[show abstract][hide abstract] ABSTRACT: Hyperprolactinemia is a common endocrine disorder that can be associated with significant morbidity. We conducted a systematic review and meta-analyses of outcomes of hyperprolactinemic patients, including microadenomas and macroadenomas, to provide evidence-based recommendations for practitioners. Through this review, we aimed to compare efficacy and adverse effects of medications, surgery and radiotherapy in the treatment of hyperprolactinemia.
We searched electronic databases, reviewed bibliographies of included articles, and contacted experts in the field. Eligible studies provided longitudinal follow-up of patients with hyperprolactinemia and evaluated outcomes of interest. We collected descriptive, quality and outcome data (tumor growth, visual field defects, infertility, sexual dysfunction, amenorrhea/oligomenorrhea and prolactin levels).
After review, 8 randomized and 178 nonrandomized studies (over 3,000 patients) met inclusion criteria. Compared to no treatment, dopamine agonists significantly reduced prolactin level (weighted mean difference, -45; 95% confidence interval, -77 to -11) and the likelihood of persistent hyperprolactinemia (relative risk, 0.90; 95% confidence interval, 0.81 to 0.99). Cabergoline was more effective than bromocriptine in reducing persistent hyperprolactinemia, amenorrhea/oligomenorrhea, and galactorrhea. A large body of noncomparative literature showed dopamine agonists improved other patient-important outcomes. Low-to-moderate quality evidence supports improved outcomes with surgery and radiotherapy compared to no treatment in patients who were resistant to or intolerant of dopamine agonists.
Our results provide evidence to support the use of dopamine agonists in reducing prolactin levels and persistent hyperprolactinemia, with cabergoline proving more efficacious than bromocriptine. Radiotherapy and surgery are useful in patients with resistance or intolerance to dopamine agonists.
[show abstract][hide abstract] ABSTRACT: Hypertriglyceridemia may be associated with important complications. The aim of this study is to estimate the magnitude of association and quality of supporting evidence linking hypertriglyceridemia to cardiovascular events and pancreatitis.
We conducted a systematic review of multiple electronic bibliographic databases and subsequent meta-analysis using a random effects model. Studies eligible for this review followed patients longitudinally and evaluated quantitatively the association of fasting hypertriglyceridemia with the outcomes of interest. Reviewers working independently and in duplicate reviewed studies and extracted data.
35 studies provided data sufficient for meta-analysis. The quality of these observational studies was moderate to low with fair level of multivariable adjustments and adequate exposure and outcome ascertainment. Fasting hypertriglyceridemia was significantly associated with cardiovascular death (odds ratios (OR) 1.80; 95% confidence interval (CI) 1.31-2.49), cardiovascular events (OR, 1.37; 95% CI, 1.23-1.53), myocardial infarction (OR, 1.31; 95% CI, 1.15-1.49), and pancreatitis (OR, 3.96; 95% CI, 1.27-12.34, in one study only). The association with all-cause mortality was not statistically significant.
The current evidence suggests that fasting hypertriglyceridemia is associated with increased risk of cardiovascular death, MI, cardiovascular events, and possibly acute pancreatitis.Précis: hypertriglyceridemia is associated with increased risk of cardiovascular death, MI, cardiovascular events, and possibly acute pancreatitis.
[show abstract][hide abstract] ABSTRACT: Testing men at increased risk for osteoporotic fractures has been recommended.
The aim of this study was to estimate the magnitude of association and quality of supporting evidence linking multiple risk factors with low bone mass-related fractures in men.
We searched MEDLINE, EMBASE, Web of Science, SCOPUS and Cochrane CENTRAL through February 2010. We identified further studies by reviewing reference lists from selected studies and reviews. Study Selection: Eligible studies had to enroll men and quantitatively evaluate the association of risk factors with low bone density-related fractures.
Reviewers working independently and in duplicate determined study eligibility and extracted study description, quality, and outcome data.
Fifty-five studies provided data sufficient for meta-analysis. The quality of these observational studies was moderate with fair levels of multivariable adjustment and adequate exposure and outcome ascertainment. Statistically significant associations were established for age, low body mass index, current smoking, excessive alcohol use, chronic corticosteroid use, history of prior fractures, history of falls, history of hypogonadism, history of stroke, and history of diabetes. Statistical heterogeneity of the meta-analytic estimates of all associations was significant except for chronic corticosteroid use. None of these associations were of large magnitude (i.e. adjusted odds ratios were generally <2). No evidence supporting a particular effective testing or screening strategy was identified.
