Update Update in Endocrinology: Evidence Published in 2013 Hossein Gharib, MD
T
his update summarizes 10 important studies published in 2013 that can change clinical practice. In thyroid research, a randomized trial showed no advantage in the use of desiccated thyroid extract (DTE) over levothyroxine monotherapy in replacement therapy for hypothyroidism, although DTE resulted in modest weight loss and better patient satisfaction. A large retrospective, multinational study showed that a molecular marker, BRAF V600E mutation, present in 40% to 50% of papillary thyroid carcinomas (PTCs), was strongly associated with cancer mortality. Radioiodine (RAI) is effective in treatment, and improves outcome, of well-differentiated thyroid cancer. However, some tumors do not accumulate radioiodine and therefore cannot be treated. Selumetinib is recently shown to enhance radioiodine uptake and facilitate treatment of metastatic thyroid cancer. In diabetes practice, several developments were noteworthy. Lifestyle modifications resulted in weight reduction, decreased insulin requirement, and better glycemic control but failed to reduce cardiovascular events. In another study, higher glucose levels were associated with an increased risk for dementia. Two trials showed that bariatric surgery is useful in both obesity and diabetes— hence the term metabolic surgery—with dramatic weight loss and improved glycemic control. However, improved quality of life has not been well-documented, and costs and potential risks of surgical complications can be considerable. In bone medicine, a controlled trial documented the safety and efficacy of recombinant human parathyroid hormone (rhPTH) in the treatment of hypoparathyroidism, an important observation that should significantly improve treatment of patients with hypoparathyroidism. Another population-based study on the usefulness of a second bone mineral density (BMD) measurement in assessing risk fracture failed to support routine, serial BMD measurements. Finally, a well-designed randomized trial concluded that serum estrogens, in addition to the known effects of testosterone, play a major role in influencing body fat distribution and sexual function in men. Thyroid Disease DTE Therapy Did Not Improve Quality of Life Compared With Levothyroxine Alone Hoang TD, Olsen CH, Mai VQ, et al. Desiccated thyroid extract compared with levothyroxine in the treatment of hypothyroidism: a randomized, double-blind, crossover study. J Clin Endocrinol Metab. 2013;98:1982-90. [PMID: 23539727] Ann Intern Med. 2014;160:785-790. For author affiliation, see end of text. This article was published online first at www.annals.org on 10 April 2014.
Background: Conventional treatment of hypothyroidism consists of replacement levothyroxine monotherapy. Some patients receiving a seemingly adequate levothyroxine dose who have normal serum thyroid-stimulating hormone levels, however, continue to report hypothyroid symptoms, including fatigue, low energy, cold, constipation, weight gain, and poor sleep. It is speculated that symptoms may be caused by low serum triiodothyronine (T3) levels and that the addition of T3 should alleviate most symptoms. However, most studies comparing levothyroxine plus T3 with levothyroxine therapy have failed to confirm that combination therapy is superior at improving quality of life. This study compared the effectiveness of DTE and levothyroxine alone in a group of known hypothyroid patients. Findings: This randomized, double-blind, crossover study was conducted at a tertiary medical facility. Seventy patients, aged 18 to 65 years, with primary hypothyroidism who had been receiving a stable dose of levothyroxine for 6 months were included. Patients were randomly assigned to DTE or levothyroxine for 16 weeks and then crossed over to the other regimen for the same duration. Biochemical and neurocognitive tests were performed at baseline and at the end of the study period. Overall, symptoms and neurocognitive measurements did not differ between the 2 therapies. Patients lost 3 pounds during the DTE protocol compared with levothyroxine treatment (mean weight, 172 pounds [SD, 36.4] vs. 175.7 pounds [SD, 37.7]; P ⬍ 0.001). At the end of the study, 34 patients (48.6%) preferred DTE, 13 (18.6%) preferred levothyroxine, and 23 (32.9%) had no preference. In the subgroup analyses, patients who preferred DTE lost 4 pounds during the DTE treatment, and their subjective symptoms were significantly better while they were taking DTE, as measured by the General Health Questionnaire-12 and Thyroid Symptom Questionnaire (P ⬍ 0.001 for both). Cautions: Limitations of this study include the short duration, small sample size, low sensitivity of some of the neurocognitive tests used and biochemical variables measured, and lack of genetic testing for deiodinase polymorphism. Genetic deiodinase polymorphism, a rare finding, accounts for decreased thyroxine-to-T3 conversion in the brain, explaining why some patients remain symptomatic while receiving thyroxine monotherapy. No formal adjustment was made for multiple comparisons, and some significant findings may be due to type I error. Implications: This is the first randomized study comparing DTE with levothyroxine in hypothyroid patients. It con-
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firms that the combination of thyroxine plus T3, compared with levothyroxine alone, does not significantly improve quality-of-life measures in most patients. These data are consistent with results of most previous studies on this subject published in the past decade. However, the present study also shows that in a few patients, once-daily DTE, in place of levothyroxine, resulted in modest weight loss with possible improvements in symptoms, without apparent adverse effects. BRAF Mutation Is Associated With Increased Cancer-Related Mortality in Patients With PTC
study captured only PTC-specific deaths and could not assess all-cause mortality. Implications: In this retrospective study, the BRAF V600E mutation was found in 46% of patients with PTC and was associated with an increase in mortality, although the association diminished after adjustment for age and sex. These data are similar to those found in other reports. In low-risk PTC, the presence and absence of BRAF V600E mutation did not influence mortality, which remained low in both groups.
