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The effectiveness and safety of treatments used for polycystic ovarian syndrome management in adolescents: a systematic review and network meta-analysis protocol


Al Khalifah et al. Systematic Reviews (2015) 4:125 DOI 10.1186/s13643-015-0105-4 The effectiveness and safety of treatmentsused for polycystic ovarian syndromemanagement in adolescents: a systematicreview and network meta-analysis protocol Reem A. Al Khalifah1,2,3, Iván D. Flórez1,4* Brittany Dennis1, Binod Neupane1, Lehana Thabane1,5,6and Ereny Bassilious2 Background: Polycystic ovarian syndrome (PCOS) is a common reproductive endocrine disease that is seen amongadolescent women. Currently, there is limited evidence to support treatment options leading to considerable variationin practice among healthcare specialists. The objective of this study is to review and synthesize all the available evidenceon treatment options for PCOS among adolescent women.
Methods/design: We will conduct a systematic review of all randomized controlled trials evaluating the use ofmetformin, oral contraceptive pills as monotherapy, or as combination with pioglitazone, spironolactone, flutamide,and lifestyle interventions in the treatment of PCOS in adolescent women ages 11 to 19 years. The primary outcomemeasures are menstrual regulation and change hirsutism scores. The secondary outcome measures include acnescores, prevalence of dysglycaemia, BMI, lipid profile, total testosterone level, and adverse events. We will performliterature searches through Ovid Medline, Ovid Embase, and Cochrane Central Register of Controlled Trials (CENTRAL),and gray literature resources. Two reviewers will independently screen titles and abstracts of identified citations, reviewthe full texts of potentially eligible trials, extract information from eligible trials, and assess the risk of bias and quality ofthe evidence independently. Results of this review will be summarized narratively and quantitatively as appropriate. Wewill perform a multiple treatment comparison using network meta-analysis to estimate the pooled direct and indirecteffects for all PCOS interventions on outcomes if adequate data is available.
Discussion: PCOS treatment poses a clinical challenge to the patients and physicians. This is the first systematic reviewand network meta-analysis for PCOS treatment in adolescents. We expect that our results will help improve patient care,unify the treatment approaches among specialists, and encourage research for other therapeutic options.
Systematic review registration: PROSPERO Keywords: Adolescents, Polycystic ovarian syndrome, Hirsutism, Menstrual irregularity, Acne, Body mass index,Dysglycaemia * Correspondence: 1Department of Clinical Epidemiology & Biostatistics, McMaster University,Juravinski Site, G Wing, 2nd Floor, 711 Concession Street, Hamilton, ON L8V1C3, Canada4Department of Pediatrics, University of Antioquia, Medellín, ColombiaFull list of author information is available at the end of the article 2015 Al Khalifah et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiverapplies to the data made available in this article, unless otherwise stated.
Al Khalifah et al. Systematic Reviews (2015) 4:125 pills (OCP) to control symptoms of hyperandrogenism Polycystic ovarian syndrome (PCOS) is a common repro- or metformin therapy in patients with impaired glucose ductive endocrine disease encountered among adolescents tolerance or features of metabolic syndrome [. How- and young women [. Its prevalence varies between 1.8 ever, there is significant variability in clinical practice, and 15 % depending on the diagnostic criteria used and depending on whether the physician and patient's primary ethnicity . Patients with PCOS can present with a goal of treatment is to treat the symptoms of hyperandro- constellation of symptoms including chronic anovulation genism or the features of metabolic syndrome (amenorrhea, oligomenorrhea, irregular menstrual cycles), Additionally, in clinical practice anti-androgenic medica- clinical features of hyperandrogenism (acne and hirsut- tions such as spironolactone, flutamide, and insulin sensi- ism), biochemical evidence of hyperandrogenism, polycys- tizing agents such as pioglitazone are used as add-on tic ovaries on ultrasound, and features of metabolic therapy when OCP or metformin fail to produce the syndrome. Oligomenorrhea is the presenting feature in clinically desired outcomes yet the Endocrine about 75 % of cases [, while hirsutism and acne are Society guidelines do not comment on their use in present in 60–70 % of cases and contribute to psycho- the adolescent population.
logical distress in adolescent patients .
