testosterone (12 weeks) which will be determined by liquid-chromatography/mass spectroscopy (LCMS) (ng/dl). 6.5.5.2 Secondary Endpoints 1. DHT levels (12 weeks) which determined by using ELISA kits (pg/mL). 2. DHEAS levels (12 weeks) which determined by liquid-chromatography/mass spectroscopy (LCMS) (ng/mL). 3. A4 levels) which determined by liquid-chromatography/mass spectroscopy (LCMS) (ng/mL). 4. Number of patients who withdrawal due to adverse effects (WDAEs). Patient selection The inclusion and exclusion criteria will be based on the goal of recruiting adult patients (males only) with mild dyslipidemia and excluding individuals with conditions that might increase the risk of adverse effects from the interventions, severely shorten life expectancy, and interfere with the conduct of the trial. 67 6.6.1 Inclusion criteria 1. 30 to 60 years of age. 2. Males with normal libido. 3. Signed informed consent. 4. Mild dyslipidemia which is established with reference to diagnostic standard of Adult Treatment Panel (ATPIII) of the national cholesterol education program coordinating committee: LDL-C level, 3.4–4.1 mmol/l; and TG, 1.7–2.3 mmol/l. 5. Not treated routinely with lipid-lowering drugs in the last 3 months before recruitment. 6.6.2 Exclusion criteria 1. History of malignant disease within five years of inclusion or suspected malignancy, except treated skin cancer other than melanoma. 2. Other medications including diuretics, testosterones, thyroid hormones, glucocorticoids, or immunosuppressants within the last 1 year. 3. Participation in another intervention trial. 4. Illness with life expectancy <1 year. 5. Use of antiandrogens. 6. Use of testosterone replacement treatment. 68 Patient recruitment 6.7.1 Target population The target population of our study is men living in the province of British Columbia who have been diagnosed with mild dyslipidemia. 6.7.2 Sample selection This study will be conducted through multiple outpatient clinics throughout the Province of British Columbia. These include Vancouver General Hospital, St. Paul’s Hospital, Richmond Hospital, Royal Columbian Hospital, and Victoria University Hospital. Recruitment is expected to take place over a 3 months period starting. All patients will continue to be followed for at least 3 months 6.7.3 Sampling method Participation will be sought using advertising for physicians in general and cardiologist specialist in particular who can refer mild dyslipidemia patients as well as using posters in the clinics in BC. All individuals who respond will be assessed for eligibility for screening. This method of sampling is not random and largely dependent on referrals. However, we do not think this will have an effect on study outcome, as we are interested in the effect of laboratory tests. Eligible individuals will be asked to sign consent to undergo a screening process. Records of all individuals contacted, screened and enrolled will be kept. 69 6.7.4 Proportion expected to participate It is anticipated that at least 15% of approached subjects will agree to participate. This is a conservative estimate, since atorvastatin is usually described to this population and it is well tolerated. The cost of transportation and parking will be reimbursed as an incentive to comply with the follow-up visits. Furthermore, interpreters and translated questionnaires will be provided if a language barrier is present. Screening and baseline evaluation At the screening visit and after signing the consent, clinical information will be collected from each participant by completing a comprehensive questionnaire including age, ethnicity, demographic data, list of current medications, dosage, date of treatment initiation, comorbidities and smoking status. All patients must have a brief clinical examination which will include vital signs and anthropometric data (weight, height, and BMI). In addition, a lipid profile test will be conducted. Patients deemed eligible at screening will be asked to sign consent to be enrolled in the trial Conduct of study All patients will be seen after 3 months by the coordinating nurse at each site for documentation of adverse events and will be examined by the investigator. Investigators will seek information regarding adverse events through appropriate questioning and physical examination. Investigators are responsible for documenting adverse events in the trial case report form and informing the Sponsor in accordance with protocol instructions. 70 Investigations to be conducted At baseline and after 3 months different tests and measurement will be performed, the assessor will be blinded for the patient group: 1. liquid-chromatography/mass spectroscopy (LCMS) which will evaluate various endpoints: DHEAS, A4, and total testosterone. 2. ELISA kits will determine DHT levels. 3. Equilibrium dialysis will determine free testosterone levels. Each center will conduct all the tests and measure all the outcomes during the study under appropriate conditions and as described above in this section. All centers will collect the results of all tests and outcomes and will document the results of the tests and transferred all the documents to the coordinator center in which it will be entered, analysed, and stored in appropriate storage. Breaking of blinded codes In the event of the development serious side effects in which knowing the underlying treatment would help in patient management, the allocation code is allowed to be broken. The patients will continue to be followed according to his allocation and will enter the intention to treat analysis. Whenever a code is broken, the study coordinator is to document date, time, and reason. 71 Evaluation of compliance Adherence to study medication will be assessed at each site by the coordinating nurse using pill counts and a structured interview of pill-taking behavior. Follow-up evaluation The study medications are both easy to take and generally well tolerated, we hope that both these factors will help reduce the number of participants lost to follow-up. In support of this are findings from both the Chen 2014 and Mehmet trial, where adherence to once-daily of 10 mg atorvastatin was 90% of participants in each trial. Adherence to required study visits will be enhanced by discussing what the study involves prior to obtaining consent. Efforts will also include scheduling visits at participants’ convenience, reimbursing transportation and parking, and a reminder phone call prior to each visit. Biostatistical considerations and analysis 6.14.1 Sample size calculation Testosterone levels vary widely and what represents a clinically significant reduction of testosterone is controversial. The sample size necessary to detect a minimal reduction of 10% in free testosterone level between the two arms with 90% statistical power and 5% type1 error, is 215 patients in each arm. The expectation of the dropout rate is low. Sample size estimation was done using the G*Power software version 3.190. 72 6.14.2 Data analysis. Statistical analyses will be descriptive and include conventional summary statistics. The mean and standard deviation will be used to summarize the continuous data and it will be compared by using ANOVA method. Categorical variables will be presented as risk ratios and compared using the chi-square test. We will report the absolute mean difference and the SD of the absolute and percentage change. All tests will be two-sided. P < 0.05 will be considered statistically significant for the primary endpoint while we will use a Bonferroni adjustment, modifying the P value to account for the multiple tests performed for the secondary outcomes. Although we do not expect considerable loss of follow-up or missing data, the multiple imputation approach will be used to address the problem of missing data, which aims to allow for the uncertainty about the missing data by creating several different plausible imputed data sets and appropriately combining results given from each of them. All analysis will be done using SPSS software89 Ethics The study protocol and informed consent will be submitted for approval to the appropriate Institutional Review Boards at each centre. Written informed consent will be obtained from all study participants. The study will be conducted in accordance with the application of Health Canada regulations, International Conference on Harmonization guidelines on current Good Clinical Practice and the Declaration of Helsinki. An independent committee (the data safety and quality review committee), who are aware of the randomization, will oversee the safety of the study and the quality of data, and will do the interim analysis. 73 6.15.1 Informed consent A two-stage free written informed consent will be obtained from all participants. The first consent stage is for screening in which the study purpose and the details of the screening process will be explained. The second consent is after the screening stage. All patients who are assessed as eligible to enter the study will be asked to provide a second consent, which provides details about the treatment and the expected risks and benefits. All patients included in the study should complete both consents in the presence of a witness prior to enrolment. The consent will be verified by the consultant physician or research nurse. In the case of a language barrier, a translated consent form in the presence of translator will be provided. Study monitoring This is a multicenter trial which includes several centers, and the monitoring of the various sites involved needs to be done carefully and continually. Organization The Principal Investigator will lead the investigations in each of the participating clinical centers. In addition, each participating clinic will have a program coordinator, recruitment coordinators, pharmacists, physicians, nurses, data collectors. Coordinating center The Coordinating Center will be the St. Paul's Hospital site, and is responsible for implementing the randomization scheme, the biostatistical design, collecting, monitoring and analysing data, as well, as data storage and processing. 74 Data monitoring board The Data Monitoring Board is independent scientific body which provides external review and advice to the protocol coordinators and the Steering Committee. It will consist of four expert members; two cardiologists, one family practitioner, and one statistician. Prior to the initiation of recruitment, the Data Monitoring Board will review all study material to ensure the scientific validity of the study and safety of participants. Its principal responsibility is to monitor the emerging results of the trial, and to assess treatment effectiveness and participant safety. The board will have the authority to make amendments on the trial protocol as well as terminate the trial. Data management A network of microcomputers, one at each clinical center and one at the Coordinating Center will be used as a remote data management system. Clinical center staff will collect the data on paper forms and enter it into the site computer. All the electronic copies of the entered and updated data are transmitted weekly via network to the Coordinating Center computer, where all clinical data and electronic files will be stored in the secure environment, and they will be compiled into the trial master database with data from all clinical centers. Authorship Trial results will be disseminated through scientific peer-review publication, international and national conferences. One of the principle investigators will be responsible for initially drafting the manuscripts. Criteria defined by the International Journal of Medical Editors will determine 75 the authorship. The writing of the manuscript of the final results will be completed within 6 months of completion of the study. Limitations of the Study Generalizability could be an issue when interpreting our study results, for several reasons: 1) The sample selection may not be representative of all British Columbia population, for example certain ethnic groups may not volunteer to participate. 2) Strict exclusion criteria were applied to minimize confounding; however, this is at the expense of generalizing our results to other high-risk groups. 76 Bibliography 1. D . Sriram and P . Yogeeswari. Medicinal Chemistry. 2nd ed. Delhi: Pearson; 2010. 2. Hu J, Zhang Z, Shen WJ, Azhar S. Cellular cholesterol delivery, intracellular processing and utilization for biosynthesis of steroid hormones. Nutr Metab. 2010;7:47. doi:10.1186/1743-7075-7-47 3. Sèdes L, Thirouard L, Maqdasy S, et al. Cholesterol: A Gatekeeper of Male Fertility? Front Endocrinol (Lausanne). 2018;9:369. doi:10.3389/fendo.2018.00369 4. 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G*Power. 2014. https://www.psychologie.hhu.de/arbeitsgruppen/allgemeine-psychologie-und-arbeitspsychologie/gpower.html. 88 Appendices Appendix A Search strategy Database: Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Daily and Versions(R) <1946 to August 07, 2019> Search Date: 8 August 2019 -------------------------------------------------------------------------------- 1 atorvastatin calcium/ (6288) 2 (atorvastatin$ or atorlip or atovarol or cardyl or "ci 981" or ci981 or glustar or lipibec or lipitor or liprimar or liptonorm or lowlipen or sortis or storvas or tahor or torvast or totalip or xarator or "ym 548" or ym548 or zarator).tw,kf. (8342) 3 or/1-2 (9337) 4 randomized controlled trial.pt. (486912) 5 controlled clinical trial.pt. (93206) 6 randomized.ab. (450970) 7 placebo.ab. (199806) 8 drug therapy.fs. (2129258) 9 randomly.ab. (315847) 10 trial.ab. (472558) 11 groups.ab. (1940710) 12 or/4-11 (4497641) 13 animals/ not (humans/ and animals/) (4573930) 14 12 not 13 (3892910) 15 3 and 14 (5087) 89 16 15 and (2013 12$ or 2014$ or 2015$ or 2016$ or 2017$ or 2018$ or 2019$).dt. (1456) -------------------------------------------------------------------------------- Database: Cochrane Hypertension Specialised Register via Cochrane Register of Studies (CRS-Web) Search Date: 9 August 2019 -------------------------------------------------------------------------------- #1 MESH DESCRIPTOR atorvastatin calcium AND INREGISTER #2 (atorvastatin* OR atorlip OR atovarol OR cardyl OR glustar OR lipibec OR lipitor OR liprimar OR liptonorm OR lowlipen OR sortis OR storvas OR tahor OR torvast OR totalip OR xarator OR zarator) AND INREGISTER #3 #1 OR #2 AND INREGISTER #4 RCT:DE AND INREGISTER #5 Review:ODE AND INREGISTER #6 #4 OR #5 AND INREGISTER #7 #3 AND #6 AND INREGISTER -------------------------------------------------------------------------------- Database: Cochrane Central Register of Controlled Trials via Cochrane Register of Studies (CRS-Web) Search Date: 4 December 2019 90 -------------------------------------------------------------------------------- #1 MESH DESCRIPTOR atorvastatin calcium AND CENTRAL:TARGET #2 (atorvastatin* OR atorlip OR atovarol OR cardyl OR glustar OR lipibec OR lipitor OR liprimar OR liptonorm OR lowlipen OR sortis OR storvas OR tahor OR torvast OR totalip OR xarator OR zarator) AND CENTRAL:TARGET #3 (#1 OR #2) AND CENTRAL:TARGET -------------------------------------------------------------------------------- Database: Embase <1974 to 2019 August 07> Search Date: 8 August 2019 -------------------------------------------------------------------------------- 1 atorvastatin/ (35532) 2 (atorvastatin$ or atorlip or atovarol or cardyl or "ci 981" or ci981 or glustar or lipibec or lipitor or liprimar or liptonorm or lowlipen or sortis or storvas or tahor or torvast or totalip or xarator or "ym 548" or ym548 or zarator).mp. (36479) 3 