Multiple risk factors for fractures in men were identified, but their usefulness for stratifying and selecting men for bone density testing remains uncertain.
The Journal of clinical endocrinology and metabolism 03/2012; 97(6):1861-70. · 6.50 Impact Factor
[show abstract][hide abstract] ABSTRACT: Osteoporosis and osteopenia are associated with increased fracture incidence.
The aim of this study was to determine the comparative effectiveness of different pharmacological agents in reducing the risk of fragility fractures.
We searched multiple databases through 12/9/2011.
Eligible studies were randomized controlled trials enrolling individuals at risk of developing fragility fractures and evaluating the efficacy of bisphosphonates, teriparatide, selective estrogen receptor modulators, denosumab, or calcium and vitamin D.
Reviewers working independently and in duplicate determined study eligibility and collected descriptive, methodological quality, and outcome data.
This network meta-analysis included 116 trials (139,647 patients; median age, 64 yr; 86% females and 88% Caucasians; median follow-up, 24 months). Trials were at low to moderate risk of bias. Teriparatide had the highest risk reduction of fractures (odds ratios, 0.42, 0.30, and 0.50 for hip, vertebral, and nonvertebral fractures, respectively) and the highest probability of being ranked first for efficacy (probabilities of 42, 49, and 79% for hip, vertebral, and nonvertebral fractures, respectively). However, differences to denosumab, zoledronate, risedronate, ibandronate, and alendronate were not statistically significant. Raloxifene and bazedoxifene were likely less effective, although these data were limited. Calcium and vitamin D were ineffective given separately but reduced the risk of hip fractures if given in combination (odds ratio, 0.81; 95% confidence interval, 0.68–0.96).
Teriparatide, bisphosphonates, and denosumab are most effective in reducing the risk of fragility fractures. Differences in efficacy across drugs are small; therefore, patients and clinicians need to consider their associated harms and costs.
The Journal of clinical endocrinology and metabolism 03/2012; 97(6):1871-80. · 6.50 Impact Factor
[show abstract][hide abstract] ABSTRACT: The effect of intensive therapy to achieve tight glycemic control in patients hospitalized in non-critical care settings is unclear.
We conducted a systematic review and meta-analysis to determine the effect of intensive glycemic control strategies on the outcomes of death, stroke, myocardial infarction, incidence of infection, and hypoglycemia. We included randomized and observational studies. Bibliographic databases were searched through February 2010. Random effects model was used to pool results across studies.
Nineteen studies (nine randomized and 10 observational studies) were included. The risk of bias across studies was moderate. Meta-analysis demonstrates that intensive glycemic control was not associated with significant effect on the risk of death, myocardial infarction, or stroke. There was a trend for increased risk of hypoglycemia (relative risk, 1.58; 95% confidence interval, 0.97-2.57), particularly in surgical studies and when the planned glycemic target was achieved. Intensive glycemic control was associated with decreased risk of infection (relative risk, 0.41; 95% confidence interval, 0.21-0.77) that was mainly derived from studies in surgical settings.
Intensive control of hyperglycemia in patients hospitalized in non-critical care settings may reduce the risk of infection. The quality of evidence is low and mainly driven by studies in surgical settings.
The Journal of clinical endocrinology and metabolism 11/2011; 97(1):49-58. · 6.50 Impact Factor
[show abstract][hide abstract] ABSTRACT: Vitamin D affects bone and muscle health and likely reduces the risk of falls in the elderly.
The aim of this systematic review is to summarize the existing evidence on vitamin D use and the risk of falls.
We searched electronic databases from inception through August 2010.
Eligible studies were randomized controlled trials in which the intervention was vitamin D and the incidence of falls was reported.
Reviewers working in duplicate and independently extracted study characteristics, quality, and outcomes data.
Odds ratio and associated 95% confidence interval were estimated from each study and pooled using the random effects model.