To date, there is one systematic review and meta- Three different diagnostic criteria have been used for analyses in adolescents (in press) that identified low num- the diagnosis of PCOS: the National Institutes of Health ber of low quality evidence from head-to head trials and (NIH), the Rotterdam, and the Androgen Excess Society identified large number of trials that compared metformin Criteria All of them require the presence of men- to placebo, OCP to placebo, and other PCOS combination strual cycle disturbance and presence of clinical and/or therapy ]. A traditional meta-analysis can only evaluate biochemical hyperandrogenism, while the last two re- the direct treatment efficacy of two treatment approaches quire the presence of polycystic ovarian morphology on at a time while a network meta-analysis can provide effect ultrasound To date, the preferred diagnostic cri- estimates for all direct and indirect treatment comparisons teria in adolescents are the NIH criteria [ []. Therefore, we aim to conduct a network meta- The etiology of PCOS is complex and not well under- analysis to address the following objectives: (1) assess the stood. Primary intrinsic ovarian pathology in combination effectiveness and safety of using metformin and OCP as with hypothalamic–pituitary–ovarian axis abnormalities monotherapy in adolescents with PCOS; (2) assess the ef- may lead to increased ovarian androgen secretion [, fectiveness and safety of using metformin and/or OCP in Insulin resistance with compensatory hyperinsulinemia combination with pioglitazone, spironolactone, flutamide, may also play a role as it can lead to direct stimulation of and lifestyle interventions, as evaluated across multiple ovarian and adrenal androgen secretion, which leads to outcomes such as menstrual cycle regulation, improve- decreased hepatic sex hormone binding globulin synthesis ment in clinical and or biochemical evidence of hyperan- and therefore, to an increased bioavailability of free testos- drogenism, and metabolic profile in adolescents with terone level ]. Insulin resistance is involved in the PCOS; (3) evaluate the effectiveness of different formula- development of cardiometabolic disturbances such as dys- tions of OCPs on hirsutism and acne scores.
glycaemia, hyperlipidemia, and obesity and it hasbeen described that between 18 and 24 % of adolescents with PCOS have some degree of abnormal glucose me- This systematic review and network meta-analysis proto- tabolism [–These patients are at increased risk col is registered on PROSPERO International prospective of type 2 diabetes, hypertension, myocardial infarction, register of systematic reviews (CRD42015016148). The re- angina, and psychiatric diseases in addition to port will comply with the Preferred Reporting Items for gynecological and obstetrical complications, such as in- Systematic Review and Network Meta-Analysis Protocols fertility, higher rate for pregnancy loss, gestational dia- (PRISMA-P) [].
betes, premature delivery, as well as gynecological andnon-gynecological cancers . In addition to the Eligibility criteria aforementioned co-morbidities, patients with PCOS ex- The search for studies will be limited to randomized perience a low perceived health quality over lack of clinical trials (RCT) (including all designs such as cross- symptom improvement, primarily with weight control, over, cluster, and patient-randomized clinical trials) asses- hirsutism, acne, menstrual irregularity, and infertility as sing the efficacy, effectiveness, or safety of different inferred from qualitative studies regimen for the treatment of PCOS that enrolled adoles- Optimal first line treatment of PCOS in adolescents cent girls ages 11–19 years. The definition of adolescent remains controversial. Current Endocrine Society treatment age group is based on the widely accepted World Health guidelines first recommend lifestyle changes (dietary and Organization definition for adolescent Studies that exercise modification) followed by either oral contraceptive include both adolescents and adults participants will be Al Khalifah et al. Systematic Reviews (2015) 4:125 included in the review, and upon contact, we will ask au- search of bibliographies of identified randomized controlled thors to provide separate data for the adolescent partici- trials and guidelines; (2) trials registries (Clinicaltrials.gov, pants. If we are unable to obtain this information, we will World Health Organization WHO International Clinical include the study and we will conduct subgroup analyses Trials Registry Platform Search Portal, controlled-trials.com in order to assess the difference between studies which in- and the National Institutes of Health database of funded cluded only adolescents and studies which included both studies for ongoing or unpublished trials); and (3) confer- adolescents and adults. Sub-studies or secondary ana- ences preceding and abstracts of the North American and lysis of reported eligible studies will be excluded to European Endocrine Society and The Society of Adolescent avoid duplication.