or/1-2 (36479) 4 randomized controlled trial/ (563789) 5 crossover procedure/ (60198) 6 double-blind procedure/ (163974) 7 (randomi?ed or randomly).tw. (1165784) 8 (crossover$ or cross-over$).tw. (101204) 9 placebo.ab. (284652) 91 10 (doubl$ adj blind$).tw. (201170) 11 assign$.ab. (365450) 12 allocat$.ab. (139376) 13 or/4-12 (1700328) 14 (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.) (6205683) 15 13 not 14 (1482585) 16 3 and 15 (6340) 17 16 and (2013 12$ or 2014$ or 2015$ or 2016$ or 2017$ or 2018$ or 2019$).dc,dd. (2048) -------------------------------------------------------------------------------- Database: ClinicalTrials.gov Search Date: 8 August 2019 -------------------------------------------------------------------------------- Other terms: sex hormone* OR SHBG OR testosterone Study type: Interventional Studies (Clinical Trials) Study Results: All Studies Intervention/treatment: Atorvastatin OR lipitor -------------------------------------------------------------------------------- Database: WHO International Clinical Trials Registry Platform (ICTRP) 92 Search Date: 8 August 2019 -------------------------------------------------------------------------------- atorvastatin AND sex hormone atorvastatin AND SHBG atorvastatin AND testosterone lipitor AND sex hormone lipitor AND SHBG lipitor AND testosterone 93 Appendix B Data extraction form General review information Study ID: Name of review author completing this form: Study objective Methods Inclusion criteria Participants dose and administration Comparisons Follow-up duration Number of participants lost to follow-up statistical analysis and reporting Outcomes 94 Categorical outcomes: Comparison Atorvastatin vs placebo Outcome Withdrawal due adverse effects Timepoint Results Intervention Comparison Events No. participants Events No. participants No. of missing participants and reasons WDAEs Any other results reported noncompliance Reanalysis required? (specify - Notes and limitations 95 (e.g. correlation adjustment) Reanalysis possible? yes/no/unclear Reanalyzed results Atorvastatin Before Treatment Atorvastatin After Treatment Placebo Before Treatment Placebo After Treatment Total testosterone nmol/L Total testosterone nmol/L Total testosterone nmol/L Total testosterone nmol/L Mean SD Absolute change n 96 P t SE Absolute change SD Absolute change SHBG nmol/L SHBG nmol/L SHBG nmol/L SHBG nmol/L Mean SD Absolute change n P t SE Absolute change 97 SD Absolute change FAI FAI FAI FAI Mean SD Absolute change n P t SE Absolute change SD Absolute change 98 Appendix C Furukawa data ID n n-1 SD Variance (n-1)*Variance ID n n-1 SD Variance (n-1)*VarianceTobert 1982 47 46 5.7 32.49 1494.54 Lovastatin Tobert 1982 10 9 8 64 576 placeboBoehm 2004 6 5 2.4 5.76 28.8 Pravastatin Boehm 2004 9 8 3.2 10.24 81.92 placeboDobs 2000-9 37 36 6.4 40.96 1474.56 Simvastatin Dobs 2000-9 39 38 4.4 19.36 735.68 placeboDobs 2000-1 85 84 5.4 29.16 2449.44 Simvastatin Dobs 2000-1 28 27 4 16 432 placebo171 5447.34 82 1825.631.856 22.263SD 5.644 4.718ID n n-1 SD Variance (n-1)*VarianceTobert 1982 47 46 5.7 32.49 1494.54 LovastatinBoehm 2004 6 5 2.4 5.76 28.8 PravastatinDobs 2000-9 37 36 6.4 40.96 1474.56 Simvastatin Dobs 2000-1 85 84 5.4 29.16 2449.44 SimvastatinTobert 1982 10 9 8 64 576 LovastatinBoehm 2004 9 8 3.2 10.24 81.92 Pravastatin ControlTreatmentAllTestosterone in Males Data taken from Schooling 2013 page 6 of 9 99 ID n n-1 SD Variance (n-1)*Variance ID n n-1 SD Variance (n-1)*VarianceRaja-Khan 2011 9 8 0.8599 0.7394 5.9154 Atorvastatin Raja-Khan 2011 11 10 0.8967 0.80407089 8.0407089 placeboRashidi 2011 32 31 1.2 1.44 44.640 Simvastatin Rashidi 2011 29 28 1.2 1.44 40.32 placeboBanaszewska 2007 45 44 0.8 0.64 28.16 Simvastatin Banaszewska 2007 48 47 0.8 0.64 30.08 placeboBanaszewska 2009 37 36 0.6 0.36 12.96 Simvastatin Banaszewska 2009 36 35 0.8 0.64 22.4 placeboKazerooni 2010 42 41 0.2 0.04 1.64 Simvastatin Kazerooni 2010 42 41 0.1 0.01 0.41 placeboAkbari 2016 20 19 0.892 0.796 15.12 Atorvastatin Akbari 2016 20 19 0.461 0.21 4.04 placebo179 108.43 180 105.290.606 0.585SD 0.778 0.765 n n-1 SD Variance (n-1)*VarianceRaja-Khan 2011 9 8 0.8599 0.73942801 5.91542408 AtorvastatinRashidi 2011 32 31 1.2 1.44 44.640 Simvastatin Banaszewska 2007 45 44 0.8 0.64 28.16 Simvastatin Banaszewska 2009 37 36 0.6 0.36 12.96 Simvastatin Kazerooni 2010 42 41 0.2 0.04 1.64 Simvastatin Akbari 2016 20 19 0.892 0.80 15.12 AtorvastatinRaja-Khan 2011 11 10 0.8967 0.80407089 8.0407089 Atorvastatin Rashidi 2011 29 28 1.2 1.44 40.32 Simvastatin Banaszewska 2007 48 47 0.8 0.64 30.08 SimvastatinBanaszewska 2009 36 35 0.8 0.64 22.4 SimvastatinKazerooni 2010 42 41 0.1 0.01 0.41 SimvastatinAkbari 2016 20 19 0.461 0.21 4.04 Atorvastatin359 213.720.595SD 0.772Testosterone in FemalesTreatment ControlAll 100 ID n n-1 SD Variance (n-1)*Variance ID n n-1 SD Variance (n-1)*VarianceJedel 2011 29 28 1.676 2.8090 78.6513 electroacupuncture 16 weeks Jedel 2011 15 14 1.6760 2.8090 39.3257 no intervention at 16 weeksJedel 2011 30 29 1.9204 3.6879 106.9501 physical exercise 16 weeks Jedel 2011 15 14 1.1173 1.2484 17.4770 no intervention at 32 weeksJedel 2011 29 28 1.7458 3.0478 85.3389 electroacupuncture 32 weeks Vigorito 2007 45 44 1.1264 1.2688 55.8262 unstructured exerciseJedel 2011 30 29 1.7807 3.1709 91.9559 physical exercise 32 weeks Douglas 2006 11 10 1.3966 1.9505 19.5049 standard dietVigorito 2007 45 44 1.0546 1.1122 48.9360 structured exercise Pizzo 2014 25 24 0.6640 0.4409 10.5815 D-Chiro-inositolDouglas 2006 11 10 1.3966 1.9505 19.5049 MUFA Ozay 2016 54 53 7.7689 60.3558 3198.8578 combined oral contraceptivesDouglas 2006 11 10 1.0475 1.0973 10.9726 Low CHO Nordio 2012 24 23 4.4480 19.7847 455.0482 myo-inositolPizzo 2014 25 24 0.9788 0.9580 22.9932 myo-inositol Raja-Khan 2011 11 10 1.819 3.308761 33.08761 placeboOzay 2016 52 51 10.7147 114.8048 5855.0446 myo-inositol Sathyapalan 2012 18 17 5.88 34.5744 587.7648 placeboNordio 2012 26 25 4.4073 19.4243 485.6073 myo-inositol + D-Chiro-inositolRaja-Khan 2011 9 8 1.817 3.301489 26.41 atorvastatinSathyapalan 2012 19 18 1.85 3.4225 61.6050 atorvastatin 304 6893.97 209 4417.4722.68 21.14 SD 4.76 4.60 ID n n-1 SD Variance (n-1)*Variance Jedel 2011 29 28 1.676 2.8090 78.6513Jedel 2011 30 29 1.9204 3.6879 106.9501 Jedel 2011 29 28 1.7458 3.0478 85.3389 Jedel 2011 30 29 1.7807 3.1709 91.9559Vigorito 2007 45 44 1.0546 1.1122 48.9360Douglas 2006 11 10 1.3966 1.9505 19.5049Douglas 2006 11 10 1.0475 1.0973 10.9726Pizzo 2014 25 24 0.9788 0.9580 22.9932Ozay 2016 52 51 10.7147 114.8048 5855.0446Nordio 2012 26 25 4.4073 19.4243 485.6073Jedel 2011 15 14 1.6760 2.8090 39.3257Jedel 2011 15 14 1.1173 1.2484 17.4770Vigorito 2007 45 44 1.1264 1.2688 55.8262Douglas 2006 11 10 1.3966 1.9505 19.5049Pizzo 2014 25 24 0.6640 0.4409 10.5815Ozay 2016 54 53 7.7689 60.3558 3198.8578Nordio 2012 24 23 4.4480 19.7847 455.0482Raja-Khan 2011 9 8 1.817 3.301489 26.41 Sathyapalan 2012 19 18 1.85 3.4225 61.6050Raja-Khan 2011 11 10 1.819 3.308761 33.08761Sathyapalan 2012 18 17 5.88 34.5744 587.7648513 11311.445422.0496012SD 4.70Androstenedione in FemalesTreatment ControlAll 101 ID n n-1 SD Variance (n-1)*Variance ID n n-1 SD Variance (n-1)*VarianceBanaszewska 2007 45 44 0.65 0.4225 18.59 Simvastatin + Oral contraceptive pill Banaszewska 2007 48 47 0.6 0.36 16.92 Oral contraceptive pillBanaszewska 2009 37 36 2.1898 4.7952 172.6281 Simvastatin + Metformin Banaszewska 2009 36 35 1.8 3.24 113.4 MetforminKazerooni 2010 42 41 2.95 8.7025 356.8025 Simvastatin + Metformin Kazerooni 2010 42 41 2.87 8.2369 337.7129 Placebo + MetforminRashidi 2011 32 31 0.6 0.36 11.16 Simvastatin Rashidi 2011 29 28 0.8 0.64 17.92 PlaceboRaja-Khan 2011 9 8 7.662 58.7062 469.6500 Atorvastatin Raja-Khan 2011 11 10 7.835 61.387225 613.8723 PlaceboBanaszewska 2011 44 43 2.0563 4.2284 181.8199 Simvastatin + Metformin Banaszewska 2011 47 46 2.5366 6.43433956 295.9796 MetforminCelik 2012 18 17 1.38 1.9044 32.3748 Metformin + Rosuvastatin Celik 2012 20 19 1.275 1.625625 30.8869 MetforminSathyaplan 2012 19 18 1.88 3.5344 63.6192 Atorvastatin Sathyaplan 2012 18 17 2.31 5.3361 90.7137 PlaceboPuurunen 2013 15 14 1.65 2.7225 38.115 Atorvastatin Puurunen 2013 13 12 1.47 2.1609 25.9308 PlaceboSeyam 2018 100 99 2 4 396 Simvastatin Seyam 2018 100 99 1 1 99 PlaceboAkbari 2016 20 19 2.757 7.6010 144.4199 Atorvastatin Akbari 2016 20 19 0.341 0.116281 2.2093 Placebo370 1885 373 16455.095 4.409SD 2.26 2.10ID n n-1 SD Variance (n-1)*VarianceBanaszewska 2007 45 44 0.65 0.4225 18.59 Simvastatin + Oral contraceptive pill Banaszewska 2009 37 36 2.1898 4.79522404 172.6280654 Simvastatin + MetforminKazerooni 2010 42 41 2.95 8.7025 356.8025 Simvastatin + Metformin Rashidi 2011 32 31 0.6 0.36 11.16 SimvastatinRaja-Khan 2011 9 8 7.662 58.706244 469.649952 AtorvastatinBanaszewska 2011 44 43 2.0563 4.22836969 181.8198967 Simvastatin + Metformin Celik 2012 18 17 1.38 1.9044 32.3748 Metformin + RosuvastatinSathyaplan 2012 19 18 0.95 0.9025 16.245 Atorvastatin Puurunen 2013 15 14 1.65 2.7225 38.115 Atorvastatin Seyam 2018 100 99 2 4 396 SimvastatinBanaszewska 2007 48 47 0.6 0.36 16.92 Oral contraceptive pillBanaszewska 2009 36 35 1.8 3.24 113.4 MetforminKazerooni 2010 42 41 2.87 8.2369 337.7129 Placebo + MetforminRashidi 2011 29 28 0.8 0.64 17.92 PlaceboRaja-Khan 2011 11 10 7.835 61.387225 613.87225 PlaceboBanaszewska 2011 47 46 2.5366 6.43433956 295.9796198 MetforminCelik 2012 20 19 1.275 1.625625 30.886875 MetforminSathyaplan 2012 18 17 1 1 17 PlaceboPuurunen 2013 13 12 1.47 2.1609 25.9308 PlaceboSeyam 2018 100 99 1 1 99 PlaceboAkbari 2016 20 19 2.757 7.601049 144.419931Akbari 2016 20 19 0.341 0.116281 2.209339743 34094.5877SD 2.14DHEAS in FemalesTreatment ControlAll 102 Appendix D Characteristics of included studies and their risk of bias assessment AKBARI 2016 Methods Study design: Randomised placebo controlled Masking: Double blind Number of arms: 2 Participants Inclusion criteria: women with a diagnosis of PCOS based upon existence of 2 of the 3 criteria specified by Rotterdam, BMI > 25.2, LDL > 100, not pregnant, no other reasons for obesity and metabolic and hormone and glands and metabolism issues, no use of metformin and other medicines that create sensitivity to insulin and no use of oral contraceptive pills (OCP) (?) over the last three months and no consumption of medicines that reduce androgen, not sensitive to atorvastatin, and participants are 18 to 35 years old Exclusion criteria: pregnancy, using metformin or any other medicines that cause sensitivity to insulin and OCP over the last 3 months before the research and androgen reducer (using progesterone for withdrawal or keeping mensturation was ok), LDL < 100, BMI < 25, 103 any hormonal or metabolic disorders not related to PCOS, any sensitivity to atorvastatin exhibited by the rise of liver enzymes more than three times the normal level and severe muscle cramps Baseline Characteristics Placebo • n: 20 • sex:female • BMI: 26.3 • Age:27.7 • Total cholesterol: 224.5 mg/dL (5.81 mmol/L) • LDL cholesterol: 138.3 mg/dl (3.58 mmol/L) • HDL cholesterol: 50.2 mg/dL (1.30 mmol/L) • Triglycerides: 182.4 mg/dL (2.06 mmol/L) • Total testosterone: 0.69 nmol/L (19.90 ng/dL) • Androstenedione: 2.3 • DHEAS: 232.6 • Left ovary size: 13.1 • Right ovary size: 13.6 40 mg atorvastatin 104 • n: 20 • sex:female • BMI: 26.7 • Age:30.9 • Total cholesterol: 223.4 mg/dL (5.78 mmol/L) • LDL cholesterol: 146.1 mg/dL (3.78 mmol/L) • HDL cholesterol: 50.0 mg/dL (1.29 mmol/L) • Triglycerides: 134.9 mg/dL (1.52 mmol/L) • Total testosterone: 0.72 nmol/L (20.77 ng/dL) • Androstenedione: 2.5 • DHEAS: 225.3 • Left ovary size: 14.9 • Right ovary size: 15.1 Interventions Intervention Characteristics 40 mg/day for 6 weeks Placebo for 6 weeks Outcomes Total testosterone, DHEAS and Androstenedione statistical analysis and reporting Sequential nonrandom sampling method was used in both groups. The resulting information was analyzed using SPSS 16. As for qualitative variables, indicators 105 such as frequency, mode, mean, and average were calculated. The frequency of qualitative variables was also measured. Independent t test was used to study qualitative variables, while repeated measures test was used to calculate the changes observed in two groups before and after intervention. Forward linear regression was used to study the confounding effect. Number of participants lost to follow-up 0 Source of funding not reported Notes Location: clinic of Firouzgar Hospital, Tehran, Iran Ethical approval: The ethics committee of Iran University of Medical Sciences studied the ethical aspects of this research and approved it under the code 93/D/105/4431. The ethical principles specified in treaty of Helsinki were observed. Risk of bias table Bias Authors' judgement Support for judgement 106 Random sequence generation (selection bias) used block randomisation but the process for selecting the blocks was not specified "People qualified for the research were randomly divided into randomized blocks containing 4 people in each one" Allocation concealment (selection bias) method of concealment is not described Blinding of participants and personnel (performance bias) objective outcomes like serum total testosterone, DHEAS and androstenedione are not likely to be influences by lack of blinding Blinding of outcome assessment (detection bias) androgen parameters were measured in a laboratory and the outcome measurements were not likely to be influenced by lack of blinding Blinding of outcome assessment (detection bias) WDAEs blinding method was not described Selective reporting (reporting bias) no protocol was found and there is insufficient information to judge if it is low or high risk of bias Unclear riskUnclear riskLow riskLow riskUnclear riskUnclear risk 107 Selective reporting (reporting bias) WDAEs WDAE outcome reported Source of funding, sponsorship and conflict of interest source of funding not reported Incomplete outcome data (attrition bias) Total testosterone all participants were included in the efficacy analysis Incomplete outcome data (attrition bias) Free testosterone Not applicable since the trial did not report on this particular outcome Incomplete outcome data (attrition bias) Free Androgen Index Not applicable since the trial did not report on this particular outcome Incomplete outcome data (attrition bias) Androstenedione all participants were included in the efficacy analysis Incomplete outcome data (attrition bias) SHBG Not applicable since the trial did not report on this particular outcome Incomplete outcome data (attrition bias) DHEAS all participants were included in the efficacy analysis Chen 2014 Methods Study design: Randomised controlled Masking: Open label Low riskUnclear riskLow riskUnclear riskUnclear riskLow riskUnclear riskLow risk 108 Number of arms: 2 Participants Inclusion criteria: subjects diagnosed with mild dyslipidemia and osteopenia before recruitment; and subjects not treated routinely with lipid-lowering drugs in the last 3 months before recruitment Exclusion criteria: history of medications for diseases affecting bone metabolism; therapy for osteoporosis with diphosphonate and calcitriol within the last 6 months; other medications including diuretics, testosterones, thyroid hormones, glucocorticoids, or immunosuppressants within the last 1 year; relevant diseases: malignant tumors, severe hepatic or renal dysfunction, hyperthyroidism, and hyperparathyroidism. Baseline Characteristics Lifestyle guidance • n: 32 • sex:male • age: 79.3 • BMI: 23.2 • Total cholesterol: 158.5 mg/dL (4.1 mmol/L) 109 • LDL cholesterol: 138.3 mg/dL (3.6 mmol/L) • HDL cholesterol: 50.2 mg/dL (1.2 mmol/L) • Triglycerides: 182.4 mg/dL (1.9 mmol/L) • Total testosterone: 295.63 ng/dL (10.25 nmol/L) 10 mg/day atorvastatin and lifestyle guidance • n: 32 • sex:male • age: 80.8 • BMI: 23.1 • Total cholesterol: 154.7 mg/dL (4.0 mmol/L) • LDL cholesterol: 143.1 mg/dL (3.7 mmol/L) • HDL cholesterol: 46.4 mg/dL (1.2 mmol/L) • Triglycerides: 168.3 mg/dL (1.9 mmol/L) • Total testosterone: 306.59 ng/dL (10.63 nmol/L) Interventions 10 mg/day atorvastatin and lifestyle guidance for 12 months lifestyle guidance for 12 months Outcomes Total testosterone (6-12 months) statistical analysis and reporting Statistical analyses were conducted using SPSS package for Windows, version 17.0. All data were expressed as 110 means SEM. Comparison of baseline characteristics between atorvastatin and control groups was based on independent-sample t-test for continuous variables and chi-square test for categorical variables. In follow-up, comparison of parameters between groups was performed at 6 and 12 months using independent-sample t-test or ANOVA for repeated measurements with treatment group as the independent variables and changing of parameters from baseline as the dependent variables as a function of time. In addition, Mauchly’s test of sphericity was analyzed to evaluate the assumption of ANOVA for repeated measurements to adjust the degrees of freedom, according to Greenhouse–Geisser correction coefficient e, if necessary. Moreover, comparison of parameters within groups at different time points of follow-up was performed using one-way ANOVA followed by least significant differences test (LSD test). After obtaining the statistical significance of primary and secondary endpoints, Pearson correlation analysis of changed parameters was undertaken. All analyses were two-tailed and P value of <0.05 was considered significant. 