We found 26 eligible trials of moderate quality that enrolled 45,782 participants, the majority of which were elderly and female. Vitamin D use was associated with statistically significant reduction in the risk of falls (odds ratio for suffering at least one fall, 0.86; 95% confidence interval, 0.77-0.96). This effect was more prominent in patients who were vitamin D deficient at baseline and in studies in which calcium was coadministered with vitamin D. The quality of evidence was low to moderate because of heterogeneity and publication bias.
Vitamin D combined with calcium reduces the risk of falls. The reduction in studies without calcium coadministration did not reach statistical significance. The majority of the evidence is derived from trials enrolling elderly women.
The Journal of clinical endocrinology and metabolism 07/2011; 96(10):2997-3006. · 6.50 Impact Factor
[show abstract][hide abstract] ABSTRACT: Several studies found association between vitamin D levels and hypertension, coronary artery calcification, and heart disease.
The aim of this study was to summarize the evidence on the effect of vitamin D on cardiovascular outcomes.
We searched electronic databases from inception through August 2010 for randomized trials. Reviewers working in duplicate and independently extracted study characteristics, quality, and the outcomes of interest. Random-effects meta-analysis was used to pool the relative risks (RR) and the weighted mean differences across trials.
We found 51 eligible trials with moderate quality. Vitamin D was associated with nonsignificant effects on the patient-important outcomes of death [RR, 0.96; 95% confidence interval (CI), 0.93, 1.00; P = 0.08], myocardial infarction (RR, 1.02; 95% CI, 0.93, 1.13; P = 0.64), and stroke (RR, 1.05; 95% CI, 0.88, 1.25; P = 0.59). These analyses were associated with minimal heterogeneity. There were no significant changes in the surrogate outcomes of lipid fractions, glucose, or diastolic or systolic blood pressure. The latter analyses were associated with significant heterogeneity, and the pooled estimates were trivial in absolute terms.
Trial data available to date are unable to demonstrate a statistically significant reduction in mortality and cardiovascular risk associated with vitamin D. The quality of the available evidence is low to moderate at best.
The Journal of clinical endocrinology and metabolism 06/2011; 96(7):1931-42. · 6.50 Impact Factor
[show abstract][hide abstract] ABSTRACT: The natural history of pituitary incidentalomas (PIs) and nonfunctioning pituitary adenomas (NFPAs) remains poorly understood.
The objective of the study was to synthesize the literature on the prognostic factors involved in the progression of PIs and NFPAs in patients followed up conservatively.
We searched MEDLINE, EMBASE, and Cochrane CENTRAL. We sought to identify further studies by reviewing the reference lists from selected studies and reviews and by querying experts.
Eligible studies were longitudinal observational cohort studies that enrolled patients with PIs/NFPAs and followed them up without any treatment from the time of detection and reported on mortality, lesion progression, and development of pituitary hormonal deficiency, apoplexy, or visual field defects.
Reviewers working independently and in duplicate determined studies' eligibility and collected descriptive, methodological quality, and outcome data. Event rates per 100 person-years (PYs) and associated 95% confidence intervals (CIs) were estimated from each study and pooled using the random-effects model.
The 11 included studies had noncomparative single-cohort design. Follow-up duration ranged from 3 to 15 yr. There was a greater tendency for tumor growth in macroadenomas (12.5 per 100 PYs; 95% CI 7.9, 17.2) and in solid lesions (5.7 per 100 PYs; 95% CI 2.3, 9.2) in comparison with microadenomas (3.3 per 100 PYs; 95% CI 2.1, 4.5) and cystic lesions (0.05 per 100 PYs; 95% CI 0.0, 0.2). The development of pituitary apoplexy and worsening of visual field defects were rare. The overall incidence of new endocrine dysfunction was 2.4 per 100 PYs; 95% CI 0.0, 6.4. The majority of these analyses were associated with significant heterogeneity. There was a trend that did not reach statistical significance for greater incidence of pituitary apoplexy and new endocrine dysfunction worsening in macroadenomas compared with microadenomas. The quality of the evidence (risk of bias) was very low due to heterogeneity, methodological limitations, and imprecision caused by the small number of events.
Despite the relatively high prevalence of PIs/NFPAs, the evidence on the natural history of these entities is scarce and of low quality. PIs/NFPAs seem to have fairly rare complications that may be more common when lesions are large (>10 mm) and solid.
