Incidental Adrenal Masses: Adherence to Guidelines and Methods to Improve Initial Follow-Up: A Systematic Review.

OBJECTIVE: Incidental adrenal masses (IAMs) are detected in approximately 1%-2% of abdominal computed tomography (CT) scans. Recent estimates suggest that more than 70-million relevant CT scans are performed annually in the United States; thus, IAMs represent a significant clinical entity. Most clinical guidelines recommend an initial follow-up evaluation that includes imaging and biochemical testing after index IAM detection. METHODS: Systematic review of literature in the PubMed, EMBASE and Web of Science databases to determine whether guidelines regarding IAM evaluation are followed and to identify effective management strategies. Our initial search was in January 2018 and updated in November, 2019. RESULTS: 31 studies met inclusion criteria. In most institutions, only a minority of patients with IAMs undergo initial follow-up imaging (median 34%, IQR 20%-50%) or biochemical testing (median 18%, IQR 15%-28%). 2 interventions shown to improve IAM evaluation are IAM-specific recommendations in radiology reports and dedicated multi-disciplinary teams. Interventions focused solely on alerting the ordering clinician or primary care provider to the presence of an IAM have not demonstrated effectiveness. Patients who are referred to an endocrinologist are more likely to have a complete IAM evaluation, but few are referred. DISCUSSION: Most patients with an IAM do not have an initial evaluation. The radiology report has been identified as a key component in determining whether IAMs are evaluated appropriately. Care teams dedicated to management of incidental radiographic findings also improve IAM follow-up. Although the evidence base is sparse, these interventions may be a starting point for further inquiry into optimizing care in this common clinical scenario.

Effects of Testosterone Administration for 3 Years on Subclinical Atherosclerosis Progression in Older Men With Low or Low-Normal Testosterone Levels: A Randomized Clinical Trial.

IMPORTANCE: Testosterone use in older men is increasing, but its long-term effects on progression of atherosclerosis are unknown. OBJECTIVE: To determine the effect of testosterone administration on subclinical atherosclerosis progression in older men with low or low-normal testosterone levels. DESIGN, SETTING, AND PARTICIPANTS: Testosterone's Effects on Atherosclerosis Progression in Aging Men (TEAAM) was a placebo-controlled, double-blind, parallel-group randomized trial involving 308 men 60 years or older with low or low-normal testosterone levels (100-400 ng/dL; free testosterone <50 pg/mL), recruited at 3 US centers. Recruitment took place between September 2004 and February 2009; the last participant completed the study in May 2012. INTERVENTIONS: One hundred fifty-six participants were randomized to receive 7.5 g of 1% testosterone and 152 were randomized to receive placebo gel packets daily for 3 years. The dose was adjusted to achieve testosterone levels between 500 and 900 ng/dL. MAIN OUTCOMES AND MEASURES: Coprimary outcomes included common carotid artery intima-media thickness and coronary artery calcium; secondary outcomes included sexual function and health-related quality of life. RESULTS: Baseline characteristics were similar between groups: patients were a mean age of 67.6 years; 42% had hypertension; 15%, diabetes; 15%, cardiovascular disease; and 27%, obesity. The rate of change in intima-media thickness was 0.010 mm/year in the placebo group and 0.012 mm/year in the testosterone group (mean difference adjusted for age and trial site, 0.0002 mm/year; 95% CI, -0.003 to 0.003, P = .89). The rate of change in the coronary artery calcium score was 41.4 Agatston units/year in the placebo group and 31.4 Agatston units/year in the testosterone group (adjusted mean difference, -10.8 Agatston units/year; 95% CI, -45.7 to 24.2; P = .54). Changes in intima-media thickness or calcium scores were not associated with change in testosterone levels among individuals assigned to receive testosterone. Sexual desire, erectile function, overall sexual function scores, partner intimacy, and health-related quality of life did not differ significantly between groups. Hematocrit and prostate-specific antigen levels increased more in testosterone group. CONCLUSIONS AND RELEVANCE: Among older men with low or low-normal testosterone levels, testosterone administration for 3 years vs placebo did not result in a significant difference in the rates of change in either common carotid artery intima-media thickness or coronary artery calcium nor did it improve overall sexual function or health-related quality of life. Because this trial was only powered to evaluate atherosclerosis progression, these findings should not be interpreted as establishing cardiovascular safety of testosterone use in older men. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00287586.

Prospective Study of a System-Wide Adrenal Incidentaloma Quality Improvement Initiative.