Medicine and Health. Search alerts are set up for monthly The diagnosis of PCOS will be based on the known notification, and the search will be repeated before the final PCOS diagnostic criteria: Endocrine Society Guidelines, manuscript submission to identify any new literature. We NIH criteria, Rotterdam criteria, and the Androgen Excess will contact the authors of unpublished work to establish Society criteria We will exclude studies that in- eligibility and methodological quality of the study.
cluded normal control participants or patients with othercauses of oligomenorrhea or hyperandrogenism, such as hyperprolactinemia, thyroid dysfunction, androgen secret- Two reviewers (RA and IF) will independently and in ing tumors, or late-onset congenital adrenal hyperplasia.
duplicate screen the title and abstract available of identi- We will include studies that evaluated single and/or fiable articles to assess its eligibility. In case of disagree- combined interventions, at any dose, such as metformin, ment, the full text will be retrieved and reviewed OCP, pioglitazone, spironolactone, flutamide, and life- independently by one of the authors (EB), to resolve dis- style interventions. In order to be included, the study crepancy. We will refer to inclusion and exclusion cri- will have had to report the effectiveness of one of these teria during the screening process. Records of ineligible interventions and the intervention effect on one or more articles along with the reason for ineligibility will be of the outcomes of interest.
saved for future reference. Eligible articles citations will Our primary outcomes are menstrual cycle regulation be saved in EndnoteX6 library. We will include the and hirsutism scores. The secondary outcomes include PRISMA flow diagram demonstrating the search and acne scores, prevalence of dysglycaemia, BMI, total tes- screening process (Fig. We will contact authors of tosterone level, lipid profile (triglyceride, total choles- primary studies during data extraction to provide any terol, LDL, HDL), and adverse events; Table shows the definitions of outcome measures. We chose not to re-port on pregnancy outcomes because it necessities chan- ging the scope of the review to involve fertility induction The study data will be collected in standardized online medications. Hence, we will exclude studies that only data extraction forms (Google forms) according to pre- used fertility induction medications and which primary specified instructions. The data extraction form will outcome of interest was pregnancy.
include information pertaining to study background, lan-guage of publication, country, funding sources, confirm Data sources and search strategy study eligibility, participant ages, PCOS diagnostic cri- We performed literature search through Ovid MEDLINE, teria, the study design, number of intervention groups, Ovid EMBASE, and Cochrane Central Register of Con- intervention details, number of participants allocated to trolled Trials (CENTRAL) from the database inception to each intervention group, randomization, concealment of January 2015 using combination of controlled terms, i.e., allocation, blinding, length of follow up, analysis type, Medical Subject Heading (MeSH), Emtree terms, and outcome definition, unit of measurement, ascertainment free-text terms with various synonyms for polycystic of the outcome, estimate of intervention effect with con- ovarian syndrome (PCOS), adolescent, metformin, pio- fidence interval, and missing follow up data. When stud- glitazone, oral contraceptive pills, flutamide, and life- ies measure outcomes at more than one time point, we style interventions ).
