Mifepristone Treatment for Mild Autonomous Cortisol Secretion Due to Adrenal Adenomas: A Pilot Study

Objective: Adrenal incidentalomas are increasingly detected with the widespread use of thoracic and abdominal imaging. The most common secretory syndrome in adrenal nodules is autonomous cortisol secretion (ACS). Recent data show that even mild cortisol excess is associated with adverse outcomes. The glucocorticoid receptor antagonist mifepristone has been used in patients with overt Cushing syndrome and hyperglycemia. The purpose of our study was to determine the effect of mifepristone on metabolic parameters in patients with ACS and concomitant prediabetes or diabetes.Methods: Eight patients with either unilateral or bilateral adrenal nodules with ACS were included in the study. Fasting laboratory tests including glucose and insulin levels to calculate homeostatic model assessment for insulin resistance (HOMA-IR) were performed at baseline and again after either 3 months (3 patients) or 6 months (5 patients) on mifepristone 300 mg daily treatment. Patients also completed several validated surveys on mood and quality of life at baseline and follow-up.Results: There were significant reductions in fasting glucose measurements and insulin resistance as measured by HOMA-IR in the 6 of 8 study patients in whom these measurements were available (P = .03).Conclusion: This pilot study demonstrates that mifepristone treatment of ACS is associated with a significant decrease in fasting glucose and insulin resistance as measured by HOMA-IR scores. Mifepristone treatment of ACS may be considered as a medical option for patients with ACS due to adrenal adenomas with concomitant abnormal glucose parameters in whom surgical removal is not being considered.Abbreviations: ACS = autonomous cortisol secretion; ACTH = adrenocorticotropic hormone; AI = adrenal incidentaloma; DHEAS = dehydroepiandrosterone sulfate; GR = glucocorticoid receptor; HbA1c = hemoglobin A1c; HOMA-IR = homeostatic model assessment for insulin resistance; ODT = overnight dexamethasone suppression test; QoL = quality of life; STAI = state trait anxiety inventory; TSH = thyroid stimulating hormone; UFC = urinary free cortisol     

Evaluation of Body Composition in Patients With and Without Adrenal Tumors and Without Overt Hypersecretory Syndromes

ObjectiveTo compare body composition between patients with autonomous cortisol secretion (ACS), those with nonfunctioning adrenal incidentalomas (NFAIs), and control subjects without adrenal tumors.MethodsA cross-sectional study was performed, incluidng the following 3 groups: patients with ACS (cortisol post–dexamethasone suppression test [DST] >1.8 μg/dL), NFAIs (cortisol post-DST ≤ 1.8 μg/dL), and patients without adrenal tumors (control group). Patients of the 3 groups were matched according to age (±5 years), sex, and body mass index (±5 kg/m²). Body composition was evaluated by bioelectrical impedance and abdominal computed tomography (CT) and urinary steroid profile by gas chromatography mass spectrometry.ResultsThis study enrolled 25 patients with ACS, 24 with NFAIs, and 24 control subjects. Based on CT images, a weak positive correlation between the serum cortisol level post-DST and subcutaneous fat area (r = 0.3, P =.048) was found. As assessed by bioelectrical impedance, lean mass and bone mass were positively correlated with the excretion of total androgens (r = 0.56, P <.001; and r = 0.58, P <.001, respectively); visceral mass was positively correlated with the excretion of glucocorticoid metabolites and total glucocorticoids (r = 0.28, P =.031; and r = 0.42, P =.001, respectively). Based on CT imaging evaluation, a positive correlation was observed between lean mass and androgen metabolites (r = 0.30, P =.036) and between visceral fat area, total fat area, and visceral/total fat area ratio and the excretion of glucocorticoid metabolites (r = 0.34, P =.014; r = 0.29, P =.042; and r = 0.31, P =.170, respectively).ConclusionThe urinary steroid profile observed in adrenal tumors, comprising a low excretion of androgen metabolites and high excretion of glucocorticoid metabolites, is associated with a lower lean mass and bone mass and higher level of visceral mass in patients with adrenal tumors.     