BACKGROUND: Appropriate follow-up of incidental adrenal masses (IAMs) is infrequent. We implemented a quality improvement (QI) program to improve management of IAMs. STUDY DESIGN: This system-wide initiative targeted primary care providers (PCPs) after IAM detection. It incorporated (1) chart-based messages and emails to PCPs, (2) an evidence-based IAM evaluation algorithm, (3) standardized recommendations in radiology reports, and (4) access to a multispecialty adrenal clinic. Patients diagnosed with an IAM from January 1, 2018, to December 31, 2019, were prospectively included (the "QI cohort") and compared with a historical, preintervention cohort diagnosed with IAMs in 2016. The primary outcomes were the initiation of an IAM investigation by the PCP, defined as relevant clinical history-taking, laboratory screening, follow-up imaging, or specialist referral. RESULTS: The QI cohort included 437 patients and 210 in the historical cohort. All patients had 12 months or more of follow-up. In the QI cohort, 35.5% (155 of 437) met the primary endpoint for PCP-initiated evaluation, compared with 27.6% (58 of 210) in the historical cohort (p = 0.0496). Among the subgroup with a documented PCP working within our health system, 46.3% (74 of 160) met the primary endpoint in the QI cohort vs 33.3% (38 of 114) in the historical cohort (p = 0.035). After adjusting for insurance status, presence of current malignancy, initial imaging setting (outpatient, inpatient, or emergency department), and having an established PCP within our health system, patients in the QI cohort had 1.70 times higher odds (95% CI 1.16 to 2.50) of undergoing a PCP-initiated IAM evaluation. Adrenal surgery was ultimately performed in 2.1% (9 of 437) of QI cohort patients and 0.95% (2 of 210) of historical cohort patients (p = 0.517). CONCLUSIONS: This simple, moderately labor-intensive QI intervention was associated with increased IAM evaluation initiated by PCPs.

Adverse events associated with testosterone administration.

BACKGROUND: Testosterone supplementation has been shown to increase muscle mass and strength in healthy older men. The safety and efficacy of testosterone treatment in older men who have limitations in mobility have not been studied. METHODS: Community-dwelling men, 65 years of age or older, with limitations in mobility and a total serum testosterone level of 100 to 350 ng per deciliter (3.5 to 12.1 nmol per liter) or a free serum testosterone level of less than 50 pg per milliliter (173 pmol per liter) were randomly assigned to receive placebo gel or testosterone gel, to be applied daily for 6 months. Adverse events were categorized with the use of the Medical Dictionary for Regulatory Activities classification. The data and safety monitoring board recommended that the trial be discontinued early because there was a significantly higher rate of adverse cardiovascular events in the testosterone group than in the placebo group. RESULTS: A total of 209 men (mean age, 74 years) were enrolled at the time the trial was terminated. At baseline, there was a high prevalence of hypertension, diabetes, hyperlipidemia, and obesity among the participants. During the course of the study, the testosterone group had higher rates of cardiac, respiratory, and dermatologic events than did the placebo group. A total of 23 subjects in the testosterone group, as compared with 5 in the placebo group, had cardiovascular-related adverse events. The relative risk of a cardiovascular-related adverse event remained constant throughout the 6-month treatment period. As compared with the placebo group, the testosterone group had significantly greater improvements in leg-press and chest-press strength and in stair climbing while carrying a load. CONCLUSIONS: In this population of older men with limitations in mobility and a high prevalence of chronic disease, the application of a testosterone gel was associated with an increased risk of cardiovascular adverse events. The small size of the trial and the unique population prevent broader inferences from being made about the safety of testosterone therapy. (ClinicalTrials.gov number, NCT00240981.)

Effect of testosterone replacement on response to sildenafil citrate in men with erectile dysfunction: a parallel, randomized trial.