will collect results for the last measurement point in the We used the randomized controlled trial filter created study. The data extraction form will be pilot tested by all from McMaster University for Ovid Embase platform reviewers independently before its use. Four reviewers and the Cochrane library filter for Ovid Medline platform will perform data extraction (RA, IF, EB, BD), working These filters provide a good balance between sensi- in pairs independently and in duplicate. In case of dis- tivity and specificity. Our search strategy was developed in agreement in assessing the methodological quality of the liaison with an experienced librarian. No language, publica- study, we will try to resolve it by consensus. If consensus tion status, or date limit was used. Additionally, we per- cannot be reached, a third designated reviewer from the formed a gray literature search through (1) manual hand team will be involved.
Al Khalifah et al. Systematic Reviews (2015) 4:125 Table 1 Outcome measures Measurement of variable (units) Statistical estimates andmeasurement of associationof this outcome Menstrual regulation Number of girls achieved regular menses Number of cycles per year Mean difference ± SD Ferriman Gallawey score Mean difference ± SD Lesion counting or grading Standardized mean difference ± SD The rate of occurrence of T2DM, impaired glucose tolerance, and impaired fasting glucose assessed by oral glucose tolerancetest and/or fasting blood glucose, and/or HBA1c Mean difference ± SD Total testosterone level Mean difference ± SD Total cholesterol Mean difference ± SD Mean difference ± SD Mean difference ± SD Mean difference ± SD Number of girls developed: 1- GI: all GI related adverse events: • Nausea• Vomiting• Diarrhea• Constipation• Abdominal pain• Flatulence• Gastritis• GI bleeding 2- thrombosis: all vascular events related to thrombusformation such as: • Deep venous thrombosis• Stroke• Myocardial infarction• Pulmonary embolism 3- serious: adverse events that are of majormorbidity such as: • Any bleeding not including GI bleed• Lactic acidosis• Liver failure• Renal failure• Vasculitis• Electrolyte imbalance• Agranulocytosis• Photosensitivity• Hypertension• Pancreatitis• Anaphylaxis• Chorea• Depression Al Khalifah et al. Systematic Reviews (2015) 4:125 Table 1 Outcome measures (Continued) 4- minor: adverse events that are of minormorbidity such as: • Headache• Fatigue• Beast tenderness• Vaginal bleeding (spotting)• Edema• Weight gain• Metallic taste• Muscle cramp• Rash• Fever• Hot flashes• Glucose intolerance• Infection OR odds ratio, T2DM type 2 diabetes mellitus, BMI body mass index, LDL low-density lipoprotein, HDL high-density lipoprotein, GI gastrointestinal Assessment of risk of bias in included studies risk," or "unclear risk." We will further categorize the "un- Two independent reviewers will assess each included study clear risk" to "probably low risk" or "probably high risk" in for risk of bias using the modified Cochrane handbook for order to give a better understanding of the unclear risk of systematic reviews of interventions tool [, which as- bias score. We will rate the overall risk of bias score for sesses six elements: (1) sequence generation, (2) allocation each study as "high risk" if the study meets more than two concealment, (3) blinding of participants, personnel and criteria for high risk of bias, "moderate risk of bias" if the outcome assessors, (4) completeness of follow up, (5) se- study meets one to two criteria for high risk of bias, and lective outcome reporting, and 6) presence of other biases.
"low risk of bias" if the study does not meet any high risk Each domain will be assigned a score of "low risk," "high of bias criteria [].