Xing M, Alzahrani AS, Carson KA, et al. Association between BRAF
RAI Uptake Can Be Enhanced by Selumetinib in Patients With Advanced Follicular Cell–Derived Thyroid Cancer
V600E mutation and mortality in patients with papillary thyroid
Ho AL, Grewal RK, Leboeuf R, et al. Selumetinib-enhanced radio-
cancer. JAMA. 2013;309:1493-501. [PMID: 23571588]
iodine uptake in advanced thyroid cancer. N Engl J Med. 2013;368:
Background: Papillary thyroid carcinoma accounts for approximately 90% of all thyroid cancers and has an excellent 5-year survival rate of 95% to 97%. Some tumors, however, exhibit aggressive behavior, and the challenge is to identify and treat these subtypes. Several studies have shown that mutations in the BRAF gene V600E (that is, the amino acid valine in position 600 is replaced by glutamic acid) are associated with lower survival in patients with PTC. The clinical significance of this mutation with regard to PTC-related mortality remains uncertain. This multicenter study examined and defined the association between the BRAF V600E mutation and mortality caused by PTC. Findings: This retrospective multicenter study of 1849 patients with PTC found that the BRAF V600E mutation is present in 46% of patients with PTC. The mortality rate was 53% (45 of 845 patients [95% CI, 3.9% to 7.1%]) in BRAF V600E–positive patients and 1.1% (11 of 1004 [CI, 0.5% to 2.0%]) in mutation-negative patients (P ⬍ 0.001). Deaths per 1000 person-years in the analysis of all patients with PTC were 12.87 versus 0.52 in BRAF V600E mutation–positive versus mutation-negative patients; the hazard ratio (HR) was 2.66 (CI, 1.30 to 5.43) after adjustment for age at diagnosis, sex, and medical center. Deaths per 1000 person-years in patients with conventional PTC were 11.80 in BRAF-positive patients and 2.25 in BRAFnegative patients. When lymph node metastasis, extrathyroid invasion, and distant metastasis were included in the model, the association of BRAF V600E with mortality for all patients with PTC was no longer significant. For example, in patients with nodal metastasis, deaths per 1000 person-years were 26.26 (CI, 19.18 to 35.94) versus 5.93 (CI, 2.96 to 11.86) in mutation-positive versus mutationnegative patients (unadjusted HR, 4.43 [CI, 2.06 to 9.51]; adjusted HR, 1.46 [CI, 0.62 to 3.47]). Cautions: The low number of PTC-specific deaths reduced the power to find associations and resulted in wide CIs, and higher BRAF V600E–associated mortality was attenuated after adjustment for patient age. Moreover, many patients had relatively short clinical follow-up. Finally, the
623-32. [PMID: 23406027]
Background: Well-differentiated carcinoma accounts for 90% to 95% of all thyroid cancers. These tumors arise from follicular cells and include PTC and follicular cancers. Radioiodine is the principal treatment for metastatic follicular cell– derived cancer. Unfortunately, many metastatic cancers do not accumulate RAI and, therefore, cannot be effectively treated. The 10-year survival rate is significantly improved for iodine-avid versus non–iodine-avid tumors (60% vs. 10%, respectively). Previous attempts using lithium, retinoids, or other compounds resulted in modest clinical benefits. The new anticancer agent selumetinib blocks mitogen-activated protein kinase (MAPK) and improves response to RAI. Findings: Twenty patients (age range, 44 to 77 years; 9 women) were studied: Five had classic PTC, 8 had tall-cell PTC, and 7 had poorly differentiated tumors. Nine had BRAF V600E, 5 had NRAS, 3 had RET/PTC, and 3 had wild-type oncogenes. Selumetinib increased the uptake of RAI in 9 of 20 patients. Eight of 12 patients reached the dosimetry threshold for RAI therapy, 5 had partial response, and 3 had stable disease. No significant adverse effects were recorded. According to imaging and by thyroglobulin measurements, tumor activity decreased significantly after selumetinib-induced RAI treatment. Cautions: This small study included only 20 patients, and follow-up was only 6 months. Although uptake in metastatic sites increased and response to administered RAI improved, whether this response influences survival is not known. Implications: This study is important because it shows that selumetinib can help patients with RAI-refractory, metastatic differentiated thyroid cancer. The gene BRAF is part of the MAPK pathway that facilitates growth factor activity at the cellular level. Inhibition of MAPK should, therefore, be beneficial, and selumetinib blocks the kinase subtypes MEK1 and MEK2, thereby reducing MAPK activity. This may enhance iodine uptake, with increased retention in tumor tissues in 60% of patients; the result is an improved response to the administered RAI dose. After 6 months a
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variable reduction of metastatic target lesions was observed in all patients. Larger studies and longer follow-up are needed to confirm these early, positive results.
Update
other strategies to evaluate the effect of lifestyle changes and weight loss on additional outcomes in diabetic patients. Higher Glucose Levels May Be a Risk Factor for Dementia
Diabetes
Crane PK, Walker R, Hubbard RA, et al. Glucose levels and risk of
Lifestyle Modification May Reduce Weight in Patients With Type 2 Diabetes Mellitus but Does Not Decrease Rate of Cardiovascular Events
dementia. N Engl J Med. 2013;369:540-8. [PMID: 23924004]
Wing RR, Bolin P, Brancati FL, et al; Look AHEAD Research Group. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013;369:145-54. [PMID: 23796131]
Background: Lifestyle modification is the cornerstone of therapy in diabetes according to many clinical studies and clinical experience. For example, the Swedish Obese Subjects clinical trial showed reduced cardiovascular events, but it was not a randomized study (1). No previous prospective trial, however, had evaluated long-term effects of intensive lifestyle intervention on morbidity and mortality from cardiovascular events. The Look AHEAD (Action for Health in Diabetes) group undertook this multicenter, randomized trial to answer this question. Findings: In 16 study centers in the United States, 5145 overweight or obese patients with type 2 diabetes (mean age, 59 years) were randomly assigned to an intensive intervention (2570 patients) that promoted weight loss through decreased food intake and increased physical activity or to a control group (2575 patients) who received conventional diabetes education and support. The primary outcomes were fatal or nonfatal cardiovascular events (such as myocardial infarction and stroke). These events occurred equally in both groups for a maximum follow-up of 13.5 years. Therefore, the trial was stopped early after a median follow-up of 9.6 years, when analysis suggested that further follow-up would not alter results. Cautions: These findings have several limitations. It is possible that an intervention aimed at altering dietary composition (rather than caloric intake only) might have had a different outcome. Moreover, although patients lost 5% of their body weight, perhaps a more sustained weight loss would reduce risk for cardiovascular disease. Statin use was higher in the control group, which might have blunted a difference in cardiovascular outcomes between the groups. Finally, other important end points, such as prognosis of diabetic retinopathy, were not reported and may have differed between the 2 groups. Implications: The findings confirm the clinical impression that lifestyle modification can reduce weight in diabetic patients but may not reduce the risk for cardiovascular events. Did weight reduction have other benefits? Lifestyle modification reduced glycated hemoglobin levels, patients were less likely to require treatment with insulin, and rate of partial remission of diabetes increased. In addition, physicians can tell patients that lifestyle interventions are safe and may improve quality of life. We need future trials of www.annals.org