The Journal of clinical endocrinology and metabolism 04/2011; 96(4):905-12. · 6.50 Impact Factor
[show abstract][hide abstract] ABSTRACT: Patients at higher than average risk of heritable cancer may process risk information differently than the general population. However, little is known about clinical, demographic, or psychosocial predictors that may impact risk perception in these groups. The objective of this study was to characterize factors associated with perceived risk of developing cancer in groups at high risk for cancer based on genetics or family history.
We searched Ovid MEDLINE, Ovid Embase, Ovid PsycInfo, and Scopus from inception through April 2009 for English-language, original investigations in humans using core concepts of "risk" and "cancer." We abstracted key information and then further restricted articles dealing with perceived risk of developing cancer due to inherited risk.
Of 1028 titles identified, 53 articles met our criteria. Most (92%) used an observational design and focused on women (70%) with a family history of or contemplating genetic testing for breast cancer. Of the 53 studies, 36 focused on patients who had not had genetic testing for cancer risk, 17 included studies of patients who had undergone genetic testing for cancer risk. Family history of cancer, previous prophylactic tests and treatments, and younger age were associated with cancer risk perception. In addition, beliefs about the preventability and severity of cancer, personality factors such as "monitoring" personality, the ability to process numerical information, as well as distress/worry also were associated with cancer risk perception. Few studies addressed non-breast cancer or risk perception in specific demographic groups (e.g. elderly or minority groups) and few employed theory-driven analytic strategies to decipher interrelationships of factors.
Several factors influence cancer risk perception in patients at elevated risk for cancer. The science of characterizing and improving risk perception in cancer for high risk groups, although evolving, is still relatively undeveloped in several key topic areas including cancers other than breast and in specific populations. Future rigorous risk perception research using experimental designs and focused on cancers other than breast would advance the field.
Hereditary Cancer in Clinical Practice 01/2011; 9:2. · 1.71 Impact Factor
[show abstract][hide abstract] ABSTRACT: Surgery is commonly used in the management of pituitary nonfunctioning adenomas (NFPA). The goal of this systematic review and meta-analysis is to evaluate the effect of surgery on mortality, surgical complications, pituitary function and vision.
We searched MEDLINE, EMBASE and Cochrane CENTRAL, queried experts and reviewed the reference list of included publications. Eligible studies were comparative and noncomparative longitudinal studies that enroled patients with NFPA who underwent surgery (alone or in combination with other therapies). Reviewers, working independently and in duplicate, determined study eligibility with adequate reproducibility and extracted descriptive, quality and outcome data. Risks, relative risks (RR) and 95% confidence intervals (CIs) were estimated from each study and pooled using random-effects meta-analysis.
Most included studies were uncontrolled case series in which patients received a combination of surgery and radiotherapy. The overall quality of the evidence was very low. Median follow-up was 4·29 years. When surgery was not combined with radiotherapy, there was an increased risk of tumour recurrence (RR 1·97; 95% CI, 1·15-3·35). Complications were more likely with the transcranial than with the transsphenoidal approach (mortality RR 4·89; 95% CI, 3·15-6·47; new anterior pituitary deficits RR 4·90; 95% CI, 2·94-7·82; and persistent diabetes insipidus RR 2·50; 95% CI, 1·05-5·35). Overall, transsphenoidal surgery had fairly low perioperative mortality (≤ 1%) and low complication rate (≤ 5% for all patient-important outcomes), but only less than a third of the patients had improvement in pituitary function.
Observational evidence supports the association between a combined approach of transsphenoidal surgery with radiotherapy and improvements in visual field defects and reduction in tumour recurrence.
[show abstract][hide abstract] ABSTRACT: Prenatal treatment with dexamethasone to prevent virilization in pregnancies at risk for classical congenital adrenal hyperplasia (CAH) remains controversial.
To conduct a systematic review and meta-analyses of studies that evaluated the effects of dexamethasone administration during pregnancies at risk for classical CAH because of 21-hydroxylase deficiency (CYP21A2).
We searched MEDLINE, EMBASE, and Cochrane CENTRAL from inception through August 2009. Review of reference lists and contact with CAH experts further identified candidate studies.