BACKGROUND: Erectile dysfunction and low testosterone levels frequently occur together. OBJECTIVE: To determine whether addition of testosterone to sildenafil therapy improves erectile response in men with erectile dysfunction and low testosterone levels. DESIGN: Randomized, double-blind, parallel, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00512707) SETTING: Outpatient academic research center. PARTICIPANTS: Men aged 40 to 70 years with scores of 25 or less for the erectile function domain (EFD) of the International Index of Erectile Function, total testosterone levels less than 11.45 nmol/L (<330 ng/dL), or free testosterone levels less than 173.35 pmol/L (<50 pg/mL). INTERVENTION: Sildenafil dose was optimized, and 140 participants were then randomly assigned to 14 weeks of daily transdermal gel that contained 10-g testosterone for 70 participants and placebo for the remaining 70 participants. All participants were included in the primary analysis, although 10 in the testosterone group and 12 in the placebo group did not complete the study. RESULTS: At baseline, the 2 groups had similar EFD scores. Administration of sildenafil alone was associated with a substantial increase in EFD score (mean, 7.7 [95% CI, 6.5 to 8.8]), but change in EFD score after randomization did not differ between the groups (difference, 2.2 [CI, -0.8 to 5.1]; P = 0.150). The findings were similar for other domains of sexual function in younger men, more obese men, and men with lower baseline testosterone levels or an inadequate response to sildenafil alone. Frequency of adverse events was similar for testosterone and placebo groups. LIMITATION: Whether testosterone could improve erectile function without sildenafil was not studied. CONCLUSION: Sildenafil plus testosterone was not superior to sildenafil plus placebo in improving erectile function in men with erectile dysfunction and low testosterone levels. PRIMARY FUNDING SOURCE: National Institute of Child Health and Human Development.

Point-of-care access to clinical guidelines may improve management of incidental findings in the primary care setting.

RATIONALE: Incidental radiographic findings are common, and primary care providers (PCPs) are often charged with the conducting or initiating an appropriate evaluation. Clinical guidelines are available for management of common 'incidentalomas' including lung and adrenal nodules, but guidelines-adherent evaluations are not always performed; for example, in the setting of incidental adrenal masses (IAMs), recent literature suggests that an evidence-based evaluation occurs in <25% of patients for whom it is warranted-a quality and safety concern. AIMS AND OBJECTIVES: The objective of this study was to examine whether point-of-care access to concise clinical guidelines would promote appropriate evaluations of two common incidentalomas: IAMs and lung nodules. METHOD: This study was a survey-based, single-blinded, randomized experiment of decision-making within clinical vignettes. Respondents were PCPs in a variety of clinical practice settings, and half were randomly assigned to surveys that included concise clinical guidelines while the other half served as controls without access to guidelines. Scenarios involved patients with IAMs and lung nodules, and the scenarios included both higher-risk and lower-risk lesions. Our primary analysis examined safe versus inappropriate clinical decisions, while a secondary analysis compared guidelines-concordant versus guidelines-discordant responses. RESULTS: For both the higher-risk IAM and higher-risk lung nodule scenarios, safe answer choices were selected at a similar rate by respondents regardless of whether they had access to guidelines or not. However, for the lower risk scenarios, inappropriate answer choices were chosen substantially more frequently by respondents without access to guidelines compared to those with the guidelines (lung: 29.3% vs. 4.5%, p = 0.003, adrenal: 31.6% vs. 7.0%, p = 0.01). There was less variation in the secondary analysis. CONCLUSION: Survey respondents were significantly more likely to make safe management decisions in lower-risk clinical scenarios when clinical guidelines were available. Point-of-care access to clinical guidelines for incidentalomas is an intervention that may reduce management errors and improve patient safety.

Effect of testosterone supplementation with and without a dual 5α-reductase inhibitor on fat-free mass in men with suppressed testosterone production: a randomized controlled trial.