Background: Dementia is increasingly being recognized and has many potential causes. Rates of obesity and diabetes are also increasing. Studies evaluating the association between obesity or diabetes and the risk for dementia have yielded inconsistent results. The authors used the Adult Changes in Thought (ACT) study to obtain data from a prospective cohort with quality case ascertainment to determine whether glucose levels are associated with risk for dementia. Findings: The ACT study included 2067 participants (1228 women), mean age 76 years, without dementia at baseline; 232 had diabetes, and 1835 did not. A total of 35 264 values were available for fasting and random glucose levels, and 10 208 values were available for glycated hemoglobin levels (total or A1c). Participants were assessed for dementia every 2 years by using the Cognitive Abilities Screening Instrument, and dementia and probable or possible Alzheimer disease were diagnosed on the basis of research criteria. During a median follow-up of 6.8 years, dementia developed in 524 participants (74 with and 450 without diabetes). In diabetic and nondiabetic participants, higher average glucose levels were associated with an increased risk for dementia. Cautions: The study was limited to available glucose measurements obtained at irregular intervals. Large differences in glycemia between participants with and without diabetes were recorded; however, despite frequent glucose (17 per person) and glycated hemoglobin (5 per person) recordings, these differences may have been minimized. Implications: This large, community-based prospective study, which had a large sample and access to extensive laboratory and medical data, found higher glucose levels to be associated with an increased risk for dementia. Although the mechanisms are largely speculative, possibilities include acute and chronic hyperglycemia with insulin resistance and increased microvascular disease of the central nervous system. It seems that hyperglycemia should now be considered a risk factor for dementia, even among those without diabetes. Substantial Weight Loss Persists 3 Years After Bariatric Surgery for Severe Obesity Courcoulas AP, Christian NJ, Belle SH, et al; Longitudinal Assessment of Bariatric Surgery (LABS) Consortium. Weight change and health outcomes at 3 years after bariatric surgery among individuals with severe obesity. JAMA. 2013;310:2416-25. [PMID: 24189773]
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tury, with substantial health and economic consequences. Bariatric surgery results in profound, sustained weight loss in severely obese persons and as a result has become a common solution to a common problem. However, few data are available on long-term results of bariatric surgery, including benefits and complications. The National Institutes of Health funded the Longitudinal Assessment of Bariatric Surgery (LABS) Consortium. LABS is a multicenter observational cohort study that enrolled 2458 patients, 18 to 78 years of age, 79% women, with a median body mass index of 45.9 kg/m2 and a 33% prevalence of diabetes. Findings: This is 1 of 4 LABS reports; it included 1738 patients treated with Roux-en-Y gastric bypass (RYGB) surgery and 610 who underwent laparoscopic adjustable gastric banding (LAGB) as their first bariatric operation. Another 110 participants treated with less common procedures were not included. The 3-year median weight loss was 41 kg (31.5% of initial body weight) after RYGB and 20 kg (15.9%) after LAGB. After RYGB procedures, 16 patients died, 3 within 30 days of surgery. Five patients died after LAGB, but none in the 30-day postsurgical period. Cautions: Although the results suggested successful outcome with regard to weight loss after RYGB and LAGB, most weight loss was evident during the first year after surgery for both procedures, and the amount and trajectories of the change varied. However, these data should be considered in light of adverse outcomes: death, reoperation, and nutritional deficiencies. In addition to the deaths noted above, 4 RYGB procedures and 77 LAGB procedures were performed as revision surgeries. Implications: Clearly, bariatric surgery is effective in severe obesity, and these data provide important new information on medium-term safety and efficacy. This report, as well as other recent data, suggest that dramatic weight loss seems to be sustained. However, quality-of-life improvement is not well documented in studies to date, and complications, including death, are not negligible. Although bariatric procedures for obesity continue to improve, with lower-risk approaches being developed, a careful risk–benefit analysis must be undertaken for each case.
ment alone in obese patients with type 2 diabetes, but efficacy and safety outcomes remain controversial. This is the first trial comparing RYGB with intense lifestyle modifications and medical management to treat obese patients with type 2 diabetes by using composite specified therapeutic goals. Findings: The authors conducted a 12-month, multinational, multicenter, unblinded, randomized, controlled trial of 120 diabetic patients with a body mass index of 30 to 39.9 kg/m2 and poor glycemic control. Half (n ⫽ 60) were randomly assigned to undergo RYGB. All patients had intense lifestyle modifications with medical management for their obesity, diabetes, hypertension, and hyperlipidemia. The primary end point was a composite goal of hemoglobin A1c value less than 7%, low-density lipoprotein cholesterol level less than 100 mg/dL (2.59 mmol/L), and systolic blood pressure less than 130 mm Hg. At 12 months, 28 patients (49%) in the RYGB group and 11 patients (19%) in the lifestyle–medical management group achieved the composite end point. Cautions: These data are from short-term follow-up. In addition, adverse effects reported were significant, including 22 and 15 serious complications in the RYGB and lifestyle–medical management groups, respectively. Although no patients in the surgical group died, 2 had serious effects with long-term disability. Other adverse effects included nutritional deficiencies and hypoglycemia. Overall, patients in the RYGB group had 50% more serious and 55% more nonserious complications than did those in the lifestyle–medical management group. Implications: Bariatric surgery results in dramatic weight loss and improved glycemic control. It is useful in both obesity and diabetes; hence, the term metabolic surgery is used to describe this class of procedures because they are aimed at improving a physiologic, rather than an anatomical, defect. Long-term safety and efficacy will require more randomized trials. Until then, in each patient it is prudent to consider beneficial effects of bariatric surgery vis-a`-vis higher costs and the potential risks of surgical complications.
Bone Disease Bariatric Surgery in Mildly to Moderately Obese Diabetic Patients Results in Greater Short-Term Weight Loss and Glycemic Control Than Intensive Medical Management Alone
rhPTH Is Effective and Safe in Hypoparathyroidism Mannstadt M, Clarke BL, Vokes T, et al. Efficacy and safety of recombinant human parathyroid hormone (1-84) in hypoparathy-
Ikramuddin S, Korner J, Lee WJ, et al. Roux-en-Y gastric bypass vs
roidism (REPLACE): a double-blind, placebo-controlled, randomised,
intensive medical management for the control of type 2 diabetes,
phase 3 study. Lancet Diabetes Endocrinol. 2013;1:275-83. [PMID:
hypertension, and hyperlipidemia: the Diabetes Surgery Study ran-
24622413]
domized clinical trial. JAMA. 2013;309:2240-9. [PMID: 23736733]
Background: Hypoparathyroidism is a rare disease caused by deficient PTH production. The clinical symptoms are caused by hypocalcemia; can be mild or severe; and include paresthesia, muscle cramps, tetany, and seizures. Conventional treatment— oral calcium plus vitamin D
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replacement— has been effective but is associated with nephrolithiasis and renal failure. The availability of fulllength rhPTH (1-84) might minimize these untoward effects. This study evaluated the efficacy and safety of rhPTH in hypoparathyroidism. Findings: This was a multinational, multicenter, randomized, placebo-controlled, double-blind study. A total of 134 eligible patients with hypoparathyroidism (age 18 to 85 years; 105 women) were recruited and randomly assigned to rhPTH (n ⫽ 90) or placebo (n ⫽ 44). The treatment period was 24 weeks and included an initial dose of 50 mcg of rhPTH or placebo subcutaneously selfinjected daily (dose could be uptitrated). Symptoms and serum calcium, serum phosphate, serum vitamin D, and 24-hour urine calcium levels were monitored. Forty-eight (53%) patients in the rhPTH group versus 1 (2%) in placebo group (P ⬍ 0.0001) achieved the primary endpoint of a 50% or greater reduction from baseline in daily dose of oral calcium and active vitamin D while maintaining serum calcium at baseline levels or higher and at the upper limit of normal or lower. Cautions: These short-term results do not allow conclusions about long-term efficacy or safety. In addition, a more flexible dose regimen for rhPTH administration is desirable, in contrast to this study, which used a fixed daily dose of rhPTH. Implications: Although hypoparathyroidism is a rare disease, its treatment has been challenging and it is associated with renal complications and fluctuating, difficult-tocontrol symptoms in both adult and pediatric patients. The results of the current trial are encouraging and show that this treatment can maintain normal serum calcium and phosphate levels without the specter of hypercalciuria and nephrocalcinosis. The drug seems safe and welltolerated, but long-term studies are needed.
