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What is the sensitivity and specificity of the cosyntropin (ACTH) stimulation test for adrenal insufficiency? Evidence-Based Answer Standard-dose, 250-mcg cosyntropin (ACTH) stimulation testing is 97.5% sensitive and 95% specific for the diagnosis of primary adrenal insufficiency. For the diagnosis of secondary adrenal insufficiency, the testing is less sensitive. With specificity set to 95%, the 250-mcg test has a sensitivity of 57% and the 1-mcg test has a sensitivity of 61%. No demonstrable difference has been found between the standard-dose and low-dose tests in diagnosing secondary adrenal insufficiency. (SOR A, based on systematic review of consistent level 1 studies.) A 2003 systematic review of the diagnosis of primary and secondary adrenal insufficiency compiled data from 1966 to 2002 from MEDLINE.1 A total of 122 cases of previously diagnosed primary adrenal insufficiency were included from 8 cohort studies. Additionally, 347 cases of suspected or confirmed secondary adrenal insufficiency were included from 20 cohort studies. Either insulin tolerance tests or metyrapone tests were used as gold-standard diagnostics. Sensitivity and specificity data were extracted and compiled to create summary receiver-operator characteristics (ROC) curves. ROC curves were compared using area under the curve (AUC) methods. Cortisol cutoff limits were selected to obtain a specificity of 95% in an attempt to minimize the number of false-positive results. The authors asserted that this strategy was important, as often patients with abnormal cosyntropin testing will not undergo further confirmatory testing.1 In the case of primary adrenal insufficiency, a serum cortisol cutoff of 415 nmol/L was chosen. Levels were measured 30 to 60 minutes after the administration of 250 mcg cosyntropin. Aggregate sensitivity, positive likelihood ratio (LR+), and negative likelihood ratio (LR–) were 97.5% (95% confidence interval [CI], 95%–100%), 19.5 (95% CI, 19.0–20.0), and 0.026 (95% CI, 0.0–0.6), respectively, with specificity set to 95%.1 For the diagnosis of secondary adrenal insufficiency, a serum cortisol cutoff of 500 nmol/L was chosen. In the case of the 250-mcg test (standard), the aggregate sensitivity, LR+, and LR– were 57% (95% CI, 44%–71%), 11.5 (95% CI, 8.7–14.2), and 0.45 (95% CI, 0.3–0.6), respectively, with specificity set to 95%. In the case of the 1-mcg test (low dose), the aggregate sensitivity, LR+, and LR– were 61.4% (95% CI, 45%–78%), 12.3 (95% CI, 9.0–15.5), and 0.41 (95% CI, 0.24–0.58), respectively, again with specificity set to 95%.1 The 1-mcg and 250-mcg tests were compared via AUC analysis of the ROC curves. No statistically significant differences were observed between the low-dose and standard-dose cosyntropin tests for secondary adrenal insufficiency at either 30 or 60 minutes after cosyntropin administration (P=.18 and .50, respectively).1 Kimberly Johnson, MD Joshua Merok, MD UIC/Illinois Masonic FMR Chicago, IL 1. Dorin RI, Qualls CR, Crapo LM. Diagnosis of adrenal insufficiency. Ann Intern Med. 2003; 139(3):194–204. [LOE 1a] What is the risk of breast cancer in women who take oral contraceptives? Evidence-Based Answer In older studies, oral contraceptive (OC) use in women was associated with a small increase in the relative risk of breast cancer during use and in the first 10 years after stopping. Newer studies of patients using lower dose OCs have not found such an association. (SOR B, based on heterogeneous cohort studies) It is estimated that since the introduction of OCs in the 1960s, more than 300 million women have used them.1 The assessment of teratogenic risk from their use has evolved over time. In 1996, the Collaborative Group on Hormonal Factors in Breast Cancer analyzed data from 54 studies of various types, conducted in 25 countries, examining 53,297 women with breast cancer and 100,239 women without breast cancer.2 In women taking OCs, there was a small but definite increase of having breast cancer (relative risk 1.24; 95% confidence interval [CI], 1.15–1.33), but no significant excess risk 10 or more years after stopping. The study also found that the cancers diagnosed in women using combined OCs were less clinically advanced, and the pattern of risk and exposure Evidence-Based Practice / Vol. 12, No. 8 9 seemed incompatible with a genotoxic effect (damaging to DNA and thereby capable of causing mutations or cancer).2 Similarly, the International Agency for Research in Cancer