CONTEXT: Steroid 5α-reductase inhibitors are used to treat benign prostatic hyperplasia and androgenic alopecia, but the role of 5α-dihydrotestosterone (DHT) in mediating testosterone's effects on muscle, sexual function, erythropoiesis, and other androgen-dependent processes remains poorly understood. OBJECTIVE: To determine whether testosterone's effects on muscle mass, strength, sexual function, hematocrit level, prostate volume, sebum production, and lipid levels are attenuated when its conversion to DHT is blocked by dutasteride (an inhibitor of 5α-reductase type 1 and 2). DESIGN, SETTING, AND PATIENTS: The 5α-Reductase Trial was a randomized controlled trial of healthy men aged 18 to 50 years comparing placebo plus testosterone enthanate with dutasteride plus testosterone enanthate from May 2005 through June 2010. INTERVENTIONS: Eight treatment groups received 50, 125, 300, or 600 mg/wk of testosterone enanthate for 20 weeks plus placebo (4 groups) or 2.5 mg/d of dutasteride (4 groups). MAIN OUTCOME MEASURES: The primary outcome was change in fat-free mass; secondary outcomes: changes in fat mass, muscle strength, sexual function, prostate volume, sebum production, and hematocrit and lipid levels. RESULTS: A total of 139 men were randomized; 102 completed the 20-week intervention. Men assigned to dutasteride were similar at baseline to those assigned to placebo. The mean fat-free mass gained by the dutasteride groups was 0.6 kg (95% CI, -0.1 to 1.2 kg) when receiving 50 mg/wk of testosterone enanthate, 2.6 kg (95% CI, 0.9 to 4.3 kg) for 125 mg/wk, 5.8 kg (95% CI, 4.8 to 6.9 kg) for 300 mg/wk, and 7.1 kg (95% CI, 6.0 to 8.2 kg) for 600 mg/wk. The mean fat-free mass gained by the placebo groups was 0.8 kg (95% CI, -0.1 to 1.7 kg) when receiving 50 mg/wk of testosterone enanthate, 3.5 kg (95% CI, 2.1 to 4.8 kg) for 125 mg/wk, 5.7 kg (95% CI, 4.8 to 6.5 kg) for 300 mg/wk, and 8.1 kg (95% CI, 6.7 to 9.5 kg) for 600 mg/wk. The dose-adjusted differences between the dutasteride and placebo groups for fat-free mass were not significant (P = .18). Changes in fat mass, muscle strength, sexual function, prostate volume, sebum production, and hematocrit and lipid levels did not differ between groups. CONCLUSION: Changes in fat-free mass in response to graded testosterone doses did not differ in men in whom DHT was suppressed by dutasteride from those treated with placebo, indicating that conversion of testosterone to DHT is not essential for mediating its anabolic effects on muscle. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00493987.

Strategies to optimize management of incidental radiographic findings in the primary care setting: A mixed methods study.

BACKGROUND: Incidental adrenal masses (IAMs) are common. Primary care providers (PCPs) are frequently responsible for incidentaloma evaluations. We evaluated whether PCPs view this paradigm effective, barriers faced, and strategies to optimize care delivery. METHODS: This is a sequential explanatory study, comprised of surveys followed by focus groups of PCPs. Because lung nodules are another type of common incidental finding, we compared PCP views on management of lung nodules to their views on IAMs. RESULTS: For IAMs, 22.3% of PCPs "always refer" to specialists, but for lung nodules this was 11.5% (p = 0.026). For lung nodules, the most significant barrier was insufficient time/support to longitudinally follow results (69%), but for IAMs it was uncertainty about which tests to order (68%). Fear of litigation was equal (lung = 22.5%, IAMs = 21.3%). Consistent themes regarding the "ideal" system included specific recommendations in radiology reports; automation of orders for follow-up tests; longitudinal tracking tools; streamlined consultations; and decision guides embedded within the electronic health record. CONCLUSIONS: Respondents are more comfortable with lung nodules than IAMs. Management of "incidentalomas" is within their scope of practice, but the current system can be optimized.

Germline SUCLG2 Variants in Patients With Pheochromocytoma and Paraganglioma.

BACKGROUND: Pheochromocytoma and paraganglioma (PPGL) are neuroendocrine tumors with frequent mutations in genes linked to the tricarboxylic acid cycle. However, no pathogenic variant has been found to date in succinyl-CoA ligase (SUCL), an enzyme that provides substrate for succinate dehydrogenase (SDH; mitochondrial complex II [CII]), a known tumor suppressor in PPGL. METHODS: A cohort of 352 patients with apparently sporadic PPGL underwent genetic testing using a panel of 54 genes developed at the National Institutes of Health, including the SUCLG2 subunit of SUCL. Gene deletion, succinate levels, and protein levels were assessed in tumors where possible. To confirm the possible mechanism, we used a progenitor cell line, hPheo1, derived from a human pheochromocytoma, and ablated and re-expressed SUCLG2. RESULTS: We describe 8 germline variants in the guanosine triphosphate-binding domain of SUCLG2 in 15 patients (15 of 352, 4.3%) with apparently sporadic PPGL. Analysis of SUCLG2-mutated tumors and SUCLG2-deficient hPheo1 cells revealed absence of SUCLG2 protein, decrease in the level of the SDHB subunit of SDH, and faulty assembly of the complex II, resulting in aberrant respiration and elevated succinate accumulation. CONCLUSIONS: Our study suggests SUCLG2 as a novel candidate gene in the genetic landscape of PPGL. Large-scale sequencing may uncover additional cases harboring SUCLG2 variants and provide more detailed information about their prevalence and penetrance.

Evaluation of incidental adrenal masses at a tertiary referral and trauma center.