Update
T-score of ⫺1.0 or greater and 52.7% had a T-score between ⫺1.01 and ⫺2.49. The median duration of follow-up after the second BMD test was 9.6 years. During follow-up, 113 (14.1%) participants experienced at least 1 major fracture. Forty-eight participants were reclassified as high risk after the second BMD test; 8.3% fractured a hip. Among 76 participants with hip fractures, 4 were reclassified as high risk after the second BMD test. Among 726 patients without hip fracture, 28 were reclassified as low risk and 44 reclassified as high risk after the repeat BMD test. Cautions: One shortcoming of this study was that most participants had BMD measured on 2 different machines. In addition, treatment information was incomplete except for estrogen use. When the researchers calculated risk probabilities, family history was not available. Finally, because all participants were white, these findings may not apply to other ethnic or racial groups. Implications: In this population-based study, BMD changes in the femoral neck during an average of 3.7 years were independently associated with hip and major osteoporotic fracture. Moreover, BMD change failed to provide useful additional information beyond baseline BMD result in predicting fracture risk. With the second BMD test, only a small fraction of participants were reclassified as high risk. Therefore, the results question the utility of routinely performing serial BMD tests on average 2.2-year intervals. Repeating a BMD test within 4 years would rarely change clinical management of elderly patients with osteoporosis based on risk scores of hip fractures. If these results are confirmed, they are likely to change practice and reduce the cost of caring for the elderly. In Men, Estrogen Deficiency, Not Testosterone Deficiency, Accounts for Increased Body Fat Finkelstein JS, Lee H, Burnett-Bowie SA, et al. Gonadal steroids and
In Untreated Older Patients, a Second BMD Measure After 4 Years Does Not Improve Hip Fracture Risk Assessment
body composition, strength, and sexual function in men. N Engl
Berry SD, Samelson EJ, Pencina MJ, et al. Repeat bone mineral
Background: Male hypogonadism is characterized by decreased muscle mass and strength, increased body fat, and decreased libido and potency. Androgen deficiency, diagnosed when testosterone levels are at least 2 SDs below the mean value for healthy men, is considered responsible for the symptoms of male hypogonadism. More than 80% of circulating estradiol in men comes from aromatization of testosterone. This study suggests that estrogen deficiency significantly contributes to male hypogonadism and its complications. Findings: A total of 198 healthy men, aged 20 to 50 years, with normal testosterone levels were recruited. All participants received goserelin acetate to suppress gonadal steroid production. Participants were then randomly assigned to receive placebo or different strengths of 1% testosterone gel, used daily for 16 weeks. Another cohort also received anastrozole, 1 mg daily, to block the aromatization of tes-
density screening and prediction of hip and major osteoporotic fracture. JAMA. 2013;310:1256-62. [PMID: 24065012]
Background: Testing of BMD is important for the diagnosis and treatment of osteoporosis. Assessment of BMD is recommended as a screening test that estimates the 10-year risk for hip and major osteoporotic fractures. Although BMD is useful, the value of a second BMD test is unclear. The U.S. Preventive Services Task Force recommends waiting 2 years before repeating BMD testing, and Medicare reimburses for BMD screening every 2 years regardless of baseline BMD results. If a second BMD test is not necessary, its elimination would reduce inconvenience and cost of care. Findings: This population-based study included 310 men and 492 women with a mean age of 75 years at baseline BMD testing. At baseline, 21.9% of participants had a www.annals.org
J Med. 2013;369:1011-22. [PMID: 24024838]
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tosterone to estrogen. Dual-energy x-ray absorptiometry– based body fat and lean mass were measured. Subcutaneous and abdominal fat areas were determined by computed tomography. Results show that percentage of body fat in men receiving placebo or testosterone without anastrozole increased. Lean mass and thigh-muscle mass decreased in groups receiving placebo or low-dose testosterone without anastrozole. Sexual dysfunction in men has been considered solely due to low testosterone. However, this report shows that both testosterone and estrogen deficiency contribute to diminished sexual function in men. Cautions: This was a short-term study and a difficult one to analyze. It did not account for the small portion of estrogen directly secreted by the testes. Moreover, in physiologic terms gonadal function declines gradually, in contrast to the rapid decline created in this trial. Implications: Until now, we believed that, in men, only serum testosterone levels determine lean mass, muscle strength, and fat mass. This report shows that estrogens also play a major role influencing body fat and sexual function in men. Estrogen deficiency is important in male hy-
HIGHLIGHTS
pogonadism, and measurement of estradiol is useful in the evaluation of male hypogonadism. Androgen deficiency causes diminished lean mass, muscle size, and strength, and decreased estrogen accounts for increases in body fat. From Mayo Clinic College of Medicine, Rochester, Minnesota. Potential Conflicts of Interest: None disclosed. Forms can be viewed at
www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum ⫽M14-0047. Requests for Single Reprints: Hossein Gharib, MD, Mayo Clinic College of Medicine, 200 First Street, Rochester, MN 55905; e-mail, [email protected].
Author contributions are available at www.annals.org.
Reference 1. Romeo S, Maglio C, Burza MA, Pirazzi C, Sjo¨holm K, Jacobson P, et al. Cardiovascular events after bariatric surgery in obese subjects with type 2 diabetes. Diabetes Care. 2012;35:2613-7. [PMID: 22855732]
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Annals of Internal Medicine Author Contributions: Conception and design: H. Gharib.
Analysis and interpretation of the data: H. Gharib. Drafting of the article: H. Gharib. Critical revision of the article for important intellectual content: H. Gharib. Final approval of the article: H. Gharib. Statistical expertise: H. Gharib. Administrative, technical, or logistic support: H. Gharib.