concluded in 2005 that there was a small but increased risk of breast cancer among OC users.3 The report also concluded that OCs provide a protective effect against endometrial and ovarian cancers. The authors recommended that the small excess risk of breast cancer be put into perspective with overall risks versus benefits when counseling women on OC use. Conversely, the largest modern study, published in 2002, was a population-based, case-control study focusing on the risk of breast cancer among current and former users of OCs.4 More than 9,000 women (4,575 with breast cancer and 4,682 controls) between 35 and 64 years of age were interviewed. The relative risk of breast cancer was 1.0 for women currently using OCs and 0.9 for women who had previously used OCs.4 These results were similar for both black and white women, and were not found to increase consistently with longer periods of use or higher doses of estrogen.4 Thus, among the defined age group, neither current nor former OC use was associated with a significantly increased risk of breast cancer.4 In 2007, a UK cohort study was published that tracked 45,950 women for an average of 24 years, beginning in 1968. Incident data were used to examine the absolute risks or benefits of cancer associated with OCs.1 This study also concluded that OCs were not associated with an overall increased risk of cancer. Women who had ever used OCs actually had a 12% reduction in the risk of any cancer compared with women who had never used OCs (adjusted relative risk 0.88; 95% CI, 0.83–0.94).1 Deepa Sharma, DO Amy D. Gruber, MD Overlook Family Practice Summit, NJ 1. Hannaford PC, Selvaraj S, Elliot AM, Angus V, Iversen L, Lee AJ. Cancer risk among users of oral contraceptives: cohort data from the Royal College of General Practitioner’s oral contraception study. BMJ. 2007; 335(7621):651. [LOE 2b] 2. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Lancet. 1996; 347(9017):1713-1727. [LOE 2a] 3. Casey PM, Cerhan JR, Pruthi S. Oral contraceptive use and risk of breast cancer. Mayo Clin Proc. 2008; 83(1):86–90. [LOE 2a] 4. Marchbanks PA, McDonald JA, Wilson HG, et al. Oral contraceptives and the risk of breast cancer. N Engl J Med. 2002; 346(26):2025–2032. [LOE 3b] 10 Evidence-Based Practice / August 2009 What is the best treatment for pseudogout? Evidence-Based Answer Intramuscular steroid injections are an effective option for patients with acute pseudogout. (SOR B, based on a case series.) Nonsteroidal anti-inflammatory drugs (NSAIDs) and intraarticular steroids are also recommended for acute pseudogout. (SOR C, based on expert opinion.) Colchicine and hydroxychloroquine are effective in treating chronic pseudogout with recurrent attacks. (SOR B, based on small clinical trials.) Pseudogout is a painful, inflammatory arthritis resulting from the deposition of calcium pyrophosphate dehydrate crystals within the joint space. Pseudogout is classified based on the number of joints involved and frequency of attacks into the following categories: monoarticular, polyarticular, acute, or chronic. There are no good clinical trials evaluating the best treatment for pseudogout and most recommendations come from expert opinion or small case series that are extrapolated from studies on gout. NSAIDs are widely used for treatment of acute mono- and polyarticular pseudogout.1 A literature review showed effectiveness with NSAIDs in the treatment of gout, but no clinical trials focused on pseudogout.1 In 1997, a small case series demonstrated subjective improvement in all 14 patients with crystal-proven pseudogout who were prospectively treated with 60 mg daily intramuscular triamcinolone over a 30-day period.2 Intraarticular steroids have benefit in gout and are assumed to help with pseudogout.1 Colchicine is commonly used in the treatment of acute pseudogout similar to its use for acute gout attacks. In 1986, a small, prospective, self-controlled clinical trial compared colchicine prophylaxis in 10 male patients with recurrent attacks of crystal proven pseudogout.3 In the year before starting 0.6 mg BID colchicine, 32 acute pseudogout attacks were recorded compared with only 10 attacks during the year after initiation of therapy (P<.001).3 In 1997, hydroxychloroquine was evaluated in a small but well-designed prospective, parallel group, double-blind, randomized control trial of 36 patients with radiologic-proven chronic pseudogout.4 Hydroxychloroquine reduced the number of affected joints by 4.8±2.7 compared with a reduction of