BACKGROUND: Incidental adrenal masses are those that are found on imaging performed for any nonadrenal evaluation. Published guidelines define accepted follow-up criteria for incidental adrenal masses; however, adherence to these guidelines and barriers to appropriate follow-up are not well understood. We aimed to describe practice patterns for the discovery, evaluation, and follow-up of incidental adrenal masses. METHODS: Medical records of patients with an incidental adrenal mass underwent retrospective review at a tertiary referral and level-1 trauma center, as well as regional ambulatory care locations. Individuals ≥18 years of age with an incidental adrenal mass identified during 2016 were included. Patterns of evaluation, follow-up, and associated adrenal diagnoses were determined. RESULTS: From a total of 19,171 cross-sectional imaging procedures (computed tomography and magnetic resonance imaging), 244 patients with new incidental adrenal masses were identified. A majority (52%) were discovered as part of an evaluation in the emergency department. Of 153 patients with an identifiable primary care provider, approximately 75% had an in-network primary care provider, and 12 (7.8%) had both follow-up imaging and biochemical evaluation. Twenty-three percent of patients with an in-network primary care provider underwent an appropriate cross-sectional imaging procedure in follow-up compared to 29% for a non-network primary care provider (P = .54). Patients with a mass described with benign terminology were less likely to undergo follow-up imaging compared to those with indeterminate terminology (5% vs 37%, P < .001). Patients with imaging ordered as an outpatient were more likely to receive follow-up with imaging (22.8% outpatient vs 11.5% inpatient, P = .042). There was no difference between any groups regarding biochemical evaluation, which inappropriately was performed in only 15% of patients with an incidental adrenal mass. CONCLUSION: To optimize follow-up of incidental adrenal masses, efforts should be made to assure and prioritize inpatient/emergency department incidental findings and to communicate to the appropriate primary care provider the necessary next steps for evaluation. Further, efforts to increase biochemical testing should be pursued.

Self-monitoring of blood glucose with finger tip versus alternative site sampling: effect on glycemic control in insulin-using patients with type 2 diabetes.

OBJECTIVE: This study compared glycemic control in finger tip versus forearm sampling methods of self-monitoring of blood glucose (SMBG). RESEARCH DESIGN AND METHODS: One hundred seventy-four insulin-using patients with type 2 diabetes were randomized to SMBG using either finger-tip testing (FT) or forearm alternative site testing (AST) and followed up for 7 months. Hemoglobin A1C (HbA1C) was measured at baseline, month 4, and month 7. The study was designed to test the noninferiority of the AST method for the primary end point of change in HbA1C from baseline to month 7. Adherence with the testing schedule and frequency of hypoglycemic episodes were also measured. RESULTS: The FT (n = 85) and AST (n = 89) groups each had significant decreases in mean HbA1C from baseline to month 7 (FT, -0.4 +/- 1.4%, P = 0.008; AST, -0.3 +/- 1.2%, P = 0.045), and noninferiority between groups was demonstrated with a margin of equivalence of 0.5 (P = 0.043). There was no observable difference in HbA1C change between the groups (P = 0.442). Adherence was better in the FT (87%) than the AST (78%) group (P = 0.003), which may have been because of the difficulty some subjects had in obtaining blood samples for AST. The number of hypoglycemic episodes was too small to assess for a difference between groups. CONCLUSIONS: SMBG by the AST, rather than FT, method did not have a detrimental effect on long-term glycemic control in insulin-using patients with type 2 diabetes. Although adherence with testing was expected to be better in the AST group, it was actually better in the FT group.

Effect of Protein Intake on Lean Body Mass in Functionally Limited Older Men: A Randomized Clinical Trial.