Nonfunctioning Adrenal Incidentalomas are not Clinically Silent: A Longitudinal Cohort Study

Objective: The association between nonfunctioning adrenal incidentalomas (NFAIs) and cardiometabolic diseases remains controversial. This retrospective cohort study investigated whether NFAIs are related with prevalent and incident cardiometabolic diseases.Methods: This study included 154 patients with biochemically confirmed NFAIs and 1:3 age and sex-matched controls without adrenal incidentalomas (n = 462) among subjects who underwent abdominal computed tomography at a single healthcare center in 2003–2012. Electronic medical records were reviewed for comorbidities at baseline and during a mean follow-up of 7.5 years. The logistic regression analysis for prevalent cardiometabolic diseases and the survival analysis for incident cardiometabolic diseases were performed.Results: The subjects were 55.7 ± 8.8 years of age and predominantly male (73.1%). The NFAI group had a higher body mass index compared to the age and sex-matched control group (25.1 ± 2.8 vs. 24.0 ± 2.8 kg/m²; P<.001). In a cross-sectional design, covariate-adjusted logistic regression showed significantly higher odds ratios (ORs) for diabetes mellitus and hypertension in the NFAI group (adjusted OR [95% confidence interval [CI]], 1.89 [1.17 to 3.06] and 2.26 [1.47 to 3.50], respectively). The NFAI group had a 2-fold higher risk of insulin resistance (adjusted ORs [95% CI], 2.03 [1.06 to 3.90]). Moreover, NFAI subjects with diabetes mellitus had a greater increase in size of adrenal lesions than those without diabetes mellitus (3.4 ± 5.5 vs. 1.4 ± 5.5 mm; P =.048). However, in the survival analysis, the incidence of any cardiometabolic diseases did not differ between the NFAI and control groups.Conclusion: NFAIs are related to prevalent diabetes mellitus or hypertension in our cross-sectional study. However, the presence of NFAIs did not affect the development of cardiometabolic diseases.Abbreviations: ACTH = adrenocorticotropic hormone; AI = adrenal incidentaloma; BMI = body mass index; CI = confidence interval; CT = computed tomography; HbA1c = hemoglobin A1c; HOMA-IR = homeostasis model assessment of insulin resistance; HU = Hounsfield units; MACE = mild autonomous cortisol excess; NFAI = nonfunctioning adrenal incidentaloma; OR = odds ratio     

Postsurgical Recurrent Cushing Disease: Clinical Benefit of Early Intervention in Patients with Normal Urinary Free Cortisol

Objective: To assess the performance of biochemical markers in the detection of recurrent Cushing disease (CD), as well as the potential benefit of early intervention in recurrent CD patients with elevated late-night salivary cortisol (LNSC) and normal urinary free cortisol (UFC).Methods: The design was a single-center, retrospective chart review. Patients treated by the authors from 2008–2013 were included. Recurrence was defined by postsurgical remission of CD with subsequent abnormal LNSC, UFC, or dexamethasone suppression test (DST).Results: We identified 15 patients with postsurgical recurrent CD after initial remission; all but one underwent testing with LNSC, DST, and UFC. Although 12 of 15 patients had normal UFC at time of recurrence, DST was abnormal in 11 of 15, and all 14 patients with LNSC results had ≥1 elevated measurement. Nine patients (7 with normal UFC) showed radiologic evidence of a pituitary tumor at time of recurrence. Among the 14 patients with available follow-up data, 12 have demonstrated significant improvement since receiving treatment. Five patients underwent repeat pituitary surgery and 4 achieved clinical and biochemical remission. Eight patients received mifepristone or cabergoline, and 6 showed clinical and/or biochemical improvement. Three patients (2 with prior mifepristone) underwent bilateral adrenalectomy and 2 demonstrated significant clinical improvements.Conclusion: LNSC is more sensitive than UFC or DST for detection of CD recurrence. Prompt intervention when LNSC is elevated, despite normal UFC, may yield significant clinical benefit for many patients with CD. Early treatment for patients with recurrent CD should be prospectively evaluated, utilizing LNSC elevation as an early biochemical marker.Abbreviations:ACTH = adrenocorticotropic hormoneCD = Cushing diseaseCS = Cushing syndromeCV = coefficient of variationDST = dexamethasone suppression testIPSS = inferior petrosal sinus samplingLNSC = late-night salivary cortisolQoL = quality of lifeTSS = transsphenoidal adenoma resectionUFC = urinary free cortisol     

