Effect on bone health of estrogen preparations in premenopausal women with anorexia nervosa: a systematic review and meta-analyses.

OBJECTIVE: Because estrogen therapies are widely prescribed for amenorrhea associated with anorexia nervosa (AN), we conducted a systematic review and meta-analyses to estimate the influence of estrogen preparations (EP) on bone mineral density in women with AN. METHOD: Prospective cohort studies and randomized clinical trials (RCTs) comparing the effect of EP use to no treatment or placebo on bone mineral density and bone fractures were included. Independent reviewers selected studies for inclusion and extracted study characteristics, markers of methodologic quality, and outcomes for the intention-to-treat population. RESULTS: Using random-effects meta-analyses and inconsistency across trials using the I(2) statistic, data were combined across two eligible prospective cohort studies and four RCTs; none reported effects on bone fractures. Compared with placebo or no treatment, low quality evidence found EPs have a moderate effect on bone mineral density in the lumbar spine [ES (effect size) 0.33, 95% CI (confidence interval) 0.09, 0.56; I(2) = 0%)], but no significant effect on the femoral neck (ES 0.13, 95% CI -0.16, 0.43; I(2) = 0%). There were no significant treatment-subgroup interactions. DISCUSSION: In general, EPs have uncertain benefit and should be avoided by women with AN in whom the success of weight and nutritional rehabilitation is judged by menses resumption.

A case for clarity, consistency, and helpfulness: state-of-the-art clinical practice guidelines in endocrinology using the grading of recommendations, assessment, development, and evaluation system.

CONTEXT: The Endocrine Society, and a growing number of other organizations, have adopted the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to develop clinical practice guidelines and grade the strength of recommendations and the quality of the evidence. Despite the use of GRADE in several of The Endocrine Society's clinical practice guidelines, endocrinologists have not had access to a context-specific discussion of this system and its merits. EVIDENCE ACQUISITION: The authors are involved in the development of the GRADE standard and its application to The Endocrine Society clinical practice guidelines. Examples were extracted from these guidelines to illustrate how this grading system enhances the quality of practice guidelines. EVIDENCE SYNTHESIS: We summarized and described the components of the GRADE system, and discussed the features of GRADE that help bring clarity and consistency to guideline documents, making them more helpful to practicing clinicians and their patients with endocrine disorders. CONCLUSIONS: GRADE describes the quality of the evidence using four levels: very low, low, moderate, and high quality. Recommendations can be either strong ("we recommend") or weak ("we suggest"), and this strength reflects the confidence that guideline panel members have that patients who receive recommended care will be better off. The separation of the quality of the evidence from the strength of the recommendation recognizes the role that values and preferences, as well as clinical and social circumstances, play in formulating practice recommendations.

Clinical review: Antiandrogens for the treatment of hirsutism: a systematic review and metaanalyses of randomized controlled trials.

CONTEXT: The relative efficacy of antiandrogens for the treatment of hirsutism remains unclear. OBJECTIVE: We performed a systematic review and metaanalyses of randomized controlled trials (RCTs) evaluating the effect of antiandrogens on hirsutism. DATA SOURCES: We used librarian-designed search strategies for MEDLINE, EMBASE, and Cochrane CENTRAL (up to May 2006), review of reference lists, and contact with hirsutism experts to identify eligible RCTs. STUDY SELECTION: Eligible studies were RCTs of at least 6 months of antiandrogen use in women with hirsutism. Reviewers, with acceptable chance-adjusted agreement (kappa = 0.72), independently assessed eligibility. DATA EXTRACTION: Reviewers used structured forms to assess and collect methodological quality (allocation concealment, blinding, and loss to follow-up) and study data. DATA SYNTHESIS: Of 348 candidate studies, 12 were eligible (18 comparisons). Their methodological quality was low. Random-effects metaanalyses showed that compared with placebo, antiandrogens reduce Ferriman-Gallwey scores by 3.9 [95% confidence interval (CI), 2.3-5.4; inconsistency (I(2)) = 0%]. When compared with metformin, spironolactone reduced hirsutism scores by 1.3 (CI, 0.03-2.6) and flutamide by 5.0 (CI, 3.0-7.0; I(2) = 0%). For these interventions, two to five women need to receive treatment for one to notice improvement. Spironolactone or finasteride in combination with contraceptives (1.7; CI, 0.1-3.3; I(2) = 0%) or flutamide with metformin (4.6; CI, 1.3-7.9; I(2) = 40%) appear superior to monotherapy with contraceptives and metformin, respectively. Only three RCTs reported patient self-assessments of hirsutism. CONCLUSIONS: Weak evidence suggests antiandrogens are mildly effective agents for the treatment of hirsutism.