Importance: The Institute of Medicine set the recommended dietary allowance (RDA) for protein at 0.8 g/kg/d for the entire adult population. It remains controversial whether protein intake greater than the RDA is needed to maintain protein anabolism in older adults. Objective: To investigate whether increasing protein intake to 1.3 g/kg/d in older adults with physical function limitations and usual protein intake within the RDA improves lean body mass (LBM), muscle performance, physical function, fatigue, and well-being and augments LBM response to a muscle anabolic drug. Design, Setting, and Participants: This randomized clinical trial with a 2 × 2 factorial design was conducted in a research center. A modified intent-to-treat analytic strategy was used. Participants were 92 functionally limited men 65 years or older with usual protein intake less thanor equal to 0.83 g/kg/d within the RDA. The first participant was randomized on September 21, 2011, and the last participant completed the study on January 19, 2017. Interventions: Participants were randomized for 6 months to controlled diets with 0.8 g/kg/d of protein plus placebo, 1.3 g/kg/d of protein plus placebo, 0.8 g/kg/d of protein plus testosterone enanthate (100 mg weekly), or 1.3 g/kg/d of protein plus testosterone. Prespecified energy and protein contents were provided through custom-prepared meals and supplements. Main Outcomes and Measures: The primary outcome was change in LBM. Secondary outcomes were muscle strength, power, physical function, health-related quality of life, fatigue, affect balance, and well-being. Results: Among 92 men (mean [SD] age, 73.0 [5.8] years), the 4 study groups did not differ in baseline characteristics. Changes from baseline in LBM (0.31 kg; 95% CI, -0.46 to 1.08 kg; P = .43) and appendicular (0.04 kg; 95% CI, -0.48 to 0.55 kg; P = .89) and trunk (0.24 kg; 95% CI, -0.17 to 0.66 kg; P = .24) lean mass, as well as muscle strength and power, walking speed and stair-climbing power, health-related quality of life, fatigue, and well-being, did not differ between men assigned to 0.8 vs 1.3 g/kg/d of protein regardless of whether they received testosterone or placebo. Fat mass decreased in participants given higher protein but did not change in those given the RDA: between-group differences were significant (difference, -1.12 kg; 95% CI, -2.04 to -0.21; P = .02). Conclusions and Relevance: Protein intake exceeding the RDA did not increase LBM, muscle performance, physical function, or well-being measures or augment anabolic response to testosterone in older men with physical function limitations whose usual protein intakes were within the RDA. The RDA for protein is sufficient to maintain LBM, and protein intake exceeding the RDA does not promote LBM accretion or augment anabolic response to testosterone. Trial Registration: clinicaltrials.gov Identifier: NCT01275365.

Endogenous sex hormones and cardiovascular disease incidence in men.

BACKGROUND: Data suggest that endogenous sex hormones (testosterone, dehydroepiandrosterone sulfate [DHEA-S], and estradiol) influence cardiovascular disease (CVD) risk factors and vascular function. Yet, prospective studies relating sex hormones to CVD incidence in men have yielded inconsistent results. OBJECTIVE: To examine the association of circulating sex hormone levels and CVD risk in men. DESIGN: Prospective cohort study. SETTING: Community-based study in Framingham, Massachusetts. PARTICIPANTS: 2084 middle-aged white men without CVD at baseline. MEASUREMENTS: The authors used multivariable Cox regression to relate baseline levels of testosterone, DHEA-S, and estradiol to the incidence of CVD (coronary, cerebrovascular, or peripheral vascular disease or heart failure) during 10 years of follow-up. RESULTS: During follow-up, 386 men (18.5%) experienced a first CVD event. After adjustment for baseline standard CVD risk factors, higher estradiol level was associated with lower risk for CVD (hazard ratio per SD increment in log estradiol, 0.90 [95% CI, 0.82 to 0.99]; P = 0.035). The authors observed effect modification by age: Higher estradiol levels were associated with lower CVD risk in older (median age >56 years) men (hazard ratio per SD increment, 0.86 [CI, 0.78 to 0.96]; P = 0.005) but not in younger (median age < or =56 years) men (hazard ratio per SD increment, 1.11 [CI, 0.89 to 1.38]; P = 0.36). The association of higher estradiol level with lower CVD incidence remained robust in time-dependent Cox models (updating standard CVD risk factors during follow-up). Serum testosterone and DHEA-S levels were not statistically significantly associated with incident CVD. LIMITATIONS: Sex hormone levels were measured only at baseline, and the findings may not be generalizable to women and nonwhite people. CONCLUSIONS: In the community-based sample, a higher serum estradiol level was associated with lower risk for CVD events in older men. The findings are consistent with the hypothesis that endogenous estrogen has vasculoprotective influences in men.

Effects of testosterone replacement in men with opioid-induced androgen deficiency: a randomized controlled trial.