111 Number of participants lost to follow-up one subject went abroad to visit relatives and three participants were re-treated due to other reasons Source of funding grants from National Nature Science Foundation of China (81370360) Notes Location: Ren-Ji Hospital, Shanghai Jiao-Tong University Medical School, China Ethical approval: Ethics Committee of Renji Hospital Risk of bias table Bias Authors' judgement Support for judgement Random sequence generation (selection bias) conducted with complete randomization using SPSS package for Windows, version 17.0 Allocation concealment (selection bias) method of concealment is not described Low riskUnclear risk 112 Blinding of participants and personnel (performance bias) objective outcome like serum total testosterone is not likely to be influenced by lack of blinding Blinding of outcome assessment (detection bias) testosterone was measured in a laboratory and the outcome measurement was not likely to be influenced by lack of blinding Blinding of outcome assessment (detection bias) WDAEs no blinding of outcome assessment, and the outcome measurement was likely to be influenced by lack of blinding Selective reporting (reporting bias) no protocol was found and there is insufficient information to judge if it is low or high risk of bias Selective reporting (reporting bias) WDAEs WDAE outcome reported Source of funding, sponsorship and conflict of interest government grants from China Incomplete outcome data (attrition bias) Total testosterone (2/32)*100 = 6.25% were not included in the testosterone measurement for the control group Low riskLow riskHigh riskUnclear riskLow riskLow riskLow risk 113 (2/32)*100 = 6.25% were not included in the testosterone measurement for the atorvastatin group missing outcome data balanced in numbers across intervention and control groups with similar reason for missing data across groups Incomplete outcome data (attrition bias) Free testosterone Not applicable since the trial did not report on this particular outcome Incomplete outcome data (attrition bias) Free Androgen Index Not applicable since the trial did not report on this particular outcome Incomplete outcome data (attrition bias) Androstenedione Not applicable since the trial did not report on this particular outcome Incomplete outcome data (attrition bias) SHBG Not applicable since the trial did not report on this particular outcome Incomplete outcome data (attrition bias) DHEAS Not applicable since the trial did not report on this particular outcome Unclear riskUnclear riskUnclear riskUnclear riskUnclear risk 114 Gokce 2012 Methods Study design: Randomised controlled Masking: single blind Number of arms: 2 Participants Inclusion critieria: 30–70-year-old male patients, normal libido, IIEF< 17, no previous use of PDE5 Is and normal serum testosterone levels 300 ng/dL Exclusion criteria: history of any pelvic surgery, having any kind of medication for ED, having any neurological or mental problem, liver or hepatic insufficiency, use of nitrates, and use of antiandrogens Baseline Characteristics Atorvastatin 10 mg/day • n: 41 • sex:male • age: 57.1 • Total cholesterol: 195.1 mg/dL (5.04 mmol/L) • LDL cholesterol: 127.3 mg/dL (3.29 mmol/L) • HDL cholesterol: 42.2 mg/dL (1.09 mmol/L) 115 • Triglycerides: 155.6 mg/dL (1.76 mmol/L) • Total testosterone: 323.4 ng/dL (11.21 nmol/L) No treatment • n: 39 • sex:male • age: 55.8 • Total cholesterol: 189.4 mg/dL (4.90 mmol/L) • LDL cholesterol: 128.4 mg/dL (3.32 mmol/L) • HDL cholesterol: 40.9 mg/dL (1.06 mmol/L) • Triglycerides: 149.0 mg/dL (1.68 mmol/L) • Total testosterone: 330.7 ng/dL (11.47 nmol/L) Interventions 10 mg/day atorvastatin for 3 months no treatment for 3 months Outcomes Total testosterone (3 months) statistical analysis and reporting Sample size estimation was performed by a conventional statistical program by taking into account an effect size of 50% improvement in symptoms, and minimum number of patients needed to reject the null hypothesis was 120. For randomization, NCSS program was used, and 116 patients were blinded for the treatment. The statistical analysis was performed by SPSS ver. 15.0. (SPSS Inc.,Chicago, Illinois). Data are expressed as numbers and percentages for discrete variables and as means ± SD for continuous variables. The chi-square analysis or Fisher’s exact test was used to assess the significance of differences between dichotomous variables. Continuous variables were compared by Student’s t-test or Mann–Whitney U-test. Number of participants lost to follow-up Atorvastatin group: one lost to follow up and three discontinued; Of the three that discontinued; one was due to nausea and two was due to lack of efficacy No treatment group: two lost to follow up and four discontinued; Of the four that discontinued; one was due to headache and three was due to lack of efficacy Source of funding not reported Notes Location: Department of Urology, Ankara University School of Medicine, Adnan Saygun Caddesi, Altındag˘, Ankara, Turkey 117 Department of Cardiology, Ankara University School of Medicine, Adnan Saygun Caddesi, Altındag˘, Ankara, Turkey Risk of bias table Bias Authors' judgement Support for judgement Random sequence generation (selection bias) randomization, NCSS program was used Allocation concealment (selection bias) method of concealment is not described Blinding of participants and personnel (performance bias) objective outcome like serum total testosterone is not likely to be influenced by lack of blinding Blinding of outcome assessment (detection bias) testosterone was measured in a laboratory and the outcome measurement was not likely to be influenced by lack of blinding Blinding of outcome assessment (detection bias) WDAEs no blinding of outcome assessment, and the outcome measurement was Low riskUnclear riskLow riskLow riskHigh risk 118 likely to be influenced by lack of blinding Selective reporting (reporting bias) no protocol was found and there is insufficient information to judge if it is low or high risk of bias Selective reporting (reporting bias) WDAEs WDAE outcome reported Source of funding, sponsorship and conflict of interest no source of funding reported Incomplete outcome data (attrition bias) Total testosterone (4/45)*100 = 8.9% were not included in the testosterone measurement for the atorvastatin group (6/45)*100 = 13.3% were not included in the testosterone measurement for the control group Incomplete outcome data (attrition bias) Free testosterone Not applicable since the trial did not report on this particular outcome Incomplete outcome data (attrition bias) Free Androgen Index Not applicable since the trial did not report on this particular outcome Incomplete outcome data (attrition bias) Androstenedione Not applicable since the trial did not report on this particular outcome Unclear riskLow riskUnclear riskUnclear riskUnclear riskUnclear riskUnclear risk 119 Incomplete outcome data (attrition bias) SHBG Not applicable since the trial did not report on this particular outcome Incomplete outcome data (attrition bias) DHEAS Not applicable since the trial did not report on this particular outcome Unclear riskUnclear risk 120 Puurunen 2013 Methods Study design: randomised, double blind, placebo controlled Masking: double blind Number of arms: 2 Participants Inclusion critieria: Caucasian women with PCOS diagnosis, not menopausal, and reliable nonhormonal contraception. The diagnoses of PCOS had been assigned to all subjects during their earlier visits to the Department of Obstetrics and Gynecology, the women generally being between the ages of 20 and 30 years, and the researchers confirmed the criteria before the present study. Exclusion criteria: T2DM, medication affecting glucose tolerance, lipid metabolism, or steroid synthesis in the preceding 3 months, menopause, regular smoking, abuse of alcohol, previous ovarian drilling, oophorectomy, or hysterectomy, and contraindications regarding the use of atorvastatin. 121 Baseline Characteristics Placebo • n: 19 • sex:female • age: 38.5 • BMI: 26.7 • Total testosterone: 25.96 ng/dL (0.9 nmol/L) • SHBG: 466.45 μg/dL (49.1 nmol/L) • FAI: 2.2 • DHEAS: 143.7 μg/dL (3.9 μmol/L) • Androstenedione: 252.03 ng/dL (8.8 nmol/L) 20 mg/day atorvastatin • n: 19 • sex:female • age: 40.5 • BMI: 30.4 • Total testosterone: 40.38 ng/dL (1.4 nmol/L) • SHBG:386.65 μg/dL (40.7 nmol/L) • FAI: 4.2 • DHEAS: 143.7 μg/dL (3.9 μmol/L) 122 • Androstenedione: 320.77 ng/dL (11.2 nmol/L) Interventions Placebo for 6 months Atorvastatin 20 mg/day for 6 months Outcomes Total testosterone, SHBG, FAI, DHEAS, Androstenedione statistical analysis and reporting Androgen secretion and glucose metabolism served as primary outcome measures. Secondary outcome measures were CRP concentrations and lipid profile. Sample size (power analysis) was calculated on the basis of the decrease in serum testosterone levels (baseline, [mean SD], 2.96 0.82 nmol/L; at 12 weeks, 1.76 0.70 nmol/L) during 12 weeks simvastatin treatment in women with PCOS in a study carried out by Duleba et al (13). The analysis revealed that each study group needed to have 15 subjects to have95%power.Adropout rate of 20% was expected; thus, we needed to recruit 36 subjects. All variables with skewed distribution went through logarithmic transformation before statistical analysis. All statistical analyses were conducted using SPSS software (version 15.0 for Windows; SPSS Inc). The limit of statistical 123 significance was set at P .05. To analyze changes in the levels of serum glucose, insulin, hormones, lipids, and CRP and glucose tolerance indexes within the same study group at 0, 3, and 6 months of treatment, repeated-measures ANOVA was performed for normally distributed variables and Friedman’s test was used for variables with a skewed distribution. Where ANOVA was significant or if the parameters related to glucose metabolism had only 2 time points, the paired-samples t test was used for normally distributed variables and Wilcoxon’s nonparametric test was used for variables with a skewed distribution. The independent-samples t test or the Mann-Whitney U test was used to analyze differences between the study groups. The effect of baseline testosterone was controlled in repeated-measures ANOVA using baseline testosterone as a covariate. Number of participants lost to follow-up 10 6 in the placebo group and 4 in the atorvastatin group Source of funding The Academy of Finland, the Sigrid Jusélius Foundation, the Finnish Medical Foundation, the 124 National Clinical Graduate School, the Research Foundation of Obstetrics and Gynecology, Oulu University Scholarship Foundation, the North Ostrobothnia Regional fund of the Finnish Cultural Foundation, the Tyyni Tani Foundation of the University of Oulu, and the Finnish-Norwegian Medical Foundation. Notes Location: University of Oulu and Oulu University Hospital, Finland Ethical approval: Ethics Committee of Oulu University Hospital and the Finnish Medicines Agency Risk of bias table Bias Authors' judgement Support for judgement Random sequence generation (selection bias) "Randomization was conducted using a computer-generated randomization list in blocks of 6" Low risk 125 Allocation concealment (selection bias) central allocation (pharmacy-controlled randomisation and sequentially number drug containers) "carried out at the Oulu University Hospital Pharmacy by personnel not involved in the study". "They also repacked the medication in closed envelopes, which were sequentially numbered". Blinding of participants and personnel (performance bias) objective outcome like serum androgens are not likely to be influenced by lack of blinding Blinding of outcome assessment (detection bias) androgens were measured in a laboratory and the outcome measurements were not likely to be influenced by lack of blinding Blinding of outcome assessment (detection bias) WDAEs blinding method was not described Selective reporting (reporting bias) study protocol is available (NCT01072097) and all the study's prespecified outcomes were reported Low riskLow riskLow riskUnclear riskLow risk 126 Selective reporting (reporting bias) WDAEs WDAEs were reported Source of funding, sponsorship and conflict of interest government grants "This work was supported by the Academy of Finland, the Sigrid Jusélius Foundation, the Finnish Medical Foundation, the National Clinical Graduate School, the Research Foundation of Obstetrics and Gynecology, Oulu University Scholarship Foundation, the North Ostrobothnia Regional fund of the Finnish Cultural Foundation, the Tyyni Tani Foundation of the University of Oulu, and the Finnish-Norwegian Medical Foundation". Incomplete outcome data (attrition bias) Total testosterone (19-15)*100/19 = 21.1% were not included in the analysis for the atorvastatin group Low riskLow riskHigh risk 127 (19-13)*100/19 = 31.6% were not included in the analysis for the placebo group Incomplete outcome data (attrition bias) Free testosterone Not applicable since the trial did not report on this particular outcome Incomplete outcome data (attrition bias) Free Androgen Index (19-15)*100/19 = 21.1% were not included in the analysis for the atorvastatin group (19-13)*100/19 = 31.6% were not included in the analysis for the placebo group Incomplete outcome data (attrition bias) Androstenedione (19-15)*100/19 = 21.1% were not included in the analysis for the atorvastatin group (19-13)*100/19 = 31.6% were not included in the analysis for the placebo group Incomplete outcome data (attrition bias) SHBG (19-15)*100/19 = 21.1% were not included in the analysis for the atorvastatin group Unclear riskHigh riskHigh riskHigh risk 128 (19-13)*100/19 = 31.6% were not included in the analysis for the placebo group Incomplete outcome data (attrition bias) DHEAS (19-15)*100/19 = 21.1% were not included in the analysis for the atorvastatin group (19-13)*100/19 = 31.6% were not included in the analysis for the placebo group High risk 129 Raja-khan 2011 Methods Study design: randomised, double blind, placebo controlled Masking: double blind Number of arms: 2 Participants Inclusion critieria: Women with PCOS and LDL-cholesterol >100 mg/dL were eligible to participate in the study. Exclusion criteria: not reported Baseline Characteristics Placebo • n: 11 • sex:female • age: 29.4 • BMI: 36.0 • Total cholesterol: 202.8 mg/dL (5.24 mmol/L) • LDL cholesterol: 131.3 mg/dL (3.40 mmol/L) • HDL cholesterol: 46.5 mg/dL (1.20 mmol/L) 130 • Triglycerides: 125.5 mg/dL (1.42 mmol/L) • Total testosterone: 92.3 ng/dL (3.20 nmol/L) • Free testosterone: 20.2 ng/dL (0.70 nmol/L) • DHEAS: 170.2 μg/dL (4.62 μmol/L) • Androstenedione: 380 ng/dL (13.27 nmol/L) 40 mg/day atorvastatin • n: 9 • sex:female • age: 33.8 • BMI: 40.1 • Total cholesterol: 215.8 mg/dL (5.58 mmol/L) • LDL cholesterol: 140.7 mg/dL (3.64 mmol/L) • HDL cholesterol: 44.4 mg/dL (1.15 mmol/L) • Triglycerides: 153.3 mg/dL (1.73 mmol/L) • Total testosterone: 61.3 ng/dL (2.13 nmol/L) • Free testosterone: 18.1 ng/dL (0.63 nmol/L) • DHEAS: 162.9 μg/dL (4.42 μmol/L) • Androstenedione: 340 ng/dL (11.87 nmol/L) Interventions Placebo for 6 weeks Atorvastatin 40 mg/day for 6 weeks 131 Outcomes Total testosterone, Free testosterone, Androstenedione and DHEAS statistical analysis and reporting Linear mixed-effects models, extensions of regression that account for within-subject correlation inherent in pre-post designs, were fit to continuous outcomes to assess the change from baseline to 6weeks within and between treatment groups. All hypotheses tests were two-sided. All analyses were performed by intention-to-treat using SAS software, version 9.1 (SAS Institute Inc., Cary, NC) Number of participants lost to follow-up 2 Source of funding National Institutes of Health (NIH) grant number K12HD055882, GCRC grant M01 RR10732 and construction grant C06 RR016499 to Pennsylvania State University and a research grant from Pfizer Notes Location: Department of Medicine, Pennsylvania State University College of Medicine, Hershey, Pennsylvania Ethical approval: The institutional review board of Pennsylvania State University approved the study. 