Clinical review: Insulin sensitizers for the treatment of hirsutism: a systematic review and metaanalyses of randomized controlled trials.

CONTEXT: Insulin sensitizers, including metformin and thiazolidinediones (TZDs), improve hyperinsulinemia and reproductive dysfunctions in some women with hyperandrogenism. The extent to which these agents improve hirsutism remains unclear. OBJECTIVE: Our objective was to conduct a systematic review and metaanalyses of randomized controlled trials of metformin or TZDs for the treatment of hirsutism. DATA SOURCES: We searched the following databases: MEDLINE, EMBASE, and Cochrane CENTRAL (up to May 2006). Review of reference lists and contact with hirsutism experts further identified candidate trials. STUDY SELECTION: Reviewers working independently and in duplicate, with acceptable chance-adjusted agreement (kappa = 0.72), determined trial eligibility. Eligible trials randomly assigned women with hirsutism to at least 6 months of insulin sensitizers or control and measured hirsutism outcomes. DATA EXTRACTION: Reviewers working independently and in duplicate determined the methodological quality of trials and collected data on patient characteristics, interventions, and outcomes. DATA SYNTHESIS: Of 348 candidate studies, 16 trials (22 comparisons) were eligible. The methodological quality of these trials was low. Random-effects metaanalyses showed a small decrease in Ferriman-Gallwey scores in women treated with insulin sensitizers compared with placebo [pooled weighted mean difference (WMD) of -1.5; 95% confidence interval (CI), -2.8 to -0.2; inconsistency (I(2)) = 75%]. There was no significant difference between insulin sensitizers and oral contraceptives (WMD of -0.5; CI, -5.0, 3.9; I(2) = 79%). Metformin was inferior to both spironolactone (WMD of 1.3; CI, 0.03, 2.6) and flutamide (WMD of 5.0; CI, 3.0, 7.0; I(2) = 0%). CONCLUSIONS: Imprecise and inconsistent evidence of low to very low quality suggests that insulin sensitizers provide limited or no important benefit for women with hirsutism.

Evaluation and treatment of hirsutism in premenopausal women: an endocrine society clinical practice guideline.

OBJECTIVE: Our objective was to develop clinical practice guidelines for the evaluation and treatment of hirsutism in premenopausal women. PARTICIPANTS: The Task Force was composed of a chair, selected by the Clinical Guidelines Subcommittee (CGS) of The Endocrine Society, six additional experts, two methodologists, and a medical writer. The Task Force received no corporate funding or remuneration. EVIDENCE: Systematic reviews of available evidence were used to formulate the key treatment and prevention recommendations. We used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) group criteria to describe both the quality of evidence and the strength of recommendations. We used "recommend" for strong recommendations, and "suggest" for weak recommendations. CONSENSUS PROCESS: Consensus was guided by systematic reviews of evidence and discussions during one group meeting, several conference calls, and e-mail communications. The drafts prepared by the Task Force with the help of a medical writer were reviewed successively by The Endocrine Society's CGS, Clinical Affairs Core Committee (CACC), and Council. The version approved by the CGS and CACC was placed on The Endocrine Society's Web site for comments by members. At each stage of review, the Task Force received written comments and incorporated needed changes. CONCLUSIONS: We suggest testing for elevated androgen levels in women with moderate or severe hirsutism or hirsutism of any degree when it is sudden in onset, rapidly progressive, or associated with other abnormalities such as menstrual dysfunction, obesity, or clitoromegaly. For women with patient-important hirsutism despite cosmetic measures, we suggest either pharmacological therapy or direct hair removal methods. For pharmacological therapy, we suggest oral contraceptives for the majority of women, adding an antiandrogen after 6 months if the response is suboptimal. We recommend against antiandrogen monotherapy unless adequate contraception is used. We suggest against using insulin-lowering drugs. For women who choose hair removal therapy, we suggest laser/photoepilation.

Methodology for clinical practice guidelines for the management of arteriovenous access.