© 2014 American College of Physicians W-471
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T
his update summarizes 10 important studies published in 2013 that can change clinical practice. In thyroid research, a randomized trial showed no advantage in the use of desiccated thyroid extract (DTE) over levothyroxine monotherapy in replacement therapy for hypothyroidism, although DTE resulted in modest weight loss and better patient satisfaction. A large retrospective, multinational study showed that a molecular marker, BRAF V600E mutation, present in 40% to 50% of papillary thyroid carcinomas (PTCs), was strongly associated with cancer mortality. Radioiodine (RAI) is effective in treatment, and improves outcome, of well-differentiated thyroid cancer. However, some tumors do not accumulate radioiodine and therefore cannot be treated. Selumetinib is recently shown to enhance radioiodine uptake and facilitate treatment of metastatic thyroid cancer. In diabetes practice, several developments were noteworthy. Lifestyle modifications resulted in weight reduction, decreased insulin requirement, and better glycemic control but failed to reduce cardiovascular events. In another study, higher glucose levels were associated with an increased risk for dementia. Two trials showed that bariatric surgery is useful in both obesity and diabetes— hence the term metabolic surgery—with dramatic weight loss and improved glycemic control. However, improved quality of life has not been well-documented, and costs and potential risks of surgical complications can be considerable. In bone medicine, a controlled trial documented the safety and efficacy of recombinant human parathyroid hormone (rhPTH) in the treatment of hypoparathyroidism, an important observation that should significantly improve treatment of patients with hypoparathyroidism. Another population-based study on the usefulness of a second bone mineral density (BMD) measurement in assessing risk fracture failed to support routine, serial BMD measurements. Finally, a well-designed randomized trial concluded that serum estrogens, in addition to the known effects of testosterone, play a major role in influencing body fat distribution and sexual function in men. Thyroid Disease DTE Therapy Did Not Improve Quality of Life Compared With Levothyroxine Alone Hoang TD, Olsen CH, Mai VQ, et al. Desiccated thyroid extract compared with levothyroxine in the treatment of hypothyroidism: a randomized, double-blind, crossover study. J Clin Endocrinol Metab. 2013;98:1982-90. [PMID: 23539727] Ann Intern Med. 2014;160:785-790. For author affiliation, see end of text. This article was published online first at www.annals.org on 10 April 2014.
Background: Conventional treatment of hypothyroidism consists of replacement levothyroxine monotherapy. Some patients receiving a seemingly adequate levothyroxine dose who have normal serum thyroid-stimulating hormone levels, however, continue to report hypothyroid symptoms, including fatigue, low energy, cold, constipation, weight gain, and poor sleep. It is speculated that symptoms may be caused by low serum triiodothyronine (T3) levels and that the addition of T3 should alleviate most symptoms. However, most studies comparing levothyroxine plus T3 with levothyroxine therapy have failed to confirm that combination therapy is superior at improving quality of life. This study compared the effectiveness of DTE and levothyroxine alone in a group of known hypothyroid patients. Findings: This randomized, double-blind, crossover study was conducted at a tertiary medical facility. Seventy patients, aged 18 to 65 years, with primary hypothyroidism who had been receiving a stable dose of levothyroxine for 6 months were included. Patients were randomly assigned to DTE or levothyroxine for 16 weeks and then crossed over to the other regimen for the same duration. Biochemical and neurocognitive tests were performed at baseline and at the end of the study period. Overall, symptoms and neurocognitive measurements did not differ between the 2 therapies. Patients lost 3 pounds during the DTE protocol compared with levothyroxine treatment (mean weight, 172 pounds [SD, 36.4] vs. 175.7 pounds [SD, 37.7]; P ⬍ 0.001). At the end of the study, 34 patients (48.6%) preferred DTE, 13 (18.6%) preferred levothyroxine, and 23 (32.9%) had no preference. In the subgroup analyses, patients who preferred DTE lost 4 pounds during the DTE treatment, and their subjective symptoms were significantly better while they were taking DTE, as measured by the General Health Questionnaire-12 and Thyroid Symptom Questionnaire (P ⬍ 0.001 for both). Cautions: Limitations of this study include the short duration, small sample size, low sensitivity of some of the neurocognitive tests used and biochemical variables measured, and lack of genetic testing for deiodinase polymorphism. Genetic deiodinase polymorphism, a rare finding, accounts for decreased thyroxine-to-T3 conversion in the brain, explaining why some patients remain symptomatic while receiving thyroxine monotherapy. No formal adjustment was made for multiple comparisons, and some significant findings may be due to type I error. Implications: This is the first randomized study comparing DTE with levothyroxine in hypothyroid patients. It con-
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firms that the combination of thyroxine plus T3, compared with levothyroxine alone, does not significantly improve quality-of-life measures in most patients. These data are consistent with results of most previous studies on this subject published in the past decade. However, the present study also shows that in a few patients, once-daily DTE, in place of levothyroxine, resulted in modest weight loss with possible improvements in symptoms, without apparent adverse effects. BRAF Mutation Is Associated With Increased Cancer-Related Mortality in Patients With PTC
study captured only PTC-specific deaths and could not assess all-cause mortality. Implications: In this retrospective study, the BRAF V600E mutation was found in 46% of patients with PTC and was associated with an increase in mortality, although the association diminished after adjustment for age and sex. These data are similar to those found in other reports. In low-risk PTC, the presence and absence of BRAF V600E mutation did not influence mortality, which remained low in both groups.