Reviewers working independently and in duplicate determined trial eligibility. Eligible studies reported the effects on either foetal or maternal outcomes of dexamethasone administered during pregnancy compared to a control group that did not receive any treatment.
Reviewers working independently and in duplicate determined the methodological quality of studies and collected data on patient characteristics, interventions, and outcomes.
We identified only four eligible observational studies (325 pregnancies treated with dexamethasone). The methodological quality of the included studies was overall low. Meta-analysis demonstrates a reduction in foetus virilization measured by Prader score in female foetuses treated with dexamethasone initiated early during pregnancy (weighted mean difference, -2.33, 95% CI, -3.38, -1.27). No deleterious effects of dexamethasone on stillbirths, spontaneous abortions, foetal malformations, neuropsychological or developmental outcomes were found although these data are quite sparse. There was increased oedema and striae in the mothers treated with dexamethasone. There were no data on long-term follow-up of physical and metabolic outcomes in children exposed to dexamethasone.
The observational nature of the available evidence and the overall small sample size of the whole body of the literature significantly weaken inferences about the benefits and harms of dexamethasone in this setting. Dexamethasone seems to be associated with reduction in foetus virilization without significant maternal or foetal adverse effects. However, this review underscores the current uncertainty and further investigation is clearly needed. The decision about initiating treatment should be based on patients' values and preferences and requires fully informed and consenting parents.
[show abstract][hide abstract] ABSTRACT: Treatment for patients with congenital adrenal hyperplasia (CAH) may affect the final height of these patients.
Our objective was to determine the distribution of achieved height in patients with classic CAH diagnosed at infancy or early childhood and treated with glucocorticoids.
We searched MEDLINE, EMBASE, Cochrane Library, ISI Web of Science, and Scopus through September 2008; the reference sections of included studies; and expert files.
Eligible studies included patients diagnosed with CAH before age 5 and followed to final height.
Reviewers working in duplicate independently extracted data on study characteristics and outcomes and determined each study's risk of bias.
The sd score (SDS) for final height and corrected height (defined as final height SDS - midparental height SDS) were estimated from each study and pooled using random-effects metaanalysis. The I(2) statistic was used to assess inconsistency in results across studies.
We found 35 eligible studies, most of which were retrospective single-cohort studies. The final height SDS achieved by CAH patients was -1.38 (-1.56 to -1.20; I(2) = 90.2%), and the corrected height SDS was -1.03 (-1.20 to -0.86; I(2) = 63.1%). This was not significantly associated with age at diagnosis, gender, type and dose of steroid, and age of onset of puberty. Mineralocorticoid users had a better height outcome in comparison with the nonusers (P = 0.02).
Evidence derived from observational studies suggests that the final height of CAH patients treated with glucocorticoids is lower than the population norm and is lower than expected given parental height.
The Journal of clinical endocrinology and metabolism 09/2010; 95(9):4161-72. · 6.50 Impact Factor
[show abstract][hide abstract] ABSTRACT: The risks of testosterone therapy in men remain poorly understood.
The aim of this study was to conduct a systematic review and meta-analyses of testosterone trials to evaluate the adverse effects of testosterone treatment in men.
We searched MEDLINE, EMBASE, and Cochrane CENTRAL from 2003 through August 2008. Review of reference lists and contact with experts further identified candidate studies.
Eligible studies were comparative, randomized, and nonrandomized and reported the effects of testosterone on outcomes of interest (death, cardiovascular events and risk factors, prostate outcomes, and erythrocytosis). Reviewers, working independently and in duplicate, determined study eligibility.
Reviewers working independently and in duplicate determined the methodological quality of studies and collected descriptive, quality, and outcome data.
The methodological quality of the 51 included studies varied from low to medium, and follow-up duration ranged from 3 months to 3 yr. Testosterone treatment was associated with a significant increase in hemoglobin [weighted mean difference (WMD), 0.80 g/dl; 95% confidence interval (CI), 0.45 to 1.14] and hematocrit (WMD, 3.18%; 95% CI, 1.35 to 5.01), and a decrease in high-density lipoprotein cholesterol (WMD, -0.49 mg/dl; 95% CI, -0.85 to -0.13). There was no significant effect on mortality, prostate, or cardiovascular outcomes.