Standard direct comparisonsWe will perform a pairwise meta-analysis using R soft-ware. Effect estimates and their 95th confidence interval(CI) will be calculated using risk ratio (RR) for binaryoutcomes and mean difference for continuous outcomesif they are reported using the same metrics; otherwise,estimates reported using different metrics will be con-verted into standardized mean difference (SMD). Wewill pool all direct evidence using random-effect meta-analysis with the maximal likelihood (ML) estimatorWe will assess for heterogeneity by estimating thevariance between studies using the chi-square test andquantify it using the I2 test statistic. We will interpretthe I2 using the thresholds set forth by the CochraneCollaboration The network meta-analysisGiven that many of the treatment combinations availableto treat PCOS were not compared in head-to-head stud-ies, a network meta-analysis (NMA) will be necessary toprovide effect estimates for all indirect comparisonsWe will perform a multiple treatment comparison Fig. 1 The primary selection process to estimate the pooled direct, indirect, and the network Al Khalifah et al. Systematic Reviews (2015) 4:125 estimates (mixed evidence from direct and indirect esti- hierarchical regression model but considers multiple com- mates) for all PCOS interventions on outcomes if the as- ponents of an intervention as dummy variables in the same sumptions of homogeneity and similarity are judged to model. Hence, the analysis allows the estimation of the ef- be reasonable. Effect estimates will be presented along fects and ranking of a combination of all possible and ap- with their corresponding 95 % credibility intervals (CrIs); propriate components. Thus, it is possible to explore such these are the Bayesian analog of 95 % CIs. However, a combination that could have been the best for the treat- mixed evidence will only be used if the consistency as- ment of PCOS but has never been tested before in any sumption is met.
trial. Further, such an analysis allows the assessment of We will fit a Bayesian random-effect hierarchical additive or multiplicative (interaction) effects between two model with non-informative priors using vague normal or more components if sufficient data are available. We distribution (mean 0, variance 10,000) and adjusting for will re-analyze the data under complex intervention ap- correlation between effects in multi-arm trials. We will proach as well [to assess if there exists a potentially bet- ter combination of components which have been ever or Monte-Carlo (MCMC) simulation technique running never assessed.
the analysis in four parallel chains. We will use a series We will perform the Bayesian network meta-analysis of 100,000 burn-in simulations to allow convergence in JAGS (version 3.4.0) or WinBUGS software (version and then a further 20,000 simulations (succeeding 1.4.3, MRC Biostatistics Unit, Cambridge, UK) inter- 50,000 simulations saved at an interval of 10 in each facing through R software.
chain) to produce the outputs. We will assess modelconvergence using Gelman and Rubin diagnostic test ].
The Bayesian model provides flexibility for moderate In case there is significant heterogeneity and inconsistency, levels of treatment heterogeneity, sampling variability, we will use meta-regression to explain the heterogeneity, and incoherence This model introduces a ran- provided we have enough data to do so; otherwise, we will dom effect representing any changes in the observed perform subgroup analyses. We will perform meta- treatment effect that may be due to the comparison regression using study level covariates: methodological being made We will interpret variability in this quality (high risk of bias versus low risk of bias), partici- random effect as incoherence [We will use the pant's average age, BMI status (obese and/or overweight node-splitting method to detect incoherence between BMI ≥25 kg/m2 versus normal <25 kg/m2), homeostatic direct and indirect evidence within a closed loop as model assessment (HOMA-IR) (high and moderate ≥3 well as identify loops with large inconsistency [ versus low <3), medication dose, length of treatment We will measure the goodness-of-fit of the model using (≥3 months versus <3 months), use of ultrasound to docu- the deviance information criterion (DIC) ment polycystic ovaries (used versus not used), and studies To ensure interpretability of the NMA results, we will that included young adults versus adolescents only to present the network geometry, the results with probabil- examine the improvement or change in model fit after co- istic statements, and also the estimates of interventions variates are included into the model. We will also perform effects and corresponding 95 % CrIs, as well as forest a subgroup analysis to evaluate the effectiveness of differ- plots. We will first rank the intervention and report each ent oral formulations of contraceptive pill on changes of interventions' probability of ranking first (being the best hirsutism and acne scores.
treatment) as well as the surface under the cumulativeranking curve (SUCRA) values High SUCRA values Rating the confidence in estimates of the effect in NMA are expected for the best treatments, and low SUCRA The confidence in the estimates (quality of evidence) for values are expected for the worst treatments.