The Society for Vascular Surgery considers the placement and maintenance of arteriovenous hemodialysis access to be an important component of any vascular surgery practice. Therefore, the Society has long been involved in setting the standards for the management of arteriovenous access. Formulating clinical recommendations in this area is the latest effort by the Society to improve the management of arteriovenous access on a national level. To provide an unbiased study of the evidence and to help in formulating the recommendations, the Society used the Knowledge and Encounter Research (KER) Unit of the Mayo Clinic College of Medicine, Rochester, Minn, to review the available evidence and advise a multidisciplinary group of access surgeons and nephrologists in formulating the clinical recommendations. To review the evidence, randomized and observational study designs were both considered. Whenever possible, systematic reviews and meta-analyses of the literature were used because, compared with individual studies, they generate more precise estimates of treatment effects and their results are applicable to a wider range of patients. On behalf of the Society, the group issued its recommendations following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) format; this format disentangles the strength of recommendations from the quality of the evidence and encourages statements about the underlying values and preferences relevant to the particular recommendation. The recommendations are classified as strong (denoted by the phrase "we recommend") or weak (denoted by the phrase "we suggest"); and the quality of evidence is classified as high, moderate, low, or very low. These recommendations are not meant to supersede clinical judgment; rather, they should be used as a guide for the practicing surgeon and nephrologist as the decision is being made for the placement and subsequent procedures and management of arteriovenous hemodialysis access are being considered.

Patient-important outcomes in registered diabetes trials.

CONTEXT: Concerns about the safety and efficacy of diabetes interventions persist, in part because randomized clinical trials (RCTs) have not measured their effect on patient-important outcomes, ie, death and quality of life (morbidity, pain, function). OBJECTIVE: To systematically determine the extent to which ongoing and future RCTs in diabetes will ascertain patient-important outcomes. DATA SOURCES: On November 10, 2007, we searched primary RCT registries ClinicalTrials.gov (http://www.clinicaltrials.gov), International Standard Randomized Controlled Trial Number Register (http://isrctn.org), and Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au). STUDY SELECTION: We identified phase 2 through 4 RCTs enrolling patients with diabetes. Of 2019 RCTs, 1054 proved eligible. We randomly sampled 50% of the eligible RCTs (527 of 1054) and selected 436 registered since registration became mandatory (2004). DATA EXTRACTION: Pairs of reviewers working independently collected study characteristics and determined the outcomes measured and their type (physiological outcomes, surrogate outcomes thought to reflect an increased risk for patient-important outcomes, and patient-important outcomes). RESULTS: Of the 436 registered RCTs included in this analysis, 24 (6%) had not started enrollment, 109 (25%) were actively enrolling, and 303 (69%) had completed enrollment. Primary outcomes were patient-important outcomes in only 78 of 436 RCTs (18%; 95% confidence interval [CI], 14%-22%), physiological and laboratory outcomes in 69 of 436 (16%; 95% CI, 13%-20%), and surrogate outcomes in 268 of 436 (61%; 95% CI, 57%-66%). Patient-important outcomes were reported as primary or secondary outcomes in 201 of 436 (46%; 95% CI, 41%-51%). In multivariate analysis, large trials (odds ratio [OR], 1.10; 95% CI, 1.02-1.19 for every additional 100 patients) and trials of longer duration (OR, 1.03; 95% CI, 1.01-1.06 for every additional 30 days) were more likely while parallel design RCTs (OR, 0.15; 95% CI, 0.05-0.44) and type 2 diabetes trials (OR, 0.23; 95% CI, 0.09-0.61) were less likely to assess patient-important outcomes as a primary outcome. CONCLUSION: In this sample of registered ongoing RCTs in diabetes, only 18% included patient-important outcomes as primary outcomes.

Use of a decision aid to improve treatment decisions in osteoporosis: the osteoporosis choice randomized trial.

OBJECTIVE: Poor adherence to therapy, perhaps related to unaddressed patient preferences, limits the effectiveness of osteoporosis treatment in at-risk women. A parallel patient-level randomized trial in primary care practices was performed. METHODS: Eligible postmenopausal women with bone mineral density T-scores less than -1.0 and not receiving bisphosphonate therapy were included. In addition to usual primary care, intervention patients received a decision aid (a tailored pictographic 10-year fracture risk estimate, absolute risk reduction with bisphosphonates, side effects, and out-of-pocket cost), and control patients received a standard brochure. Knowledge transfer, patient involvement in decision-making, and rates of bisphosphonate start and adherence were studied. Data came from medical records, post-visit written and 6-month phone surveys, video recordings of clinical encounters, and pharmacy prescription profiles. RESULTS: A total of 100 patients (range of 10-year fracture risk, 6%-60%) were allocated randomly to receive the decision aid (n=52) or usual care (n=48). Patients receiving the decision aid were 1.8 times more likely to correctly identify their 10-year fracture risk (49% vs 28%; 95% confidence interval [CI], 1.03-3.2) and 2.7 times more likely to identify their estimated risk reduction with bisphosphonates (43% vs 16%; 95% CI, 1.3-5.7). Patient involvement improved with the decision aid by 23% (95% CI, 13.6-31.4). Bisphosphonates were started by 44% of patients receiving the decision aid and 40% of patients receiving usual care. Adherence at 6 months was similarly high across both groups, but the proportion with more than 80% adherence was higher with the decision aid (n=23 [100%] vs n=14 [74%]; P = .009). CONCLUSION: A decision aid improved the quality of clinical decisions about bisphosphonate therapy in at-risk postmenopausal women, did not affect start rates, and may have improved adherence.