132 Written informed consent was obtained from all participants. Risk of bias table Bias Authors' judgement Support for judgement Random sequence generation (selection bias) "The biostatistician generated a permuted block randomization scheme" Allocation concealment (selection bias) "The biostatistician generated a permuted block randomization scheme for the allocation sequence and provided it to the pharmacist" Blinding of participants and personnel (performance bias) The atorvastatin and placebo were overencapsulated by the pharmacist so that the participants, research coordinator who administered the intervention, and investigators who assessed the outcomes were blinded to group assignment and objective Low riskLow riskLow risk 133 outcome like serum androgens are not likely to be influenced by lack of blinding Blinding of outcome assessment (detection bias) androgens were measured in a laboratory and the outcome measurements were not likely to be influenced by lack of blinding Blinding of outcome assessment (detection bias) WDAEs not reported Selective reporting (reporting bias) study protocol is available (NCT00529542) and all the study's prespecified outcomes were reported Selective reporting (reporting bias) WDAEs not reported Source of funding, sponsorship and conflict of interest National Institutes of Health (NIH) grant number K12HD055882, GCRC grant M01 RR10732 and construction grant C06 RR016499 to Pennsylvania State University and a research grant from Pfizer Low riskUnclear riskLow riskHigh riskHigh risk 134 N.R-K. has nothing to disclose. A.R.K. reports ownership of Merck stock. C.S.H. has nothing to disclose. C.M.S. has nothing to disclose. L.M.D. has nothing to disclose. R.S.L. has received speaker honorarium from Merck-Serono and study support from Solvay Incomplete outcome data (attrition bias) Total testosterone (20-18)*100/20 = 10% did not complete the trial but the authors included all the data of all participants in the analysis Incomplete outcome data (attrition bias) Free testosterone only baseline free testosterone was reported in each group Incomplete outcome data (attrition bias) Free Androgen Index Not applicable since the trial did not report on this particular outcome Incomplete outcome data (attrition bias) Androstenedione (20-18)*100/20 = 10% did not complete the trial but the authors included all the data of all participants in the analysis Unclear riskHigh riskUnclear riskUnclear risk 135 Incomplete outcome data (attrition bias) SHBG Not applicable since the trial did not report on this particular outcome Incomplete outcome data (attrition bias) DHEAS (20-18)*100/20 = 10% did not complete the trial but the authors included all the data of all participants in the analysis Unclear riskUnclear risk 136 Sathyapalan 2009 Methods Study design: randomised placebo controlled Masking: double blind Number of arms: 2 Participants Inclusion criteria: female participants with PCOS and biochemical hyperandrogenemia Subjects had no concurrent illness, were not on any prescription or over-the-counter medication that was likely to affect insulin sensitivity, lipids, or ovarian function including hormonal contraceptives for the preceding 6 months. None of the patients had statin therapy in the past. Subjects were not planning to conceive and were using barrier contraception. Exclusion criteria: Nonclassical 21-hydroxylase deficiency, hyperprolactinemia, Cushing’s disease, and androgen-secreting tumors Baseline Characteristics Placebo • n: 18 137 • sex:female • age: 28.8 • BMI: 33.94 • Total cholesterol: 174.0 mg/dL (4.5 mmol/L) • LDL cholesterol: 104.4 mg/dL (2.7 mmol/L) • HDL cholesterol: 42.5 mg/dL (1.1 mmol/L) • Triglycerides: 123.1 mg/dL (1.39 mmol/L) • Total testosterone: 126.9 ng/dL (4.4 nmol/L) • FAI: 13.9 • SHBG: 303.1 μg/dL (31.9 nmol/L) 40 mg/day atorvastatin • n: 19 • sex:female • age: 26.6 • BMI: 33.20 • Total cholesterol: 215.8 mg/dL (5.58 mmol/L) • LDL cholesterol: 140.8 mg/dL (3.64 mmol/L) • HDL cholesterol: 44.5 mg/dL (1.15 mmol/L) • Triglycerides: 153.2 mg/dL (1.73 mmol/L) • Total testosterone: 118.3 ng/dL (4.1 nmol/L) • FAI: 13.4 138 • SHBG: 295.45 μg/dL (31.1 nmol/L) Interventions Placebo for 12 weeks Atorvastatin 40 mg/day for 12 weeks Outcomes Total testosterone, FAI, SHBG statistical analysis and reporting The sample size was based on the study on the known effect of atorvastatin on hsCRP in patients with impaired fasting glucose with the assumption that a similar effect would occur in those patients with PCOS. Powered specifically for CRP, the minimum difference worth detecting/observed difference was 32.7%, estimated within-group SD was 11.1; therefore, for 90% power and a significance level of 5%, a sample size of 16 per group was calculated. Adjusting for a possible 20% dropout rate meant a total of 40 patients needed to be recruited. Comparisons between both the groups from baseline were carried out using the paired t test for biochemical data and clinical observations. The Wilcoxon signed rank test was applied to biochemical data that violated the assumptions of normality when tested using the Kolmogorov-Smirnov test. The effect of treatment was evaluated by first calculating the 139 percentage change from baseline for all variables studied and then the percentage change for each variable in each patient group, thus negating the differences in the baseline values of the two groups. Between-group comparison of percent changes was performed using independent-samples t test. For all analyses, a two-tailed P 0.05 was considered to indicate statistical significance. Statistical analysis was performed using SPSS for Windows NT, version 14.0 (SPSS Inc., Chicago, IL). Number of participants lost to follow-up 3 in the atorvastatin group and 2 in the placebo group Source of funding unrestricted grant from Pfizer Notes Location: Department of Diabetes and Endocrinology , University of Hull, Hull HU6 7RX, United Kingdom; Department of Clinical Biochemistry , Hull Royal Infirmary, Hull HU3 2JZ, United Kingdom; and Department of Obstetric Ultrasound , Hull and East Yorkshire Women’s and Children’s Hospital, Hull HU3 2PZ, United Kingdom 140 Ethical approval: All patients gave informed consent. The study was approved by the Hull and East Riding Local Research Ethics committee Risk of bias table Bias Authors' judgement Support for judgement Random sequence generation (selection bias) computer-generated randomizations list Allocation concealment (selection bias) labelling was done by personnel not involved in the trial Blinding of participants and personnel (performance bias) double blind objective outcome like serum androgens are not likely to be influenced by lack of blinding Blinding of outcome assessment (detection bias) androgens were measured in a laboratory and the outcome measurements were not likely to be influenced by lack of blinding Low riskLow riskLow riskLow risk 141 Blinding of outcome assessment (detection bias) WDAEs blinding method was not described Selective reporting (reporting bias) one reported primary outcome (hs-CRP) was not prespecified in the ISRCTN24474824 registry Selective reporting (reporting bias) WDAEs Atorvastatin 1 out of 20 for non-compliance Placebo 2 out of 20 for non-compliance non-compliance may be due to WDAEs Source of funding, sponsorship and conflict of interest unrestricted grant from Pfizer sponsors had no input into study design, its execution, or interpretation of the findings All of the authors have got nothing else to disclose but in 2017 they claimed that the research did not receive any specific Unclear riskHigh riskHigh riskHigh risk 142 grant from any funding agency in the public, commercial or not-for-profit sector Incomplete outcome data (attrition bias) Total testosterone Atorvastatin group: (20-19)*100/20 = 5% were not included in the analysis Placebo group: (20-18)*100/20 = 10% were not included in the analysis Both groups: (40-37)*100/40 = 7.5% were not included in the analysis Incomplete outcome data (attrition bias) Free testosterone Not applicable since the trial did not report on this particular outcome Incomplete outcome data (attrition bias) Free Androgen Index Atorvastatin group: (20-19)*100/20 = 5% were not included in the analysis Placebo group: (20-18)*100/20 = 10% were not included in the analysis Low riskUnclear riskLow risk 143 Both groups: (40-37)*100/40 = 7.5% were not included in the analysis Incomplete outcome data (attrition bias) Androstenedione Atorvastatin group: (20-19)*100/20 = 5% were not included in the analysis Placebo group: (20-18)*100/20 = 10% were not included in the analysis Both groups: (40-37)*100/40 = 7.5% were not included in the analysis Incomplete outcome data (attrition bias) SHBG Atorvastatin group: (20-19)*100/20 = 5% were not included in the analysis Placebo group: (20-18)*100/20 = 10% were not included in the analysis Both groups: (40-37)*100/40 = 7.5% were not included in the analysis Low riskLow risk 144 Incomplete outcome data (attrition bias) DHEAS Atorvastatin group: (20-19)*100/20 = 5% were not included in the analysis Placebo group: (20-18)*100/20 = 10% were not included in the analysis Both groups: (40-37)*100/40 = 7.5% were not included in the analysis Low risk 145 Sathyapalan 2012 (associated with Sathyapalan 2009) Methods Study design: randomised placebo controlled Masking: double blind Number of arms: 2 Participants Inclusion critieria: female participants with PCOS and biochemical hyperandrogenemia Subjects had no concurrent illness, were not on any prescription or over-the-counter medication that was likely to affect insulin sensitivity, lipids, or ovarian function including hormonal contraceptives for the preceding 6 months. None of the patients had statin therapy in the past. Subjects were not planning to conceive and were using barrier contraception. Exclusion criteria: Nonclassical 21-hydroxylase deficiency, hyperprolactinemia, Cushing’s disease, and androgen-secreting tumors Baseline Characteristics Placebo 146 • n: 18 • sex:female • age: 28.8 • BMI: 33.92 • DHEAS: 265.5 μg/dL (7.2 μmol/L) • Androstenedione: 160.4 ng/dL (5.6 nmol/L) 40 mg/day atorvastatin • n: 19 • sex:female • age: 26.6 • BMI: 33.20 • DHEAS: 261.6 μg/dL (7.1 μmol/L) • Androstenedione: 163.2 ng/dL (5.7 nmol/L) Interventions Placebo for 12 weeks Atorvastatin 40 mg/day for 12 weeks Outcomes DHEAS, Androstenedione statistical analysis and reporting The sample size was based on the study on the known effect of atorvastatin on high-sensitivity C-reactive protein (CRP) in patients with impaired fasting glucose, with the assumption that a similar effect would occur in 147 those patients with PCOS. Powered specifically for CRP, the minimum difference worth detecting/observed difference was 32.7%, estimated within-group SD was 11.1; therefore, for 90% power and a significance level of 5%, a sample size of 16 per group was calculated. Adjusting for a possible 20% dropout rate meant a total of 40 patients needed to be recruited. The paired t-test was used to compare changes from baseline for the biochemical data and clinical observations within groups. The Wilcoxon signed-rank test was applied to biochemical data that violated the assumptions of normality when tested using the Kolmogorov–Smirnov test. The effect of treatment was evaluated by first computing the percentage change from baseline in all variables studied and then the percent change seen for each variable in both groups was compared, thus negating the differences in the baseline values of the two groups. Between-group comparison of percent changes was performed using independent samples t-test. For all analysis, a two-tailed P< 0.05 was considered to indicate statistical significance. Statistical analysis was 148 performed using SPSS for Windows NT, Version 14.0 (SPSS Inc, Chicago, IL, USA). Number of participants lost to follow-up 3 1 in the atorvastatin group and 2 in the placebo group Source of funding unrestricted grant form Pfizer Notes Location: Department of Diabetes, Endocrinology and Metabolism, Hull York Medical School; Department of Clinical Biochemistry, Hull Royal Infirmary; Department of Obstetric Ultrasound, Hull & East Yorkshire Women’s & Children’s Hospital, Hull, UK Ethical approval: All patients gave informed consent. The study was approved by the South Humber Research Ethics committee Risk of bias table Bias Authors' judgement Support for judgement 149 Random sequence generation (selection bias) computer-generated randomization list Allocation concealment (selection bias) labelling was done by personnel not involved in the trial Blinding of participants and personnel (performance bias) double blind objective outcome like serum androgens are not likely to be influenced by lack of blinding Blinding of outcome assessment (detection bias) androgens were measured in a laboratory and the outcome measurements were not likely to be influenced by lack of blinding Blinding of outcome assessment (detection bias) WDAEs blinding method was not described Selective reporting (reporting bias) the study protocol is available and all of the study's prespecified outcomes that are of interest in the review have been reported in the prespecified way Selective reporting (reporting bias) WDAEs Atorvastatin 1 out of 20 for non-compliance Low riskLow riskLow riskLow riskUnclear riskLow riskUnclear risk 150 Placebo 2 out