each reported outcome will be assessed independently The above analysis assumes that the interventions are by two reviewers (RA, IF) using the Grading of Recom- competing (suitable when most components forming an mendations Assessment, Development, and Evaluation intervention are pharmaceutical and hence cannot go to- Working Group (GRADE Working Group) approach; gether), so that each combination is considered to be a see Fig. for the flow of quality assessment The separate treatment. For example, a combination of com- quality of evidence is categorized by GRADE into four ponents of metformin, flutamide, and exercise forming an levels: high quality, moderate quality, low quality, and intervention and another combination of metformin and very low quality. For the direct comparisons, we will as- exercise forming another intervention are treated as com- sess and rate each outcome based on the five GRADE peting interventions and assesses whether one combination categories: risk of bias, imprecision, inconsistency, indir- is better than another. However, it is possible to perform ectness, and publication bias the network meta-analysis treating these combinations as For the assessment of confidence in the estimates ob- complex intervention [Such an analysis fits a similar tained in the NMA, we will use the recent approach


Al Khalifah et al. Systematic Reviews (2015) 4:125 Table 2 Search strategy: Ovid MEDLINE(R) in-process and othernon-indexed citations, Ovid MEDLINE(R) Daily and OvidMEDLINE(R) 1946 to January 29, 2015 Fig. 2 The quality assessment flow diagram young adult*.mp.
recommended by the GRADE working group We will assess and rate the confidence in all the indirect com- parisons, if available, obtained from first order loops fol- lowing the five GRADE categories used for assessing the direct comparisons in addition to the intransitivity assess- exp Polycystic Ovary Syndrome/ ment. Then, we will rate the confidence in each NMA ef-fect estimate using the higher quality rating when both direct and indirect evidence are present. However, the es- timate can be rated down for incoherence exp Hyperandrogenism/ PCOS treatment in adolescents poses clinical chal- lenges to patients and physicians. To our best know- ledge, our study will be the first NMA in adolescents (polycystic ovar* adj3 (syndrome or disorder or disease)).tw.
to investigate the effectiveness and safety of using metformin and OCP as monotherapy as well as in combination with pioglitazone, spironolactone, fluta-mide, or lifestyle interventions.
Our planned approach for this review has many strengths. We will implement a wide search strategy that included published and unpublished work. As adolescent women share some similar physiology with adult women and in an effort to overcome publication bias, we also exp Contraceptives, Oral/ plan to include studies that included adolescents andyoung adults. Additionally, we aim to report on many patient important outcomes as inferred from previous qualitative research. Similar to previous systematic re- views in adults with PCOS, we anticipate that we will identify studies which use different definitions of PCOS, various definitions for outcome measures of interest, and small sample sizes These factors may pose po-tential limitations to our study.
We hope that this review will provide hierarchical evi- dence to improve patient care, help unify the treatment approaches among specialists, and encourage research exp spironolactone/ for new therapeutic options.
Al Khalifah et al. Systematic Reviews (2015) 4:125 Table 2 Search strategy: Ovid MEDLINE(R) in-process and other Table 2 Search strategy: Ovid MEDLINE(R) in-process and other non-indexed citations, Ovid MEDLINE(R) Daily and Ovid non-indexed citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to January 29, 2015 (Continued) MEDLINE(R) 1946 to January 29, 2015 (Continued) exp hyperandrogenism/ exp Health Promotion/ exp oral contraceptive agent/ randomized controlled trial.pt.
Controlled clinical trial.pt.
clinical trials as topic.sh.
14 and 24 and 52 and 60 exp spironolactone/ exp pioglitazone/ Embase 1974 to 2015 January 27 exp health promotion/ exp diet therapy/ young adult*.mp.
Double blind.tw.