Xing M, Alzahrani AS, Carson KA, et al. Association between BRAF
RAI Uptake Can Be Enhanced by Selumetinib in Patients With Advanced Follicular Cell–Derived Thyroid Cancer
V600E mutation and mortality in patients with papillary thyroid
Ho AL, Grewal RK, Leboeuf R, et al. Selumetinib-enhanced radio-
cancer. JAMA. 2013;309:1493-501. [PMID: 23571588]
iodine uptake in advanced thyroid cancer. N Engl J Med. 2013;368:
Background: Papillary thyroid carcinoma accounts for approximately 90% of all thyroid cancers and has an excellent 5-year survival rate of 95% to 97%. Some tumors, however, exhibit aggressive behavior, and the challenge is to identify and treat these subtypes. Several studies have shown that mutations in the BRAF gene V600E (that is, the amino acid valine in position 600 is replaced by glutamic acid) are associated with lower survival in patients with PTC. The clinical significance of this mutation with regard to PTC-related mortality remains uncertain. This multicenter study examined and defined the association between the BRAF V600E mutation and mortality caused by PTC. Findings: This retrospective multicenter study of 1849 patients with PTC found that the BRAF V600E mutation is present in 46% of patients with PTC. The mortality rate was 53% (45 of 845 patients [95% CI, 3.9% to 7.1%]) in BRAF V600E–positive patients and 1.1% (11 of 1004 [CI, 0.5% to 2.0%]) in mutation-negative patients (P ⬍ 0.001). Deaths per 1000 person-years in the analysis of all patients with PTC were 12.87 versus 0.52 in BRAF V600E mutation–positive versus mutation-negative patients; the hazard ratio (HR) was 2.66 (CI, 1.30 to 5.43) after adjustment for age at diagnosis, sex, and medical center. Deaths per 1000 person-years in patients with conventional PTC were 11.80 in BRAF-positive patients and 2.25 in BRAFnegative patients. When lymph node metastasis, extrathyroid invasion, and distant metastasis were included in the model, the association of BRAF V600E with mortality for all patients with PTC was no longer significant. For example, in patients with nodal metastasis, deaths per 1000 person-years were 26.26 (CI, 19.18 to 35.94) versus 5.93 (CI, 2.96 to 11.86) in mutation-positive versus mutationnegative patients (unadjusted HR, 4.43 [CI, 2.06 to 9.51]; adjusted HR, 1.46 [CI, 0.62 to 3.47]). Cautions: The low number of PTC-specific deaths reduced the power to find associations and resulted in wide CIs, and higher BRAF V600E–associated mortality was attenuated after adjustment for patient age. Moreover, many patients had relatively short clinical follow-up. Finally, the
623-32. [PMID: 23406027]
Background: Well-differentiated carcinoma accounts for 90% to 95% of all thyroid cancers. These tumors arise from follicular cells and include PTC and follicular cancers. Radioiodine is the principal treatment for metastatic follicular cell– derived cancer. Unfortunately, many metastatic cancers do not accumulate RAI and, therefore, cannot be effectively treated. The 10-year survival rate is significantly improved for iodine-avid versus non–iodine-avid tumors (60% vs. 10%, respectively). Previous attempts using lithium, retinoids, or other compounds resulted in modest clinical benefits. The new anticancer agent selumetinib blocks mitogen-activated protein kinase (MAPK) and improves response to RAI. Findings: Twenty patients (age range, 44 to 77 years; 9 women) were studied: Five had classic PTC, 8 had tall-cell PTC, and 7 had poorly differentiated tumors. Nine had BRAF V600E, 5 had NRAS, 3 had RET/PTC, and 3 had wild-type oncogenes. Selumetinib increased the uptake of RAI in 9 of 20 patients. Eight of 12 patients reached the dosimetry threshold for RAI therapy, 5 had partial response, and 3 had stable disease. No significant adverse effects were recorded. According to imaging and by thyroglobulin measurements, tumor activity decreased significantly after selumetinib-induced RAI treatment. Cautions: This small study included only 20 patients, and follow-up was only 6 months. Although uptake in metastatic sites increased and response to administered RAI improved, whether this response influences survival is not known. Implications: This study is important because it shows that selumetinib can help patients with RAI-refractory, metastatic differentiated thyroid cancer. The gene BRAF is part of the MAPK pathway that facilitates growth factor activity at the cellular level. Inhibition of MAPK should, therefore, be beneficial, and selumetinib blocks the kinase subtypes MEK1 and MEK2, thereby reducing MAPK activity. This may enhance iodine uptake, with increased retention in tumor tissues in 60% of patients; the result is an improved response to the administered RAI dose. After 6 months a
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variable reduction of metastatic target lesions was observed in all patients. Larger studies and longer follow-up are needed to confirm these early, positive results.
Update
other strategies to evaluate the effect of lifestyle changes and weight loss on additional outcomes in diabetic patients. Higher Glucose Levels May Be a Risk Factor for Dementia
Diabetes
Crane PK, Walker R, Hubbard RA, et al. Glucose levels and risk of
Lifestyle Modification May Reduce Weight in Patients With Type 2 Diabetes Mellitus but Does Not Decrease Rate of Cardiovascular Events
dementia. N Engl J Med. 2013;369:540-8. [PMID: 23924004]
Wing RR, Bolin P, Brancati FL, et al; Look AHEAD Research Group. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013;369:145-54. [PMID: 23796131]
Background: Lifestyle modification is the cornerstone of therapy in diabetes according to many clinical studies and clinical experience. For example, the Swedish Obese Subjects clinical trial showed reduced cardiovascular events, but it was not a randomized study (1). No previous prospective trial, however, had evaluated long-term effects of intensive lifestyle intervention on morbidity and mortality from cardiovascular events. The Look AHEAD (Action for Health in Diabetes) group undertook this multicenter, randomized trial to answer this question. Findings: In 16 study centers in the United States, 5145 overweight or obese patients with type 2 diabetes (mean age, 59 years) were randomly assigned to an intensive intervention (2570 patients) that promoted weight loss through decreased food intake and increased physical activity or to a control group (2575 patients) who received conventional diabetes education and support. The primary outcomes were fatal or nonfatal cardiovascular events (such as myocardial infarction and stroke). These events occurred equally in both groups for a maximum follow-up of 13.5 years. Therefore, the trial was stopped early after a median follow-up of 9.6 years, when analysis suggested that further follow-up would not alter results. Cautions: These findings have several limitations. It is possible that an intervention aimed at altering dietary composition (rather than caloric intake only) might have had a different outcome. Moreover, although patients lost 5% of their body weight, perhaps a more sustained weight loss would reduce risk for cardiovascular disease. Statin use was higher in the control group, which might have blunted a difference in cardiovascular outcomes between the groups. Finally, other important end points, such as prognosis of diabetic retinopathy, were not reported and may have differed between the 2 groups. Implications: The findings confirm the clinical impression that lifestyle modification can reduce weight in diabetic patients but may not reduce the risk for cardiovascular events. Did weight reduction have other benefits? Lifestyle modification reduced glycated hemoglobin levels, patients were less likely to require treatment with insulin, and rate of partial remission of diabetes increased. In addition, physicians can tell patients that lifestyle interventions are safe and may improve quality of life. We need future trials of www.annals.org