of 20 for non-compliance non-compliance may be due to WDAEs Source of funding, sponsorship and conflict of interest unrestricted grant from Pfizer sponsors had no input into study design, its execution, or interpretation of the findings no other competing interests to declare but in 2017 they claimed that the research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector Incomplete outcome data (attrition bias) Total testosterone same data as in Sathyapalan 2009 Incomplete outcome data (attrition bias) Free testosterone Not applicable since the trial did not report on this particular outcome High riskLow riskUnclear risk 151 Incomplete outcome data (attrition bias) Free Androgen Index Atorvastatin group: (20-19)*100/20 = 5% were not included in the analysis Placebo group: (20-18)*100/20 = 10% were not included in the analysis Both groups: (40-37)*100/40 = 7.5% were not included in the analysis Incomplete outcome data (attrition bias) Androstenedione same data as in Sathyapalan 2009 Incomplete outcome data (attrition bias) SHBG same data as in Sathyapalan 2009 Incomplete outcome data (attrition bias) DHEAS Atorvastatin group: (20-19)*100/20 = 5% were not included in the analysis Placebo group: (20-18)*100/20 = 10% were not included in the analysis Both groups: (40-37)*100/40 = 7.5% were not included in the analysis Low riskLow riskLow riskLow risk 152 153 Appendix E List of excluded studies Study Title Exclusion reason Elkawy 2014 Comparing the effects of atorvastatin and vitamin E on endothelial function of sildenafil non-responders Testosterone level was measured but not reported; Schrott 1998 A multicenter, placebo-controlled, dose-ranging study of atorvastatin Outcomes specified for this review were not reported or measured Raal 2003 Avasimibe, an ACAT inhibitor, enhances the lipid lowering effect of atorvastatin in subjects with homozygous familial hypercholesterolemia Wrong study design (3-SEQUENCE CROSSOVER) Ormiston 2004 Hormonal changes with cholesterol reduction: a double-blind pilot study Placebo data not reported separate from the active treatment data Kuznetsova 2010 Non-ST-elevation acute coronary syndrome. Comparison of effects of atorvastatin and rosuvastatin on blood levels of lipids and markers of inflammation wrong duration (14 days) Soedamah-Muthu 2015 Effect of atorvastatin on C-reactive protein and benefits for cardiovascular disease in patients with type 2 diabetes: analyses from the Collaborative Atorvastatin Diabetes Trial DBP - 20150422 Outcomes specified for this review were not reported or measured 154 Outcomes specified for this review were not reported or measured vanHoek 2009 Role of plasma adiponectin on the HDL-cholesterol raising effect of atorvastatin in patients with type 2 diabetes Outcomes specified for this review were not reported or measured vanDoorn 2006 Effect of garlic powder on C-reactive protein and plasma lipids in overweight and smoking subjects Outcomes specified for this review were not reported or measured vanderHarst 2005 Effect of intensive versus moderate lipid lowering on endothelial function and vascular responsiveness to angiotensin II in stable coronary artery disease Outcomes specified for this review were not reported or measured vandeRee 2003 Strong decrease of high sensitivity C-reactive protein with high-dose atorvastatin in patients with type 2 diabetes mellitus Outcomes specified for this review were not reported or measured Strey 2006 Short-term statin treatment improves endothelial function and neurohormonal imbalance in normocholesterolaemic patients with non-ischaemic heart failure Outcomes specified for this review were not reported or measured 155 Stein 2012 Effect of a monoclonal antibody to PCSK9 on LDL cholesterol Outcomes specified for this review were not reported or measured Stefanadi 2009 Early initiation of low-dose atorvastatin treatment after an acute ST-elevated myocardial infarction, decreases inflammatory process and prevents endothelial injury and activation Outcomes specified for this review were not reported or measured Stalenhoef 2005 A comparative study with rosuvastatin in subjects with metabolic syndrome: results of the COMETS study Outcomes specified for this review were not reported or measured Sposito 2003 Atorvastatin enhances the plasma clearance of chylomicron-like emulsions in subjects with atherogenic dyslipidemia: relevance to the in vivo metabolism of triglyceride-rich lipoproteins Outcomes specified for this review were not reported or measured Sparks 2005 Atorvastatin therapy lowers circulating cholesterol but not free radical activity in advance of identifiable clinical benefit in the treatment of mild-to-moderate AD Outcomes specified for this review were not reported or measured Solem 2006 Composition of coronary plaques obtained by directional atherectomy instable angina: its relation to serum lipids and statin treatment Outcomes specified for this review were not reported or measured 156 Sola 2006 Atorvastatin improves left ventricular systolic function and serum markers of inflammation in nonischemic heart failure Outcomes specified for this review were not reported or measured Wu 2007 [Effect of atorvastatin on carotid intima-medial of thickness of primary hypertension patients of Han nationality in China]. [Chinese] Outcomes specified for this review were not reported or measured Wojnicz 2006 Usefulness of atorvastatin in patients with heart failure due to inflammatory dilated cardiomyopathy and elevated cholesterol levels Outcomes specified for this review were not reported or measured Wissing 2006 Effect of atorvastatin therapy and conversion to tacrolimus on hypercholesterolemia and endothelial dysfunction after renal transplantation Outcomes specified for this review were not reported or measured Williams 2009 Impact of statin therapy on central aortic pressures and hemodynamics: principal results of the Conduit Artery Function Evaluation-Lipid-Lowering Arm (CAFE-LLA) Study Outcomes specified for this review were not reported or measured Watts 2003 Effect of a statin on hepatic apolipoprotein B-100 secretion and plasma campesterol levels in the metabolic syndrome Outcomes specified for this review were not reported or measured Watts 2003 Differential regulation of lipoprotein kinetics by atorvastatin and fenofibrate in subjects with the metabolic syndrome Outcomes specified for this review were not reported or measured 157 Waters 2000 Comparison of aggressive lipid lowering with Atorvastatin vs. Revascularization Treatments (AVERT) and conventional care for the reduction of ischemic events in patients with stable coronary artery disease Outcomes specified for this review were not reported or measured Wassmann 2004 Effect of atorvastatin 80 mg on endothelial cell function (forearm blood flow) in patients with pretreatment serum low-density lipoprotein cholesterol levels <130 mg/dl Outcomes specified for this review were not reported or measured Wanner 2005 Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis Outcomes specified for this review were not reported or measured Wang 2001 A randomized, double-blind, placebo-controlled, 8-week study to evaluate the efficacy and safety of once daily atorvastatin (10 mg) in patients with elevated LDL-cholesterol Outcomes specified for this review were not reported or measured Vrtovec 2005 Atorvastatin therapy increases heart rate variability, decreases QT variability, and shortens QTc interval duration in patients with advanced chronic heart failure Outcomes specified for this review were not reported or measured 158 vonEynatten 2009 Changes in adiponectin multimer distribution in response to atorvastatin treatment in patients with type 2 diabetes Outcomes specified for this review were not reported or measured Vansant 2001 The effect of atorvastatin on postprandial lipidaemia in overweight or obese women homozygous for apo E3 Outcomes specified for this review were not reported or measured Vernaglione 2004 Does atorvastatin influence serum C-reactive protein levels in patients on long-term hemodialysis? Outcomes specified for this review were not reported or measured vanVenrooij 2002 Aggressive lipid lowering does not improve endothelial function in type 2 diabetes: the Diabetes Atorvastatin Lipid Intervention (DALI) Study: a randomized, double-blind, placebo-controlled trial Outcomes specified for this review were not reported or measured vanVenrooij 2003 Common cholesteryl ester transfer protein gene polymorphisms and the effect of atorvastatin therapy in type 2 diabetes Outcomes specified for this review were not reported or measured Van 2002 Comparison of extended-release niacin and atorvastatin mono-therapies and combination treatment of the atherogenic lipid profile in diabetes mellitus Outcomes specified for this review were not reported or measured 159 Server 2003 Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac outcomes Trial - Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial Outcomes specified for this review were not reported or measured See 2003 Effect of atorvastatin on postcardiac transplant increase in low-density lipoprotein cholesterol reduces development of intimal hyperplasia and progression of endothelial dysfunction Outcomes specified for this review were not reported or measured Sdringola 2008 A 6 month randomized, double blind, placebo controlled, multi-center trial of high dose atorvastatin on myocardial perfusion abnormalities by positron emission tomography in coronary artery disease Outcomes specified for this review were not reported or measured Schneider 2004 Atorvastatin improves diabetic dyslipidemia and increases lipoprotein lipase activity in vivo Outcomes specified for this review were not reported or measured Panahi 2011 Results of a randomized,open-label,clinical trial investigating the effects of supplementation with Outcomes specified for this review were not reported or measured 160 Heracleumpersicum extract as an adjunctive therapy for dyslipidemia Paiva 2005 High-dose statins and skeletal muscle metabolism in humans: a randomized, controlled trial Outcomes specified for this review were not reported or measured Paiva 2003 Effect of high-dose statin treatment on plasma concentrations of endogenous nitric oxide synthase inhibitors Outcomes specified for this review were not reported or measured Packard 2007 Atorvastatin treatment and vaccination efficacy Outcomes specified for this review were not reported or measured Ozkiris 2007 Effect of atorvastatin on ocular blood flow velocities in patients with diabetic retinopathy Outcomes specified for this review were not reported or measured Oshima 2008 LDL-cholesterol lowering therapy by atorvastatin have an impact on the carotid intima-media thickness in the hypercholesterolemia patient with type 2 diabetes Outcomes specified for this review were not reported or measured Orr 2009 Arterial destiffening with atorvastatin in overweight and obese middle-aged and older adults Outcomes specified for this review were not reported or measured 161 Oranje 2001 Effect of atorvastatin on LDL oxidation and antioxidants in normocholesterolemic type 2 diabetic patients Outcomes specified for this review were not reported or measured Ooi 2012 Effect of fenofibrate and atorvastatin on VLDL apoE metabolism in men with the metabolic syndrome Outcomes specified for this review were not reported or measured Olsson 2005 High-density lipoprotein, but not low-density lipoprotein cholesterol levels influence short-term prognosis after acute coronary syndrome: results from the MIRACL trial Outcomes specified for this review were not reported or measured Olsson 2007 Effects of high-dose atorvastatin in patients > or =65 years of age with acute coronary syndrome (from the myocardial ischemia reduction with aggressive cholesterol lowering [MIRACL] study) Outcomes specified for this review were not reported or measured Olsson 2001 Effect of rosuvastatin on low-density lipoprotein cholesterol in patients with hypercholesterolemia Outcomes specified for this review were not reported or measured Olivotti 2002 High doses of atorvastatin do not affect activity of prothrombinase in patients with acute coronary syndromes Outcomes specified for this review were not reported or measured 162 Okopien 2004 Effect of monthly atorvastatin treatment on hemostasis Outcomes specified for this review were not reported or measured Okopien 2005 Effect of monthly atorvastatin and fenofibrate treatment on monocyte chemoattractant protein-1 release in patients with primary mixed dyslipidemia Outcomes specified for this review were not reported or measured Okazaki 2004 Early statin treatment in patients with acute coronary syndrome: demonstration of the beneficial effect on atherosclerotic lesions by serial volumetric intravascular ultrasound analysis during half a year after coronary event: the ESTABLISH Study Outcomes specified for this review were not reported or measured O'Neill 2001 Determinants of variable response to statin treatment in patients with refractory familial hypercholesterolemia Outcomes specified for this review were not reported or measured Nissen 2007 Effects of a potent and selective PPAR-alpha agonist in patients with atherogenic dyslipidemia or hypercholesterolemia: two randomized controlled trials Outcomes specified for this review were not reported or measured 163 Nikitina 2009 The use of atorvastatin in patients with rheumatoid arthritis with hyperlipidemia Outcomes specified for this review were not reported or measured Sever 2010 Antihypertensive therapy and the benefits of atorvastatin in the Anglo-Scandinavian Cardiac Outcomes Trial: lipid-lowering arm extension Outcomes specified for this review were not reported or measured Sever 2005 Different time course for prevention of coronary and stroke events by atorvastatin in the Anglo-Scandinavian Cardiac Outcomes Trial - Lipid Lowering Arm (ASCOT-LLA) Outcomes specified for this review were not reported or measured Sever 2003 Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cariac Outcomes Trial - Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial Outcomes specified for this review were not reported or measured Sever 2003 Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trials-Lipid Lowering Arm Outcomes specified for this review were not reported or measured 164 (ASCOT-LLA): a multicentre randomised controlled trial Atorvastatin and folic acid improve cardiac function and inhibit ventricular remodeling in chronic heart failure patients with hyperhomocysteinemia Outcomes specified for this review were not reported or measured Effects of atorvastatin on growth differentiation factor 15, brain natriuretic peptide, cardiac troponin I and adiponectin in patients with acute myocardial infarction Outcomes specified for this review were not reported or measured Efficacy of atorvastatin in primary hypercholesterolemia. Japan Cholesterol Lowering Atorvastatin Study (J-CLAS) Group Outcomes specified for this review were not reported or measured Lipid lowering - New study with atorvastatin Outcomes specified for this review were not reported or measured Zhang 2009 Effect of atorvastatin combined with Tongxinluo capsule on intra-media thickness of common carotid artery 91 patients with primary hypertension Outcomes specified for this review were not reported or measured 165 Zhang 2009 Effects of different doses of atorvastatin on lipid levels and nervous function in patients with acute cerebral infarction. [Chinese] Outcomes specified for this review were not reported or measured Zeng 2012 Atorvastatin in pulmonary