Single blind.tw.
exp ovary polycystic disease/ 14 and 49 and 54 and 57 Al Khalifah et al. Systematic Reviews (2015) 4:125 Table 2 Search strategy: Ovid MEDLINE(R) in-process and other Author details1Department of Clinical Epidemiology & Biostatistics, McMaster University, non-indexed citations, Ovid MEDLINE(R) Daily and Ovid Juravinski Site, G Wing, 2nd Floor, 711 Concession Street, Hamilton, ON L8V MEDLINE(R) 1946 to January 29, 2015 (Continued) 1C3, Canada. 2Department of Pediatrics, Division of Endocrinology andMetabolism, McMaster University, Hamilton, Ontario, Canada. 3Department of Cochrane central: search up to 30/01/2015 20 Pediatrics, King Saud University, Riyadh, Saudi Arabia. 4Department of #1 MeSH descriptor: [Adolescent] explode all trees Pediatrics, University of Antioquia, Medellín, Colombia. 5Department ofPediatrics, McMaster University, Hamilton, Ontario, Canada. 6Department of #2 MeSH descriptor: [Child] explode all trees Pediatrics and Anesthesia, McMaster University, Hamilton, Canada.
#3 MeSH descriptor: [Young Adult] explode all trees Received: 15 July 2015 Accepted: 25 August 2015 #4 young adult.tw Li R, Zhang Q, Yang D, Li S, Lu S, Wu X, et al. Prevalence of polycystic ovary #7 MeSH descriptor: [Polycystic Ovary Syndrome] explode all trees syndrome in women in China: a large community-based study. Hum #8 Stein Leventhal Syndrome or Polycystic Ovar* or PCOS. tw Christensen SB, Black MH, Smith N, Martinez MM, Jacobsen SJ, Porter AH, et #9 MeSH descriptor: [Hirsutism] explode all trees al. Prevalence of polycystic ovary syndrome in adolescents. Fertil Steril.
#10 MeSH descriptor: [Hyperandrogenism] explode all trees Yildiz BO, Bozdag G, Yapici Z, Esinler I, Yarali H. Prevalence, phenotype and #11 hyperandrogen*. tw cardiometabolic risk of polycystic ovary syndrome under differentdiagnostic criteria. Hum Reprod. 2012;27(10):3067 #12 Hirsutism. tw Roe AH, Dokras A. The diagnosis of polycystic ovary syndrome in #13 #6 or #7 or #8 or #9 or #10 or #11 or #12 adolescents. Rev Obstet Gynecol. 2011;4(2):45–51.
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critically reviewed the manuscript, and approved the final manuscript as submitted. LT designed the study, critically reviewed the manuscript, and Flannery CA, Rackow B, Cong X, Duran E, Selen DJ, Burgert TS. Polycystic approved the final manuscript as submitted. BN drafted and critically ovary syndrome in adolescence: impaired glucose tolerance occurs across reviewed the manuscript and approved the final manuscript as submitted.
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Prevention of cardiovascular disease

Prevention of Cardiovascular Disease See separate articlesand The revised Joint British Societies' (JBS 3) guidelines on prevention of cardiovascular disease (CVD) in clinicalpractice recommend that CVD prevention should focus equally on the following three groups of patients who areat high risk of CVD: [1] Apparently healthy individuals with 20% or greater risk over 10 years of developing symptomaticatherosclerotic disease.People with diabetes mellitus (type 1 or 2).People with established atherosclerotic CVD.

Hepatic resection.pm

CASE REPORT Intracerebral haemorrhage and We report on a 65-year-old woman who presented with acute right-sided weakness because of an intracerebral (thalamic) haemorrhage.As a Qigong enthusiast with a long-standing history of hypertension,she developed a stroke syndrome soon after practising Qigong onemorning. Following neurological recovery, the patient exhibited erraticblood pressure responses while practising Qigong, despite the factthat resting blood pressure was normal. The haemodynamic responsesto exercise are discussed and a review of the therapeutic implicationsof practising Qigong is presented.