The adverse effects of testosterone therapy include an increase in hemoglobin and hematocrit and a small decrease in high-density lipoprotein cholesterol. These findings are of unknown clinical significance. Current evidence about the safety of testosterone treatment in men in terms of patient-important outcomes is of low quality and is hampered by the brief study follow-up.
The Journal of clinical endocrinology and metabolism 06/2010; 95(6):2560-75. · 6.50 Impact Factor
[show abstract][hide abstract] ABSTRACT: Theory and simulation suggest that randomized controlled trials (RCTs) stopped early for benefit (truncated RCTs) systematically overestimate treatment effects for the outcome that precipitated early stopping.
To compare the treatment effect from truncated RCTs with that from meta-analyses of RCTs addressing the same question but not stopped early (nontruncated RCTs) and to explore factors associated with overestimates of effect.
Search of MEDLINE, EMBASE, Current Contents, and full-text journal content databases to identify truncated RCTs up to January 2007; search of MEDLINE, Cochrane Database of Systematic Reviews, and Database of Abstracts of Reviews of Effects to identify systematic reviews from which individual RCTs were extracted up to January 2008.
Selected studies were RCTs reported as having stopped early for benefit and matching nontruncated RCTs from systematic reviews. Independent reviewers with medical content expertise, working blinded to trial results, judged the eligibility of the nontruncated RCTs based on their similarity to the truncated RCTs.
Reviewers with methodological expertise conducted data extraction independently.
The analysis included 91 truncated RCTs asking 63 different questions and 424 matching nontruncated RCTs. The pooled ratio of relative risks in truncated RCTs vs matching nontruncated RCTs was 0.71 (95% confidence interval, 0.65-0.77). This difference was independent of the presence of a statistical stopping rule and the methodological quality of the studies as assessed by allocation concealment and blinding. Large differences in treatment effect size between truncated and nontruncated RCTs (ratio of relative risks <0.75) occurred with truncated RCTs having fewer than 500 events. In 39 of the 63 questions (62%), the pooled effects of the nontruncated RCTs failed to demonstrate significant benefit.
Truncated RCTs were associated with greater effect sizes than RCTs not stopped early. This difference was independent of the presence of statistical stopping rules and was greatest in smaller studies.
JAMA The Journal of the American Medical Association 03/2010; 303(12):1180-7. · 29.98 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background: Randomized clinical trials (RCTs) stopped early for benefit often receive great attention and affect clinical practice, but pose interpretational challenges for clinicians, researchers, and policy makers. Because the decision to stop the trial may arise from catching the treatment effect at a random high, truncated RCTs (tRCTs) may overestimate the true treatment effect. The Study Of Trial Policy Of Interim Truncation (STOPIT-1), which systematically reviewed the epidemiology and reporting quality of tRCTs, found that such trials are becoming more common, but that reporting of stopping rules and decisions were often deficient. Most importantly, treatment effects were often implausibly large and inversely related to the number of the events accrued. The aim of STOPIT-2 is to determine the magnitude and determinants of possible bias introduced by stopping RCTs early for benefit. Methods/Design: We will use sensitive strategies to search for systematic reviews addressing the same clinical question as each of the tRCTs identified in STOPIT-1 and in a subsequent literature search. We will check all RCTs included in each systematic review to determine their similarity to the index tRCT in terms of participants, interventions, and outcome definition, and conduct new meta-analyses addressing the outcome that led to early termination of the tRCT. For each pair of tRCT and systematic review of corresponding non-tRCTs we will estimate the ratio of relative risks, and hence estimate the degree of bias. We will use hierarchical multivariable regression to determine the factors associated with the magnitude of this ratio. Factors explored will include the presence and quality of a stopping rule, the methodological quality of the trials, and the number of total events that had occurred at the time of truncation.Finally, we will evaluate whether Bayesian methods using conservative informative priors to "regress to the mean" overoptimistic tRCTs can correct observed biases. Discussion: A better understanding of the extent to which tRCTs exaggerate treatment effects and of the factors associated with the magnitude of this bias can optimize trial design and data monitoring charters, and may aid in the interpretation of the results from trials stopped early for benefit.