arterial hypertension (APATH) study Outcomes specified for this review were not reported or measured Young 2008 Effect of atorvastatin on plasma levels of asymmetric dimethylarginine in patients with non-ischaemic heart failure Outcomes specified for this review were not reported or measured Yokoyama 2005 Plasma low-density lipoprotein reduction and structural effects on coronary atherosclerotic plaques by atorvastatin as clinically assessed with intravascular ultrasound radio-frequency signal analysis: a randomized prospective study Outcomes specified for this review were not reported or measured VanDeRee 2003 Decrease of hemostatic cardiovascular risk factors by aggressive vs. conventional atorvastatin treatment in patients with Type 2 diabetes mellitus Outcomes specified for this review were not reported or measured Urso 2005 Changes in ubiquitin proteasome pathway gene expression in skeletal muscle with exercise and statins Outcomes specified for this review were not reported or measured 166 Umin 2008 Effects of lipid lowering by atorvastatin on carotid atherosclerotic plaque (ACAP) study: a randomized trial for analysis of qualitative change in carotid atherosclerrotic plaque with IB echo and Black Blood MRI CNO - CN-01814122 Outcomes specified for this review were not reported or measured Tsai 2008 Atorvastatin prevents atrial fibrillation in patients with bradyarrhythmias and implantation of an atrial-based or dual-chamber pacemaker: a prospective randomized trial Outcomes specified for this review were not reported or measured Tremblay 2011 Atorvastatin increases intestinal expression of NPC1L1 in hyperlipidemic men Outcomes specified for this review were not reported or measured Tousoulis 2011 Combined effects of atorvastatin and metformin on glucose-induced variations of inflammatory process in patients with diabetes mellitus Outcomes specified for this review were not reported or measured Tousoulis 2010 Impact of 6 weeks of treatment with low-dose metformin and atorvastatin on glucose-induced changes of endothelial function in adults with newly diagnosed type 2 diabetes mellitus: A single-blind study Outcomes specified for this review were not reported or measured 167 Tousoulis 2006 Effects of early administration of atorvastatin treatment on thrombotic process in normocholesterolemic patients with unstable angina Outcomes specified for this review were not reported or measured Tousoulis 2005 Effects of combined administration of low dose atorvastatin and vitamin E on inflammatory markers and endothelial function in patients with heart failure Outcomes specified for this review were not reported or measured Tousoulis 2007 Effects of atorvastatin and vitamin C on forearm hyperaemic blood flow, asymmentrical dimethylarginine levels and the inflammatory process in patients with type 2 diabetes mellitus Outcomes specified for this review were not reported or measured Tousoulis 2006 The impact of early administration of low-dose atorvastatin treatment on inflammatory process, in patients with unstable angina and low cholesterol level Outcomes specified for this review were not reported or measured Tousoulis 2005 Effects of atorvastatin on reactive hyperaemia and the thrombosis-fibrinolysis system in patients with heart failure Outcomes specified for this review were not reported or measured Tousoulis 2005 Effects of atorvastatin on reactive hyperemia and inflammatory process in patients with congestive heart failure Outcomes specified for this review were not reported or measured 168 Teshima 2009 Early atorvastatin therapy improves cardiac function in patients with acute myocardial infarction Outcomes specified for this review were not reported or measured Tehrani 2010 Atorvastatin has antithrombotic effects in patients with type 1 diabetes and dyslipidemia Outcomes specified for this review were not reported or measured Tantikosoom 2005 Randomized trial of atorvastatin in improving endothelial function in diabetics without prior coronary disease and having average cholesterol level Outcomes specified for this review were not reported or measured Tanriverdi 2005 Statins have additive effects to vertebral bone mineral density in combination with risedronate in hypercholesterolemic postmenopausal women Outcomes specified for this review were not reported or measured Tannous 1999 Atorvastatin increases ecNOS levels in human platelets of hyperlipidemic subjects Outcomes specified for this review were not reported or measured Taneva 2006 Early effects on endothelial function of atorvastatin 40 mg twice daily and its withdrawal Outcomes specified for this review were not reported or measured Tanaka 2009 Effect of atorvastatin on lipid profile and blood glucose level in hypercholesterolemic type 2 diabetic patients Outcomes specified for this review were not reported or measured 169 Tanaka 2001 A double-blind trial on the effects of atorvastatin on glycemic control in Japanese diabetic patients with hypercholesterolemia Outcomes specified for this review were not reported or measured Tan 2002 Atorvastatin lowers C-reactive protein and improves endothelium-dependent vasodilation in type 2 diabetes mellitus Outcomes specified for this review were not reported or measured Szramka 2007 The effect of rapid lipid lowering with atorvastatin on autonomic parameters in patients with coronary artery disease Outcomes specified for this review were not reported or measured Suleiman 2012 Atorvastatin for prevention of atrial fibrillation recurrence following pulmonary vein isolation: a double-blind, placebo-controlled, randomized trial Outcomes specified for this review were not reported or measured Strey 2005 Endothelium-ameliorating effects of statin therapy and coenzyme Q10 reductions in chronic heart failure Outcomes specified for this review were not reported or measured Schanberg 2012 Use of atorvastatin in systemic lupus erythematosus in children and adolescents Outcomes specified for this review were not reported or measured Schaefer 2004 Comparisons of effects of statins (atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin) on fasting and postprandial Outcomes specified for this review were not reported or measured 170 lipoproteins in patients with coronary heart disease versus control subjects Schaefer 2002 Effects of atorvastatin on fasting and postprandial lipoprotein subclasses in coronary heart disease patients versus control subjects Outcomes specified for this review were not reported or measured Schaefer 2005 Effects of atorvastatin versus other statins on fasting and postprandial C-reactive protein and lipoprotein-associated phospholipase A2 in patients with coronary heart disease versus control subjects Outcomes specified for this review were not reported or measured Sasmazel 2010 The effect of statin therapy on stimulation of endothelium-derived nitric oxide before and after coronary artery bypass surgery Outcomes specified for this review were not reported or measured Sardo 2002 Effects of atorvastatin treatment on sICAM-1 and plasma nitric oxide levels in hypercholesterolemic subjects Outcomes specified for this review were not reported or measured Sardo 2005 Antioxidant effect of atorvastatin is independent of PON1 gene T(-107)C, Q192R and L55M polymorphisms in hypercholesterolaemic patients Outcomes specified for this review were not reported or measured Samy 2011 Paraoxonase-1 activity, malondialdehyde and glutathione peroxidase in non-alcoholic fatty liver disease and the effect of atorvastatin Outcomes specified for this review were not reported or measured 171 Sadik 2010 Lack of effect of 8 weeks atorvastatin on microvascular endothelial function in patients with systemic sclerosis Outcomes specified for this review were not reported or measured Rosenson 2009 Effects of rosuvastatin and atorvastatin on LDL and HDL particle concentrations in patients with metabolic syndrome: a randomized, double-blind, controlled study Outcomes specified for this review were not reported or measured Riahi 2006 The effect of atorvastatin on heart rate variability and lipoproteins in patients treated with coronary bypass surgery Outcomes specified for this review were not reported or measured Renders 2001 Efficacy and drug interactions of the new HMG-CoA reductase inhibitors cerivastatin and atorvastatin in CsA-treated renal transplant recipients Outcomes specified for this review were not reported or measured Reiter 2005 Statin therapy has no significant effect on skin tissue cholesterol: results from a prospective randomized trial Outcomes specified for this review were not reported or measured Raison 2002 Effects of atorvastatin on aortic pulse wave velocity in patients with hypertension and hypercholesterolaemia: a preliminary study Outcomes specified for this review were not reported or measured 172 Raal 2000 Inhibition of cholesterol synthesis by atorvastatin in homozygous familial hypercholesterolaemia Outcomes specified for this review were not reported or measured Preston 2007 A randomized, placebo-controlled trial to evaluate the efficacy, safety, and pharmacodynamic interaction of coadministered amlodipine and atorvastatin in 1660 patients with concomitant hypertension and dyslipidemia: the respond trial Outcomes specified for this review were not reported or measured Pontrelli 2002 Atorvastatin treatment beneficially alters the lipoprotein profile and increases low-density lipoprotein particle diameter in patients with combined dyslipidemia and impaired fasting glucose/type 2 diabetes Outcomes specified for this review were not reported or measured Paolisso 2000 Effects of simvastatin and atorvastatin administration on insulin resistance and respiratory quotient in aged dyslipidemic non-insulin dependent diabetic patients Outcomes specified for this review were not reported or measured Nicholls 2011 Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial Outcomes specified for this review were not reported or measured 173 Neutel 2009 The use of a single-pill calcium channel blocker/statin combination in the management of hypertension and dyslipidemia: a randomized, placebo-controlled, multicenter study Outcomes specified for this review were not reported or measured Neil 2010 Impact of atorvastatin and omega-3 ethyl esters 90 on plasma plant sterol concentrations and cholesterol synthesis in type 2 diabetes: a randomised placebo controlled factorial trial Outcomes specified for this review were not reported or measured Negi 2011 Statin therapy for the prevention of atrial fibrillation trial (SToP AF trial) Outcomes specified for this review were not reported or measured NCT04101136 2019 Effect of Atorvastatin on Subclinical Atherosclerosis Outcomes specified for this review were not reported or measured Manuel 2003 Effects of Atorvastatin on LDL sub-fractions and peroxidation in type 1 diabetic patients: a randomised double-blind placebo-controlled study Outcomes specified for this review were not reported or measured Malekzadeh 2010 A pilot double-blind randomised placebo-controlled trial of the effects of fixed-dose combination therapy ('polypill') on cardiovascular risk factors Outcomes specified for this review were not reported or measured 174 Mal'gina 2007 Effectiveness, safety, and endothelial function effects of atorvastatin lipid-lowering therapy in coronary heart disease patients undergoing percutaneous coronary intervention Outcomes specified for this review were not reported or measured Magen 2004 Resistant arterial hypertension and hyperlipidemia: atorvastatin, not vitamin C, for blood pressure control Outcomes specified for this review were not reported or measured Macin 2005 CRSSTD - 4206501 Atorvastatin has an important acute anti-inflammatory effect in patients with acute coronary syndrome: results of a randomized, double-blind, placebo-controlled study Outcomes specified for this review were not reported or measured Macchia 2012 Statins but not aspirin reduce thrombotic risk assessed by thrombin generation in diabetic patients without cardiovascular events: the RATIONAL trial Outcomes specified for this review were not reported or measured Loughrey 2013 CRSSTD - 4206541 Increased circulating CC chemokine levels in the metabolic syndrome are reduced by low-dose atorvastatin treatment: evidence from a randomized controlled trial Outcomes specified for this review were not reported or measured Liu 2009 Atorvastatin improves endothelial function and cardiac performance in patients with dilated cardiomyopathy: the role of inflammation Outcomes specified for this review were not reported or measured 175 Lins 2004 Lipid and apoprotein changes during atorvastatin up-titration in hemodialysis patients with hypercholesterolemia: a placebo-controlled study Outcomes specified for this review were not reported or measured Li 2006 [Efficacy and safety of extended-release niacin alone or with atorvastatin for lipid profile modification] Outcomes specified for this review were not reported or measured Li 2010 Influence of atorvastatin on ischemic adverse events following cerebral middle artery stent implantation: A 12-month follow-up in 24 cases. [Chinese] Outcomes specified for this review were not reported or measured Lewandowski 2008 The influence of low dose atorvastatin on inflammatory marker levels in patients with acute coronary syndrome and its potential clinical value Outcomes specified for this review were not reported or measured Lawrence 2004 The effect of high dose atorvastatin therapy on lipids and lipoprotein subfractions in overweight patients with type 2 diabetes Outcomes specified for this review were not reported or measured Lavallee 2009 Placebo-controlled trial of high-dose atorvastatin in patients with severe cerebral small vessel disease Outcomes specified for this review were not reported or measured Lamon-Fava 2007 Effects of different doses of atorvastatin on human apolipoprotein B-100, B-48, and A-I metabolism Outcomes specified for this review were not reported or measured 176 Krysiak 2010 Pleiotropic effects of atorvastatin and fenofibrate in metabolic syndrome and different types of pre-diabetes Outcomes specified for this review were not reported or measured Konduracka 2008 Effect of atorvastatin on endothelial function and inflammation in long-duration type 1 diabetic patients without coronary heart disease and arterial hypertension Outcomes specified for this review were not reported or measured Kom 2007 Impact of atorvastatin treatment on platelet-activating factor acetylhydrolase and 15-F(2trans)-isoprostane in hypercholesterolaemic patients Outcomes specified for this review were not reported or measured Koh 2010 Atorvastatin causes insulin resistance and increases ambient glycemia in hypercholesterolemic patients Outcomes specified for this review were not reported or measured Plazak 2011 Influence of atorvastatin on coronary calcifications and myocardial perfusion defects in systemic lupus erythematosus patients: a prospective, randomized, double-masked, placebo-controlled study Outcomes specified for this review were not reported or measured Piperi 2004 Comparison of raloxifene and atorvastatin effects on serum lipids composition of healthy post-menopausal women Outcomes specified for this review were not reported or measured 177 Pfizer 2004 A 4-year, double-blind, randomized, placebo-controlled, study of atorvastatin as prevention of CHD endpoints in patients with (Type II) non-insulin dependent diabetes mellitus. (ASPEN) Outcomes specified for this review were not reported or measured Pfizer 2010 A double-blind, placebo-controlled study of atorvastatin