Background: Dementia is increasingly being recognized and has many potential causes. Rates of obesity and diabetes are also increasing. Studies evaluating the association between obesity or diabetes and the risk for dementia have yielded inconsistent results. The authors used the Adult Changes in Thought (ACT) study to obtain data from a prospective cohort with quality case ascertainment to determine whether glucose levels are associated with risk for dementia. Findings: The ACT study included 2067 participants (1228 women), mean age 76 years, without dementia at baseline; 232 had diabetes, and 1835 did not. A total of 35 264 values were available for fasting and random glucose levels, and 10 208 values were available for glycated hemoglobin levels (total or A1c). Participants were assessed for dementia every 2 years by using the Cognitive Abilities Screening Instrument, and dementia and probable or possible Alzheimer disease were diagnosed on the basis of research criteria. During a median follow-up of 6.8 years, dementia developed in 524 participants (74 with and 450 without diabetes). In diabetic and nondiabetic participants, higher average glucose levels were associated with an increased risk for dementia. Cautions: The study was limited to available glucose measurements obtained at irregular intervals. Large differences in glycemia between participants with and without diabetes were recorded; however, despite frequent glucose (17 per person) and glycated hemoglobin (5 per person) recordings, these differences may have been minimized. Implications: This large, community-based prospective study, which had a large sample and access to extensive laboratory and medical data, found higher glucose levels to be associated with an increased risk for dementia. Although the mechanisms are largely speculative, possibilities include acute and chronic hyperglycemia with insulin resistance and increased microvascular disease of the central nervous system. It seems that hyperglycemia should now be considered a risk factor for dementia, even among those without diabetes. Substantial Weight Loss Persists 3 Years After Bariatric Surgery for Severe Obesity Courcoulas AP, Christian NJ, Belle SH, et al; Longitudinal Assessment of Bariatric Surgery (LABS) Consortium. Weight change and health outcomes at 3 years after bariatric surgery among individuals with severe obesity. JAMA. 2013;310:2416-25. [PMID: 24189773]
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tury, with substantial health and economic consequences. Bariatric surgery results in profound, sustained weight loss in severely obese persons and as a result has become a common solution to a common problem. However, few data are available on long-term results of bariatric surgery, including benefits and complications. The National Institutes of Health funded the Longitudinal Assessment of Bariatric Surgery (LABS) Consortium. LABS is a multicenter observational cohort study that enrolled 2458 patients, 18 to 78 years of age, 79% women, with a median body mass index of 45.9 kg/m2 and a 33% prevalence of diabetes. Findings: This is 1 of 4 LABS reports; it included 1738 patients treated with Roux-en-Y gastric bypass (RYGB) surgery and 610 who underwent laparoscopic adjustable gastric banding (LAGB) as their first bariatric operation. Another 110 participants treated with less common procedures were not included. The 3-year median weight loss was 41 kg (31.5% of initial body weight) after RYGB and 20 kg (15.9%) after LAGB. After RYGB procedures, 16 patients died, 3 within 30 days of surgery. Five patients died after LAGB, but none in the 30-day postsurgical period. Cautions: Although the results suggested successful outcome with regard to weight loss after RYGB and LAGB, most weight loss was evident during the first year after surgery for both procedures, and the amount and trajectories of the change varied. However, these data should be considered in light of adverse outcomes: death, reoperation, and nutritional deficiencies. In addition to the deaths noted above, 4 RYGB procedures and 77 LAGB procedures were performed as revision surgeries. Implications: Clearly, bariatric surgery is effective in severe obesity, and these data provide important new information on medium-term safety and efficacy. This report, as well as other recent data, suggest that dramatic weight loss seems to be sustained. However, quality-of-life improvement is not well documented in studies to date, and complications, including death, are not negligible. Although bariatric procedures for obesity continue to improve, with lower-risk approaches being developed, a careful risk–benefit analysis must be undertaken for each case.
ment alone in obese patients with type 2 diabetes, but efficacy and safety outcomes remain controversial. This is the first trial comparing RYGB with intense lifestyle modifications and medical management to treat obese patients with type 2 diabetes by using composite specified therapeutic goals. Findings: The authors conducted a 12-month, multinational, multicenter, unblinded, randomized, controlled trial of 120 diabetic patients with a body mass index of 30 to 39.9 kg/m2 and poor glycemic control. Half (n ⫽ 60) were randomly assigned to undergo RYGB. All patients had intense lifestyle modifications with medical management for their obesity, diabetes, hypertension, and hyperlipidemia. The primary end point was a composite goal of hemoglobin A1c value less than 7%, low-density lipoprotein cholesterol level less than 100 mg/dL (2.59 mmol/L), and systolic blood pressure less than 130 mm Hg. At 12 months, 28 patients (49%) in the RYGB group and 11 patients (19%) in the lifestyle–medical management group achieved the composite end point. Cautions: These data are from short-term follow-up. In addition, adverse effects reported were significant, including 22 and 15 serious complications in the RYGB and lifestyle–medical management groups, respectively. Although no patients in the surgical group died, 2 had serious effects with long-term disability. Other adverse effects included nutritional deficiencies and hypoglycemia. Overall, patients in the RYGB group had 50% more serious and 55% more nonserious complications than did those in the lifestyle–medical management group. Implications: Bariatric surgery results in dramatic weight loss and improved glycemic control. It is useful in both obesity and diabetes; hence, the term metabolic surgery is used to describe this class of procedures because they are aimed at improving a physiologic, rather than an anatomical, defect. Long-term safety and efficacy will require more randomized trials. Until then, in each patient it is prudent to consider beneficial effects of bariatric surgery vis-a`-vis higher costs and the potential risks of surgical complications.
Bone Disease Bariatric Surgery in Mildly to Moderately Obese Diabetic Patients Results in Greater Short-Term Weight Loss and Glycemic Control Than Intensive Medical Management Alone
rhPTH Is Effective and Safe in Hypoparathyroidism Mannstadt M, Clarke BL, Vokes T, et al. Efficacy and safety of recombinant human parathyroid hormone (1-84) in hypoparathy-
Ikramuddin S, Korner J, Lee WJ, et al. Roux-en-Y gastric bypass vs
roidism (REPLACE): a double-blind, placebo-controlled, randomised,
intensive medical management for the control of type 2 diabetes,
phase 3 study. Lancet Diabetes Endocrinol. 2013;1:275-83. [PMID:
hypertension, and hyperlipidemia: the Diabetes Surgery Study ran-
24622413]
domized clinical trial. JAMA. 2013;309:2240-9. [PMID: 23736733]
Background: Hypoparathyroidism is a rare disease caused by deficient PTH production. The clinical symptoms are caused by hypocalcemia; can be mild or severe; and include paresthesia, muscle cramps, tetany, and seizures. Conventional treatment— oral calcium plus vitamin D
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replacement— has been effective but is associated with nephrolithiasis and renal failure. The availability of fulllength rhPTH (1-84) might minimize these untoward effects. This study evaluated the efficacy and safety of rhPTH in hypoparathyroidism. Findings: This was a multinational, multicenter, randomized, placebo-controlled, double-blind study. A total of 134 eligible patients with hypoparathyroidism (age 18 to 85 years; 105 women) were recruited and randomly assigned to rhPTH (n ⫽ 90) or placebo (n ⫽ 44). The treatment period was 24 weeks and included an initial dose of 50 mcg of rhPTH or placebo subcutaneously selfinjected daily (dose could be uptitrated). Symptoms and serum calcium, serum phosphate, serum vitamin D, and 24-hour urine calcium levels were monitored. Forty-eight (53%) patients in the rhPTH group versus 1 (2%) in placebo group (P ⬍ 0.0001) achieved the primary endpoint of a 50% or greater reduction from baseline in daily dose of oral calcium and active vitamin D while maintaining serum calcium at baseline levels or higher and at the upper limit of normal or lower. Cautions: These short-term results do not allow conclusions about long-term efficacy or safety. In addition, a more flexible dose regimen for rhPTH administration is desirable, in contrast to this study, which used a fixed daily dose of rhPTH. Implications: Although hypoparathyroidism is a rare disease, its treatment has been challenging and it is associated with renal complications and fluctuating, difficult-tocontrol symptoms in both adult and pediatric patients. The results of the current trial are encouraging and show that this treatment can maintain normal serum calcium and phosphate levels without the specter of hypercalciuria and nephrocalcinosis. The drug seems safe and welltolerated, but long-term studies are needed.