Symptomatic androgen deficiency is common in patients taking opioid analgesics, as these drugs potently suppress the hypothalamic-pituitary-gonadal axis. However, the efficacy of testosterone replacement in this setting remains unclear. The objective of this trial was to evaluate the efficacy of testosterone replacement on pain perception and other androgen-dependent outcomes in men with opioid-induced androgen deficiency. We conducted a randomized, double-blind, parallel placebo-controlled trial at an outpatient academic research center. Participants were men aged 18 to 64 years on opioid analgesics for chronic noncancer pain, and total testosterone levels were <350 ng/dL. Participants were randomly assigned to 14 weeks of daily transdermal gel that contained 5 g of testosterone or placebo. Primary outcomes were changes in self-reported clinical pain and objectively assessed pain sensitivity. Sexual function, quality of life, and body composition were also assessed. The mean age was 49 years. The median total and free testosterone levels at baseline were 243 ng/dL and 47 pg/mL and 251 ng/dL and 43 pg/mL in the testosterone and placebo arm, respectively. Of the 84 randomized participants, 65 had follow-up data on efficacy outcomes. Compared with men assigned to the placebo arm, those assigned to testosterone replacement experienced greater improvements in pressure and mechanical hyperalgesia, sexual desire, and role limitation due to emotional problems. Testosterone administration was also associated with an improvement in body composition. There were no between-group differences in changes in self-reported pain. In conclusion, in men with opioid-induced androgen deficiency, testosterone administration improved pain sensitivity, sexual desire, body composition, and aspects of quality of life.

Testosterone dose-response relationships in hysterectomized women with or without oophorectomy: effects on sexual function, body composition, muscle performance and physical function in a randomized trial.

OBJECTIVE: This study aims to determine the dose-dependent effects of testosterone on sexual function, body composition, muscle performance, and physical function in hysterectomized women with or without oophorectomy. METHODS: Seventy-one postmenopausal women who previously underwent hysterectomy with or without oophorectomy and had total testosterone levels less than 31 ng/dL or free testosterone levels less than 3.5 pg/mL received a standardized transdermal estradiol regimen during the 12-week run-in period and were randomized to receive weekly intramuscular injections of placebo or 3, 6.25, 12.5, or 25 mg of testosterone enanthate for 24 weeks. Total and free testosterone levels were measured by liquid chromatography-tandem mass spectrometry and equilibrium dialysis, respectively. The primary outcome was change in sexual function measured by the Brief Index of Sexual Functioning for Women. Secondary outcomes included changes in sexual activity, sexual distress, Derogatis Interview for Sexual Functioning, lean body mass, fat mass, muscle strength and power, and physical function. RESULTS: Seventy-one women were randomized; five groups were similar at baseline. Sixty-two women with analyzable data for the primary outcome were included in the final analysis. The mean on-treatment total testosterone concentrations were 19, 78, 102, 128, and 210 ng/dL in the placebo, 3-mg, 6.25-mg, 12.5-mg, and 25-mg groups, respectively. Changes in composite Brief Index of Sexual Functioning for Women scores, thoughts/desire, arousal, frequency of sexual activity, lean body mass, chest-press power, and loaded stair-climb power were significantly related to increases in free testosterone concentrations; compared with placebo, changes were significantly greater in women assigned to the 25-mg group, but not in women in the lower-dose groups. Sexual activity increased by 2.7 encounters per week in the 25-mg group. The frequency of androgenic adverse events was low. CONCLUSIONS: Testosterone administration in hysterectomized women with or without oophorectomy for 24 weeks was associated with dose and concentration-dependent gains in several domains of sexual function, lean body mass, chest-press power, and loaded stair-climb power. Long-term trials are needed to weigh improvements in these outcomes against potential long-term adverse effects.

Clinical meaningfulness of the changes in muscle performance and physical function associated with testosterone administration in older men with mobility limitation.

CONTEXT: Testosterone in Older Men with Mobility Limitations Trial determined the effects of testosterone on muscle performance and physical function in older men with mobility limitation. Trial's Data and Safety Monitoring Board recommended enrollment cessation due to increased frequency of adverse events in testosterone arm. The changes in muscle performance and physical function were evaluated in relation to participant's perception of change. METHODS: Men aged 65 years and older, with mobility limitation, total testosterone 100-350 ng/dL, or free testosterone less than 50 pg/mL, were randomized to placebo or 10 g testosterone gel daily for 6 months. Primary outcome was leg-press strength. Secondary outcomes included chest-press strength, stair-climb, 40-m walk, muscle mass, physical activity, self-reported function, and fatigue. Proportions of participants exceeding minimally important difference in study arms were compared. RESULTS: Of 209 randomized participants, 165 had follow-up efficacy measures. Mean (SD) age was 74 (5.4) years and short physical performance battery score 7.7 (1.4). Testosterone arm exhibited greater improvements in leg-press strength, chest-press strength and power, and loaded stair-climb than placebo. Compared with placebo, significantly greater proportion of men receiving testosterone improved their leg-press and chest-press strengths (43% vs 18%, p = .01) and stair-climbing power (28% vs 10%, p = .03) more than minimally important difference. Increases in leg-press strength and stair-climbing power were associated with changes in testosterone levels and muscle mass. Physical activity, walking speed, self-reported function, and fatigue did not change. CONCLUSIONS: Testosterone administration in older men with mobility limitation was associated with patient-important improvements in muscle strength and stair-climbing power. Improvements in muscle strength and only some physical function measures should be weighed against the risk of adverse events in this population.