as prevention of CHD in high risk patients with non-insulin-dependent diabetes mellitus(CARDS) Outcomes specified for this review were not reported or measured Pfizer 2006 A multi-center, randomized, open-label study to evaluate efficacy and safety of dual therapy with atorvastatin plus amlodipine when compared to amlodipine therapy alone in the treatment of subjects with concurrent hyperlipidemia and hypertension Outcomes specified for this review were not reported or measured Pfizer 2003 A Multi-National, Prospective Randomized Double-Blind, Multi-Center, Placebo-Controlled Study To Evaluate Efficacy And Safety Of A Fixed Combination Therapy Of Amlodipine And Atorvastatin In The Treatment Of Concurrent Hypertension And Hyperlipidemia - The RESPOND Trial Outcomes specified for this review were not reported or measured 178 Pfizer 2004 A multicenter, double blind, randomized, placebo controlled parallel group study to assess the efficacy and safety of atorvastatin in the treatment of men with lower urinary tract symptoms and urinary outflow obstruction associated with benign prostatic enlargement Outcomes specified for this review were not reported or measured Pfizer 2003 A Multicenter, Randomized, Double-Blind, Placebo-Controlled And Open-Label Evaluation Of The Safety And Efficacy Of Dual Therapy With Atorvastatin Plus Amlodipine When Compared To Either Therapy Alone In The Treatment Of Patients With Simultaneous Hyperlipidemia And Hypertension. (The Avalon Study) Outcomes specified for this review were not reported or measured Pfizer 2006 A phase 3, double-blind, placebo-controlled, randomized, parallel group, multicenter study of the efficacy, safety and tolerability of fixed combination torcetrapib/atorvastatin administered orally, once daily for 6 months, compared to atorvastatin alone or placebo, in subjects with mixed dyslipidemia (Frederickson types IIa and IIb) Outcomes specified for this review were not reported or measured 179 Pfizer 2009 Atorvastatin and cardiovascular complications in Type II diabetes dialysis patients. The German Diabetes Dialysis Study: 4D Study. Determination of Cardiovascular endpoints in NIDDM dialysis patients Outcomes specified for this review were not reported or measured Pfizer 2007 Carotid Atorvastatin Study in Hyperlipidemic Post-MEnopausal Women: a Randomised Evaluation of Atorvastatin Versus Placebo (CASHMERE). Protocol A2581051 Outcomes specified for this review were not reported or measured Pfizer 2003 Double-blind, placebo-controlled, dose ranging trial to evaluate the efficacy of atorvastatin on bone mineral density and markers for bone turnover in postmenopausal women with dyslipidemia and at risk for osteoporosis Outcomes specified for this review were not reported or measured Pfizer 2004 Impact Of Atorvastatin On The Distribution, Composition And Metabolism Of LDL (Low Density Lipoprotein) And HDL (High Density Lipoprotein) Subfractions: A Double-Blind Placebo-Controlled Phase IV Study With Patients Suffering From Combined Hyperlipidemia And Diabetes - Atorvastatin And LDL Profile In NIDDM (ALPIN Study) Outcomes specified for this review were not reported or measured 180 Pfizer 2005 Phase 2, multi-center, double-blind, placebo-controlled, randomized, parallel group, dose response study of the safety and efficacy of CP-529,414 combination with open-label atorvastatin once daily (QD) for 12 weeks in subjects with hypercholesterolemia and without overt cardiovascular disease Outcomes specified for this review were not reported or measured Pfiser 2003 The atorvastatin efficacy and safety study in diabetic patients to determine starting dose for effectively reducing lipids. (The ADSL study) Outcomes specified for this review were not reported or measured Petri 2011 Lupus Atherosclerosis Prevention Study (LAPS) Outcomes specified for this review were not reported or measured Pedro-Botet 2001 Apolipoprotein E genotype affects plasma lipid response to atorvastatin in a gender specific manner Outcomes specified for this review were not reported or measured Parker 2013 Effect of statins on skeletal muscle function Outcomes specified for this review were not reported or measured Parker 2011 Atorvastatin increases exercise leg blood flow in healthy adults Outcomes specified for this review were not reported or measured 181 Parini 2008 Cholesterol synthesis inhibition elicits an integrated molecular response in human livers including decreased ACAT2 Outcomes specified for this review were not reported or measured Papathanasiou 2008 Short- and long-term elevation of autoantibody titers against oxidized LDL in patients with acute coronary syndromes. Role of the lipoprotein-associated phospholipase A2 and the effect of atorvastatin treatment Outcomes specified for this review were not reported or measured NCT03784703 2018 Type 2 Diabetic Patients Maintained on Statin Therapy Outcomes specified for this review were not reported or measured NCT00603590 2008 Phase II Study of Heart Polypill Safety and Efficacy in Primary Prevention of Cardiovascular Disease Outcomes specified for this review were not reported or measured Nawrocki 1995 Reduction of LDL cholesterol by 25% to 60% in patients with primary hypercholesterolemia by atorvastatin, a new HMG-CoA reductase inhibitor Outcomes specified for this review were not reported or measured Nawrocki 1996 Reduction of LDL cholesterol by 25% to 60% in patients with primary hypercholesterolemia by atorvastatin, a new HMG-CoA reductase inhibitor Outcomes specified for this review were not reported or measured 182 Nawawi 2003 Reduction in serum levels of adhesion molecules, interleukin-6 and C-reactive protein following short-term low-dose atorvastatin treatment in patients with non-familial hypercholesterolemia Outcomes specified for this review were not reported or measured Naoumova 2003 Treatment with atorvastatin alters the ratio of interleukin-12/interleukin-10 gene expression [corrected] Outcomes specified for this review were not reported or measured Naoumova 1999 Effect of inhibiting HMG-CoA reductase on 7alpha-hydroxy-4-cholesten-3-one, a marker of bile acid synthesis: Contrasting findings in patients with and without prior up-regulation of the latter pathway Outcomes specified for this review were not reported or measured Naoumova 1997 Prolonged inhibition of cholesterol synthesis explains the efficacy of atorvastatin Outcomes specified for this review were not reported or measured Nakamura 2007 Increase in circulating levels of adiponectin after treatment with statin and fibrate in patients with coronary artery disease and hyperlipidemia Outcomes specified for this review were not reported or measured Nakamura 1997 Efficacy of atorvastatin in primary hypercholesterolemia Outcomes specified for this review were not reported or measured 183 Muscari 2001 Short term effect of atorvastatin and vitamin E on serum levels of C3, a sensitive marker of the risk of myocardial infarction in men Outcomes specified for this review were not reported or measured Monteiro 2008 Early effects of lipid lowering treatment in subjects with metabolic syndrome and acute coronary syndromes Outcomes specified for this review were not reported or measured Moini 2012 Evaluation of atorvastatin for the treatment of patients with asthma: A double-blind randomized clinical trial Outcomes specified for this review were not reported or measured Mohler 2003 Cholesterol reduction with atorvastatin improves walking distance in patients with peripheral arterial disease Outcomes specified for this review were not reported or measured Moga 2005 The influence of atorvastatin therapy on myocardial ischemia in patients with stable angina pectoris. [Polish] Outcomes specified for this review were not reported or measured Mishra 2005 The effect of atorvastatin on serum lipoproteins in acromegaly Outcomes specified for this review were not reported or measured Mills 2007 Atorvastatin treatment for men with lower urinary tract symptoms and benign prostatic enlargement Outcomes specified for this review were not reported or measured 184 Messerli 2006 Efficacy and safety of coadministered amlodipine and atorvastatin in patients with hypertension and dyslipidemia: results of the AVALON trial Outcomes specified for this review were not reported or measured Meng 2009 Assessment of arterial stiffness affected by atorvastatin in coronary artery disease using pulse wave velocity Outcomes specified for this review were not reported or measured Mehta 2007 Effect of pioglitazone and its combination with statins in coronary artery disease patients with hyperinsulinemia Outcomes specified for this review were not reported or measured McCrindle 2003 Efficacy and safety of atorvastatin in children and adolescents with familial hypercholesterolemia or severe hyperlipidemia: a multicenter, randomized, placebo-controlled trial Outcomes specified for this review were not reported or measured Martin-Ventura 2005 Intensive treatment with atorvastatin reduces inflammation in mononuclear cells and human atherosclerotic lesions in one month Outcomes specified for this review were not reported or measured Martin 2011 Residual beta cell function in newly diagnosed type 1 diabetes after treatment with atorvastatin: the Randomized DIATOR Trial Outcomes specified for this review were not reported or measured Marchesi 2000 Short-term atorvastatin treatment improves endothelial function in hypercholesterolemic women Outcomes specified for this review were not reported or measured 185 Marais 1997 Decreased production of low density lipoprotein by atorvastatin after apheresis in homozygous familial hypercholesterolemia Outcomes specified for this review were not reported or measured Koh 2005 Additive beneficial effects of fenofibrate combined with atorvastatin in the treatment of combined hyperlipidemia Outcomes specified for this review were not reported or measured Knopp 2006 Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in non-insulin-dependent diabetes mellitus (ASPEN) Outcomes specified for this review were not reported or measured Kitas 2019 Trial of atorvastatin for the primary prevention of cardiovascular events in patients with rheumatoid arthritis (TRACE RA): a multicenter, randomized, placebo controlled trial Outcomes specified for this review were not reported or measured Kishi 2009 Atorvastatin might improve ventricular electrostability and decelerate the deterioration of renal function in patients with heart failure and diabetes mellitus Outcomes specified for this review were not reported or measured 186 Katayama 2011 [Combination therapy with angiotensin receptor blocker (ARB) plus atorvastatin reduced proteinuria in type 2 diabetic patients with diabetic nephropathy] Outcomes specified for this review were not reported or measured Karam 2008 High-dose atorvastatin after stroke or transient ischemic attack: the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators Outcomes specified for this review were not reported or measured Kappelle 2009 Atorvastatin affects low density lipoprotein and non-high density lipoprotein cholesterol relations with apolipoprotein B in type 2 diabetes mellitus: Modification by triglycerides and cholesteryl ester transfer protein Outcomes specified for this review were not reported or measured Kappelle 2010 Atorvastatin treatment lowers fasting remnant-like particle cholesterol and LDL subfraction cholesterol without affecting LDL size in type 2 diabetes mellitus: Relevance for non-HDL cholesterol and apolipoprotein B guideline targets Outcomes specified for this review were not reported or measured Kanadasi 2006 The effect of early statin treatment on inflammation and cardiac events in acute coronary syndrome patients with low-density lipoprotein cholesterol Outcomes specified for this review were not reported or measured 187 Kajimoto 2009 Short-term 20-mg atorvastatin therapy reduces key inflammatory factors including c-Jun N-terminal kinase and dendritic cells and matrix metalloproteinase expression in human abdominal aortic aneurysmal wall Outcomes specified for this review were not reported or measured Kadoglou 2011 Impact of atorvastatin on serum vaspin levels in hypercholesterolemic patients with moderate cardiovascular risk Outcomes specified for this review were not reported or measured JPRN-UMIN000001114 2008 Effects of lipid lowering by atorvastatin on carotid atherosclerotic plaque (ACAP) study: a randomized trial for analysis of qualitative change in carotid atherosclerrotic plaque with IB echo and Black Blood MRI Outcomes specified for this review were not reported or measured Joy 2008 Effects of atorvastatin on Lp(a) and lipoprotein profiles in hemodialysis patients Outcomes specified for this review were not reported or measured Jayaram 2007 Randomised study to compare the efficacy and safety of isapgol plus atorvastatin versus atorvastatin alone in subjects with hypercholesterolaemia Outcomes specified for this review were not reported or measured 188 Issa 2012 Atorvastatin and hormone therapy effects on APOE mRNA expression in hypercholesterolemic postmenopausal women Outcomes specified for this review were not reported or measured Huptas 2006 Effect of atorvastatin (10 mg/day) on glucose metabolism in patients with the metabolic syndrome Outcomes specified for this review were not reported or measured Hunninghake 2001 Coadministration of colesevelam hydrochloride with atorvastatin lowers LDL cholesterol additively Outcomes specified for this review were not reported or measured Horwich 2011 Statins do not significantly affect muscle sympathetic nerve activity in humans with nonischemic heart failure: a double-blind placebo-controlled trial Outcomes specified for this review were not reported or measured Holmberg 2005 Safety and efficacy of atorvastatin in patients with severe renal dysfunction Outcomes specified for this review were not reported or measured Holman 2009 Atorvastatin in Factorial with Omega-3 EE90 Risk Reduction in Diabetes (AFORRD): a randomised controlled trial Outcomes specified for this review were not reported or measured Hernandez 2011 Effect of atorvastatin on lipoprotein (a) and interleukin-10: a randomized placebo-controlled trial Outcomes specified for this review were not reported or measured 189 CRSSTD - 4207080 Grimm 2010 Simultaneous treatment to attain blood pressure and lipid goals and reduced CV risk burden using amlodipine/atorvastatin single-pill therapy in treated hypertensive participants in a randomized controlled trial Outcomes specified for this review were not reported or measured Goldstein 2009 Statin treatment and stroke outcome in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial Outcomes specified for this review were not reported or measured Goldstein 2008 Relative effects of statin therapy on stroke and cardiovascular events in men and women: secondary analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Study Outcomes specified for this review were not reported or measured GlaxoSmithKline 2000 A 16-Week Randomized, Double-Blind, Parallel-Group Study to Evaluate the Safety and Efficacy of Hypolipidemic Therapy with an HMGCoA Reductase Inhibitor (Atorvastatin) in Type 2 Diabetes Mellitus Patients Treated with Rosiglitazone (BRL 49653C) 4mg bd Outcomes specified for this review were not reported or measured 190 Gentile 2000 Comparative efficacy study of atorvastatin vs simvastatin, pravastatin, lovastatin and placebo in type 2 diabetic patients with hypercholesterolaemia Outcomes specified for this review were not reported or measured Ge 2008 Synergistic effect of amlodipine