A systematic review and meta-analysis of randomized placebo-controlled trials of DHEA treatment effects on quality of life in women with adrenal insufficiency.

CONTEXT: Women with primary or secondary adrenal insufficiency report a decreased health-related quality of life (HRQOL) despite traditional adrenal replacement therapy. Dehydroepiandrosterone (DHEA) has been studied as an agent to improve HRQOL in these patients. OBJECTIVE: We sought to conduct a systematic review and meta-analysis of randomized controlled trials of DHEA effects on HRQOL in women with adrenal insufficiency. DATA SOURCES: We searched electronic databases (MEDLINE, EMBASE, Cochrane CENTRAL, Web of Science, CINAHL, and PsycInfo) and reference lists of eligible studies through July 2008. STUDY SELECTION: Eligible trials randomly assigned women with primary or secondary adrenal insufficiency to either DHEA or control and measured the effect of treatment on HRQOL. DATA EXTRACTION: Reviewers working independently and in duplicate assessed the methodological quality of trials and collected data on patient characteristics, interventions, and outcomes. DATA SYNTHESIS: We found 10 eligible trials that measured HRQOL and depression, anxiety, and sexual function. Random-effects meta-analysis showed a small improvement in HRQOL in women treated with DHEA compared with placebo [effect size of 0.21; 95% confidence interval, 0.08 to 0.33; inconsistency (I(2)) = 32%]. There was a small beneficial effect of DHEA on depression; effects on anxiety and sexual well-being were also small and not statistically significant. CONCLUSIONS: DHEA may improve, in a small and perhaps trivial manner, HRQOL and depression in women with adrenal insufficiency. There was no significant effect of DHEA on anxiety and sexual well-being. The evidence appears insufficient to support the routine use of DHEA in women with adrenal insufficiency.

Protocol for the Osteoporosis Choice trial. A pilot randomized trial of a decision aid in primary care practice.

BACKGROUND: Bisphosphonates can reduce fracture risk in patients with osteoporosis, but many at-risk patients do not start or adhere to these medications. The aims of this study are to: (1) preliminarily evaluate the effect of an individualized 10-year osteoporotic fracture risk calculator and decision aid (OSTEOPOROSIS CHOICE) for postmenopausal women at risk for osteoporotic fractures; and (2) assess the feasibility and validity (i.e., absence of contamination) of patient-level randomization (vs. cluster randomization) in pilot trials of decision aid efficacy. METHODS/DESIGN: This is a protocol for a parallel, 2-arm, randomized trial to compare an intervention group receiving OSTEOPOROSIS CHOICE to a control group receiving usual primary care. Postmenopausal women with bone mineral density T-scores of <-1.0, not receiving bisphosphonate therapy, and receiving care at participating primary care practices in and around Rochester, Minnesota, USA will be eligible to participate in the trial. We will measure the effect of OSTEOPOROSIS CHOICE on five outcomes: (a) patient knowledge regarding osteoporosis risk factors and treatment; (b) quality of the decision-making process for both the patient and clinician; (c) patient and clinician acceptability and satisfaction with the decision aid; (d) rate of bisphosphonate use and adherence, and (e) trial processes (e.g., ability to recruit participants, collect patient outcomes). To capture these outcomes, we will use patient and clinician surveys following each visit and video recordings of the clinical encounters. These video recordings will also allow us to determine the extent to which clinicians previously exposed to the decision aid were able to recreate elements of the decision aid with control patients (i.e., contamination). Pharmacy prescription profiles and follow-up phone interviews will assess medication start and adherence at 6 months. DISCUSSION: This pilot trial will provide evidence of feasibility, validity of patient randomization, and preliminary efficacy of a novel approach--decision aids--to improving medication adherence for postmenopausal women at risk of osteoporotic fractures. The results will inform the design of a larger trial that could provide more precise estimates of the efficacy of the decision aid. TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT00578981.