The effects of injected testosterone dose and age on the conversion of testosterone to estradiol and dihydrotestosterone in young and older men.

BACKGROUND: During testosterone (T) therapy, T is partly converted to 17beta-estradiol (E2) and 5alpha-dihydrotestosterone (DHT). Effects of age, testosterone dose, and body composition on total and free E2 and DHT levels are unknown. OBJECTIVE: We evaluated age and dose-related differences in E2 and DHT levels in response to graded doses of testosterone enanthate in young and older men. METHODS: Fifty-one young (aged 19-35 yr) and 52 older (aged 59-75 yr) men completed treatment with monthly injections of a GnRH agonist plus randomly assigned weekly doses of testosterone enanthate (25, 50, 125, 300, or 600 mg) for 5 months. RESULTS: During testosterone administration, total and free E2 levels increased dose-dependently (dose effect, P<0.001) in both young and older men. Total and free E2 levels and E2:T ratios during T administration were higher in older than young men, but age-related differences in free E2 and free E2:T ratios were not significant after adjusting for testosterone levels, percentage fat mass, and SHBG. DHT levels and DHT:T ratios were dose-related but did not differ between young and older men. Mechanistic modeling of free hormone data revealed that the conversions of T to E2 and DHT were both consistent with saturable Michaelis-Menten kinetics. The in vivo Km values were estimated to be 1.83 nm for aromatase and 3.35 nm for 5alpha-reductase, independent of age. The Vmax parameter for E2 was 40% higher in older men than younger men, but Vmax for DHT was not significantly different between age groups. CONCLUSIONS: During im testosterone administration, E2 and DHT levels exhibit saturable increases with dose. The rate of whole body aromatization is higher in older men, partly related to their higher percentage fat mass, SHBG, and testosterone levels.

Expression of cytokeratin 19 in the diagnosis of thyroid papillary carcinoma by quantitative polymerase chain reaction.

OBJECTIVE: To examine cytokeratin 19 (CK19) expression levels by immunostaining for protein and quantitative reverse-transcription polymerase chain reaction (qPCR) for messenger RNA in thyroid surgical specimens from patients with papillary carcinoma (PC) and other types of thyroid lesions. METHODS: A total of 54 randomly selected postoperative thyroid tissue samples were collected for formalin-fixed paraffin-embedded sectioning or flash-frozen total RNA extraction for complementary DNA synthesis (or both). Tissue sections were stained for CK19 expression with use of a specific monoclonal antibody. qPCR was performed on synthesized complementary DNA with sequence-specific primers for human CK19 in conjunction with ribonucleoprotein S18 for normalization. RESULTS: CK19 immunostaining was diffuse and intense in all PC lesions and considerably less in specimens that harbored both Hashimoto thyroiditis (HT) and PC. CK19 immunostaining was mostly absent in areas of multinodular goiter (MNG), with occasional focal staining. HT and Hürthle cell adenoma were essentially negative for CK19 immunostaining, except for weak staining in focal areas. Analysis of CK19 gene expression by qPCR revealed that the PC samples tested (n = 21) had significantly higher levels in comparison with all other groups (P < 0.0001). Furthermore, PC had a 32-fold mean level increase in CK19 expression in comparison with CK19 expression in MNG. Hürthle cell adenoma (n = 5) and HT (n = 7) lesions were similar to MNG in CK19 expression, with some overlap of CK19 between HT and PC. CONCLUSION: The data indicate that expression of CK19 by qPCR is a quantitative method for distinguishing PC lesions from other types of thyroid lesions, in contrast to the more qualitative immunohistochemistry. Moreover, qPCR of CK19 is a valid method that could be used as an ancillary tool in diagnosing thyroid cancer. The expression of CK19 by qPCR may be adopted, in combination with other markers, for molecular definition of the various subtypes of thyroid lesions assessed by fine-needle aspiration biopsy in the preoperative diagnosis of thyroid lesions.