Update
T-score of ⫺1.0 or greater and 52.7% had a T-score between ⫺1.01 and ⫺2.49. The median duration of follow-up after the second BMD test was 9.6 years. During follow-up, 113 (14.1%) participants experienced at least 1 major fracture. Forty-eight participants were reclassified as high risk after the second BMD test; 8.3% fractured a hip. Among 76 participants with hip fractures, 4 were reclassified as high risk after the second BMD test. Among 726 patients without hip fracture, 28 were reclassified as low risk and 44 reclassified as high risk after the repeat BMD test. Cautions: One shortcoming of this study was that most participants had BMD measured on 2 different machines. In addition, treatment information was incomplete except for estrogen use. When the researchers calculated risk probabilities, family history was not available. Finally, because all participants were white, these findings may not apply to other ethnic or racial groups. Implications: In this population-based study, BMD changes in the femoral neck during an average of 3.7 years were independently associated with hip and major osteoporotic fracture. Moreover, BMD change failed to provide useful additional information beyond baseline BMD result in predicting fracture risk. With the second BMD test, only a small fraction of participants were reclassified as high risk. Therefore, the results question the utility of routinely performing serial BMD tests on average 2.2-year intervals. Repeating a BMD test within 4 years would rarely change clinical management of elderly patients with osteoporosis based on risk scores of hip fractures. If these results are confirmed, they are likely to change practice and reduce the cost of caring for the elderly. In Men, Estrogen Deficiency, Not Testosterone Deficiency, Accounts for Increased Body Fat Finkelstein JS, Lee H, Burnett-Bowie SA, et al. Gonadal steroids and
In Untreated Older Patients, a Second BMD Measure After 4 Years Does Not Improve Hip Fracture Risk Assessment
body composition, strength, and sexual function in men. N Engl
Berry SD, Samelson EJ, Pencina MJ, et al. Repeat bone mineral
Background: Male hypogonadism is characterized by decreased muscle mass and strength, increased body fat, and decreased libido and potency. Androgen deficiency, diagnosed when testosterone levels are at least 2 SDs below the mean value for healthy men, is considered responsible for the symptoms of male hypogonadism. More than 80% of circulating estradiol in men comes from aromatization of testosterone. This study suggests that estrogen deficiency significantly contributes to male hypogonadism and its complications. Findings: A total of 198 healthy men, aged 20 to 50 years, with normal testosterone levels were recruited. All participants received goserelin acetate to suppress gonadal steroid production. Participants were then randomly assigned to receive placebo or different strengths of 1% testosterone gel, used daily for 16 weeks. Another cohort also received anastrozole, 1 mg daily, to block the aromatization of tes-
density screening and prediction of hip and major osteoporotic fracture. JAMA. 2013;310:1256-62. [PMID: 24065012]
Background: Testing of BMD is important for the diagnosis and treatment of osteoporosis. Assessment of BMD is recommended as a screening test that estimates the 10-year risk for hip and major osteoporotic fractures. Although BMD is useful, the value of a second BMD test is unclear. The U.S. Preventive Services Task Force recommends waiting 2 years before repeating BMD testing, and Medicare reimburses for BMD screening every 2 years regardless of baseline BMD results. If a second BMD test is not necessary, its elimination would reduce inconvenience and cost of care. Findings: This population-based study included 310 men and 492 women with a mean age of 75 years at baseline BMD testing. At baseline, 21.9% of participants had a www.annals.org
J Med. 2013;369:1011-22. [PMID: 24024838]
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tosterone to estrogen. Dual-energy x-ray absorptiometry– based body fat and lean mass were measured. Subcutaneous and abdominal fat areas were determined by computed tomography. Results show that percentage of body fat in men receiving placebo or testosterone without anastrozole increased. Lean mass and thigh-muscle mass decreased in groups receiving placebo or low-dose testosterone without anastrozole. Sexual dysfunction in men has been considered solely due to low testosterone. However, this report shows that both testosterone and estrogen deficiency contribute to diminished sexual function in men. Cautions: This was a short-term study and a difficult one to analyze. It did not account for the small portion of estrogen directly secreted by the testes. Moreover, in physiologic terms gonadal function declines gradually, in contrast to the rapid decline created in this trial. Implications: Until now, we believed that, in men, only serum testosterone levels determine lean mass, muscle strength, and fat mass. This report shows that estrogens also play a major role influencing body fat and sexual function in men. Estrogen deficiency is important in male hy-
HIGHLIGHTS
pogonadism, and measurement of estradiol is useful in the evaluation of male hypogonadism. Androgen deficiency causes diminished lean mass, muscle size, and strength, and decreased estrogen accounts for increases in body fat. From Mayo Clinic College of Medicine, Rochester, Minnesota. Potential Conflicts of Interest: None disclosed. Forms can be viewed at
www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum ⫽M14-0047. Requests for Single Reprints: Hossein Gharib, MD, Mayo Clinic College of Medicine, 200 First Street, Rochester, MN 55905; e-mail, [email protected].
Author contributions are available at www.annals.org.
Reference 1. Romeo S, Maglio C, Burza MA, Pirazzi C, Sjo¨holm K, Jacobson P, et al. Cardiovascular events after bariatric surgery in obese subjects with type 2 diabetes. Diabetes Care. 2012;35:2613-7. [PMID: 22855732]
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Annals of Internal Medicine Author Contributions: Conception and design: H. Gharib.
Analysis and interpretation of the data: H. Gharib. Drafting of the article: H. Gharib. Critical revision of the article for important intellectual content: H. Gharib. Final approval of the article: H. Gharib. Statistical expertise: H. Gharib. Administrative, technical, or logistic support: H. Gharib.
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