and atorvastatin on blood pressure, left ventricular remodeling, and C-reactive protein in hypertensive patients with primary hypercholesterolemia Outcomes specified for this review were not reported or measured Freed 2002 Effects of rosiglitazone alone and in combination with atorvastatin on the metabolic abnormalities in type 2 diabetes mellitus Outcomes specified for this review were not reported or measured Fogari 2006 Effects of amlodipine-atorvastatin combination on inflammation markers and insulin sensitivity in normocholesterolemic obese hypertensive patients Outcomes specified for this review were not reported or measured Fogari 2004 Effect of amlodipine-atorvastatin combination on fibrinolysis in hypertensive hypercholesterolemic patients with insulin resistance Outcomes specified for this review were not reported or measured Ferrier 2002 Cholesterol reduction and artery compliance in hypertension Outcomes specified for this review were not reported or measured 191 Ferrier 2002 Intensive cholesterol reduction lowers blood pressure and large artery stiffness in isolated systolic hypertension Outcomes specified for this review were not reported or measured Faludi 2004 Progesterone abolishes estrogen and/or atorvastatin endothelium dependent vasodilatory effects Outcomes specified for this review were not reported or measured EUCTR2004-000139-27-SE 2004 A Phase 3, Double-Blind, Placebo-Controlled, Randomized, Parallel Group, Multicenter Study of the Efficacy, Safety, and Tolerability of Fixed Combination Torcetrapib/Atorvastatin Administered Orally, Once Daily for 6 Months, Compared to Atorvastatin Alone or Placebo, in Subjects With Mixed Dyslipidemia (Frederickson Types IIa and IIb). - N/A Outcomes specified for this review were not reported or measured Economides 2004 The effects of atorvastatin on endothelial function in diabetic patients and subjects at risk for type 2 diabetes Outcomes specified for this review were not reported or measured Glinkina 2008 Comparison of the effects of carbohydrate metabolism compensation and atorvastatin treatment on lipid metabolism and c-reactive protein in type 2 diabetes mellitus Outcomes specified for this review were not reported or measured 192 Amarenco 2010 Coronary heart disease risk in patients with stroke or transient ischemic attack and no known coronary heart disease: findings from the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial Outcomes specified for this review were not reported or measured Dogra 2007 A randomized trial of the effect of statin and fibrate therapy on arterial function in CKD Outcomes specified for this review were not reported or measured Diepeveen 2005 Effects of atorvastatin and vitamin E on lipoproteins and oxidative stress in dialysis patients: a randomised-controlled trial Outcomes specified for this review were not reported or measured DiabetesAtorvastinLipidInterventionStudy 2001 The effect of aggressive versus standard lipid lowering by atorvastatin on diabetic dyslipidemia: the DALI study: a double-blind, randomized, placebo-controlled trial in patients with type 2 diabetes and diabetic dyslipidemia Outcomes specified for this review were not reported or measured Deanfield 2010 Potent anti-ischaemic effects of statins in chronic stable angina: incremental benefit beyond lipid lowering? Outcomes specified for this review were not reported or measured Davidson 2002 Comparison of effects on low-density lipoprotein cholesterol and high-density lipoprotein Outcomes specified for this review were not reported or measured 193 cholesterol with rosuvastatin versus atorvastatin in patients with type IIa or IIb hypercholesterolemia Dallinga-Thie 2006 Plasma apolipoprotein A5 and triglycerides in type 2 diabetes Outcomes specified for this review were not reported or measured Dallinga-Thie 2006 Plasma phospholipid transfer protein activity is decreased in type 2 diabetes during treatment with atorvastatin: a role for apolipoprotein E? Outcomes specified for this review were not reported or measured Cui 2006 [Effect of atorvastatin on endothelium-dependent vasodilatation function in patients with essential hypertension complicated by hyperlipidemia] Outcomes specified for this review were not reported or measured Cubeddu 2006 Comparative lipid-lowering effects of policosanol and atorvastatin: a randomized, parallel, double-blind, placebo-controlled trial Outcomes specified for this review were not reported or measured Crisostomo 2008 Vascular and metabolic response to statin in the mildly hypertensive hypercholesterolemic elderly Outcomes specified for this review were not reported or measured Cohn 2009 Coadministered amlodipine and atorvastatin produces early improvements in arterial wall compliance in hypertensive patients with dyslipidemia Outcomes specified for this review were not reported or measured 194 Colhoun 2004 Cholesterol lowering with atorvastatin for the primary prevention of cardiovascular disease in diabetic adults Outcomes specified for this review were not reported or measured Clough 2009 Muscle microvascular dysfunction in central obesity is related to muscle insulin insensitivity but is not reversed by high-dose statin treatment Outcomes specified for this review were not reported or measured Chapman 2011 Ethnic variations in lipid-lowering in response to a statin (EVIREST): a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Outcomes specified for this review were not reported or measured Chan 2006 Factorial study of the effect of n-3 fatty acid supplementation and atorvastatin on the kinetics of HDL apolipoproteins A-I and A-II in men with abdominal obesity Outcomes specified for this review were not reported or measured Chan 2002 Effect of atorvastatin on chylomicron remnant metabolism in visceral obesity: a study employing a new stable isotope breath test Outcomes specified for this review were not reported or measured Chan 2002 Factorial study of the effects of atorvastatin and fish oil on dyslipidaemia in visceral obesity Outcomes specified for this review were not reported or measured Chan 2002 Regulatory effects of HMG CoA reductase inhibitor and fish oils on apolipoprotein B-100 Outcomes specified for this review were not reported or measured 195 kinetics in insulin-resistant obese male subjects with dyslipidemia Bloomfield 2009 Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy and coadministered with atorvastatin in dyslipidemic patients Outcomes specified for this review were not reported or measured Bleda 2012 Improving total-cholesterol/HDL-cholesterol ratio results in an endothelial dysfunction recovery in peripheral artery disease patients Outcomes specified for this review were not reported or measured Berthold 2004 Age-dependent effects of atorvastatin on biochemical bone turnover markers: a randomized controlled trial in postmenopausal women Outcomes specified for this review were not reported or measured Bakker-Arkema 1996 Efficacy and safety of a new HMG-CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia Outcomes specified for this review were not reported or measured Bakker-Arkema 1996 Efficacy and safety of a new HMG-CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia Outcomes specified for this review were not reported or measured Amudha 2008 Short-term effect of atorvastatin on endothelial function in healthy offspring of parents with type 2 diabetes mellitus Outcomes specified for this review were not reported or measured 196 Amarenco 2007 The role of statins in the prevention of stroke Outcomes specified for this review were not reported or measured Amarenco 2007 Effects of intense low-density lipoprotein cholesterol reduction in patients with stroke or transient ischemic attack: the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial Outcomes specified for this review were not reported or measured Singh 2008 Comparison effect of atorvastatin (10 versus 80 mg) on biomarkers of inflammation and oxidative stress in subjects with metabolic syndrome Outcomes specified for this review were not reported or measured Soedamah-Muthu 2003 The effect of atorvastatin on serum lipids, lipoproteins and NMR spectroscopy defined lipoprotein subclasses in type 2 diabetic patients with ischaemic heart disease Outcomes specified for this review were not reported or measured Sinski 2009 Atorvastatin reduces sympathetic activity and increases baroreceptor reflex sensitivity in patients with hypercholesterolaemia and systemic arterial hypertension Outcomes specified for this review were not reported or measured Sillesen 2007 Atorvastatin treatment in patients with carotid stenosis is associated with a marked reduction in the risk of stroke, cardiovascular events and Outcomes specified for this review were not reported or measured 197 carotid revascularisation procedures. A substudy of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Trial Sillesen 2007 Atorvastatin treatment in patients with carotid stenosis is associated with a marked reduction in the risk of stroke, cardiac events and endarterectomy: a substudy of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial Outcomes specified for this review were not reported or measured Sillesen 2008 Atorvastatin reduces the risk of cardiovascular events in patients with carotid atherosclerosis: a secondary analysis of the stroke prevention by aggressive reduction in cholesterol levels (SPARCL) trial Outcomes specified for this review were not reported or measured Sharma 2001 SPARCL Study. A double-blind, randomised, placebo-controlled study of Atorvastatin as prevention of cerebrovascular events in patients with a previous transient ischaemic attack or stroke Outcomes specified for this review were not reported or measured Yamada 2007 Long-term effect of atorvastatin on neurohumoral activation and cardiac function in patients with Outcomes specified for this review were not reported or measured 198 chronic heart failure: a prospective randomized controlled study Yamada 2009 Effects of atorvastatin on carotid atherosclerotic plaques: a randomized trial for quantitative tissue characterization of carotid atherosclerotic plaques with integrated backscatter ultrasound Outcomes specified for this review were not reported or measured Xie 2010 Statin therapy shortens QTc, QTcd, and improves cardiac function in patients with chronic heart failure Outcomes specified for this review were not reported or measured Xia 2009 [Effects of low-dose atorvastatin in combination with aspirin on carotid atherosclerotic plaques and blood biochemical parameters in patients with cerebral infarction] Outcomes specified for this review were not reported or measured Amarenco 2009 Relative and cumulative effects of lipid and blood pressure control in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels trial Outcomes specified for this review were not reported or measured Amarenco 2009 Baseline blood pressure, low- and high-density lipoproteins, and triglycerides and the risk of vascular events in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial Outcomes specified for this review were not reported or measured 199 Amarenco 2014 Effect of high-dose atorvastatin on renal function in subjects with stroke or transient ischemic attack in the SPARCL trial Outcomes specified for this review were not reported or measured Amarenco 2006 High-dose atorvastatin after stroke or transient ischemic attack Outcomes specified for this review were not reported or measured Amarenco 0088 Effect of atorvastatin compared with placebo on cerebrovascular end points in patients with previous stroke or transient ischemic attack - The SPARCL Study Outcomes specified for this review were not reported or measured Amarenco 2009 Results of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial by stroke subtypes Outcomes specified for this review were not reported or measured Almroth 2009 Atorvastatin and persistent atrial fibrillation following cardioversion: a randomized placebo-controlled multicentre study Outcomes specified for this review were not reported or measured Sathyapalan 2019 The Effect of Atorvastatin (and Subsequent Metformin) on Adipose Tissue Acylation-Stimulatory-Protein Concentration and Inflammatory Biomarkers in Overweight/Obese Women with Polycystic Ovary Syndrome Outcomes specified for this review were not reported or measured 200 Iakovenko 2014 Dose-dependent effect of atorvastatin on erectile function and androgen status in men with high cardiovascular risk Outcomes specified for this review were not reported or measured Krysiak 2015 The effect of atorvastatin and atorvastatin-ezetimibe combination therapy on androgen production in hyperandrogenic women with elevated cholesterol levels Wrong comparator; absence of controls Baspinar 2016 The effects of statin treatment on adrenal and sexual function and nitric oxide levels in hypercholesterolemic male patients treated with a statin Wrong study design; Not randomized IRCT201208299626N1 2012 The effect of atorvastatin on biochemical and hemostatic profile of patients with polycystic ovary syndrome Wrong comparator Samentzas 2015 The effect of statins in erectile dysfunction Wrong study design Pons-Rejraji 0099 Evaluation of atorvastatin efficacy and toxicity on spermatozoa, accessory glands and gonadal hormones of healthy men: A pilot prospective clinical trial Wrong comparator; No control NCT02497638 0149 LIpitor and biGuanide to Androgen Delay Trial Wrong setting; Not started yet 201 NCT01555632 0153 Atorvastatin Calcium in Preventing Metabolic Syndrome in Patients With Prostate Cancer Receiving Long-Term Androgen-Deprivation Therapy Wrong setting; Study was withdrawn before participants were enrolled.; NCT00522158 0149 Effects of Achieving Very Low LDL-Cholesterol After Treatment With Statins on Steroidogenesis and Cognition Wrong comparator; no placebo; NCT00433823 0151 A Study Evaluating the Effects of Lipid Lowering Treatment on Steroid Synthesis Wrong comparator; no placebo; Maggioni 2018 The REVEAL study Wrong intervention Ishola 2017 Atorvastatin attenuates testosterone-induced benign prostatic hyperplasia in rats: role of peroxisome proliferator-activated receptor-gamma and cyclo-oxygenase-2 Wrong study design (animal study) BraamskampMJAM 2015 Gonadal steroids, gonadotropins and DHEAS in young adults with familial hypercholesterolemia who had initiated statin therapy in childhood Wrong study design (non-randomized) Krysiak 2016 The effect of testosterone on cardiometabolic risk factors in atorvastatin-treated men with late-onset hypogonadism Wrong study design (non-randomized) 202 Guo 0090 Effects of atorvastatin on serum lipids, serum inflammation and plaque morphology in patients with stable atherosclerotic plaques Outcomes specified for this review were not reported or measured Cai 2014 The role of statins in erectile dysfunction: a systematic review and meta-analysis Wrong study design (systematic review) 203 Appendix F Sensitivity analysis using random effects model (forest plots) Forest plot of comparison: Atorvastatin vs control (random effects model), outcome: Total testosterone(females). Forest plot of comparison: Atorvastatin vs control (random effects model), outcome: Androstenedione. Forest plot of comparison: Atorvastatin vs control (random effects model), outcome: Free androgen index (FAI)
Thesis/Dissertation
eng
Pharmacology and Therapeutics
Vancouver : University of British Columbia Library
Attribution-NonCommercial-NoDerivatives 4.0 International
Graduate
The effects of atorvastatin on testosterone levels in males and females : a systematic review and meta-analysis
Text