Topiramate as a Cause of False Positive in the Overnight 1-Mg Dexamethasone Suppression Test

ObjectiveTo describe that topiramate may cause a false positive in an overnight 1-mg dexamethasone suppression test (DST) for hypercortisolism screening.MethodsWe present a case in which topiramate induced dexamethasone metabolism, leading to a false positive on the DST.ResultsA 44-year-old female with an incidentally found adenoma in the right adrenal gland underwent a DST for hypercortisolism screening. The patient was taking topiramate prescribed by a psychiatrist for an affective disorder, and insufficient cortisol suppression (11.9 mcg/ dL) was observed. Her free cortisol in 24-hour urine was normal, and insufficient suppression was established in a second determination (9.3 mcg/dL). Finally, her psychiatrist switched her treatment from topiramate to bupropion, and the measurements were repeated. When she was not taking topiramate, correct suppression with 1 mg of dexamethasone was obtained (1.7 mcg/dL), and her free cortisol in 24-hour urine was again normal, thereby excluding the presence of hypercortisolism. On reviewing the literature, topiramate was not found to have been previously described as a cause of a false positive on DST, but it was proposed as a cause of hypoadrenalism in a patient taking oral corticosteroid replacement due to its capacity to induce dexamethasone metabolism.ConclusionTopiramate treatment may well be a cause of false positives in DSTs, and its presence should be taken into consideration when screening for hypercortisolism. (Endocr Pract. 2014;20:e116-e118)     

Morning Serum Cortisol Level After Transsphenoidal Surgery for Pituitary Adenoma Predicts Hypothalamic-Pituitary-Adrenal Function Despite Intraoperative Dexamethasone Use

Objective: Perioperative glucocorticoid (GC) is rarely needed in patients undergoing transsphenoidal surgery (TSS). We instituted a steroid-sparing protocol in the settings of intraoperative dexamethasone use. We evaluated the safety of using a cut off cortisol level of 14 μg/dL on postoperative day (POD)-1 and -6 after dexamethasone use during the surgery. We also analyzed the efficacy of serial morning cortisol levels for weaning GC replacement.Methods: The charts of 48 adult patients who received dexamethasone 4 mg intraoperatively were reviewed. Morning cortisol levels were measured on POD-1. Patients with cortisol ≥14 μg/dL were discharged without CG replacement. Morning cortisol level was checked routinely on POD-6, and GC replacement was initiated when the level was <14 μg/dL. Serial cortisol levels were measured in patients requiring GC after the first postoperative week.Results: Overall, 67% patients had POD-1 cortisol ≥14 μg/dL and did not require GC on discharge. After POD-6, 83% of patients were not on GC replacement. A cosyntropin stimulation testing (CST) was only performed in 3 patients. There were no hospital admissions for adrenal crisis during the postoperative period.Conclusion: A steroid-sparing protocol with POD-1 and -6 morning cortisol levels can be safely and effectively used in the settings of intraoperative dexamethasone administration. It leads to avoidance of GC in more than two-thirds of patients on discharge and more than 80% of patients after the first postoperative week. We found that dynamic adrenal testing could be omitted in the majority of patients by using serial morning cortisol levels to assess the hypothalamic-pituitary-adrenal (HPA) axis.Abbreviations: ACTH = adrenocorticotropic hormone AI = adrenal insufficiency CST = cosyntropin stimulation test ECLIA = electrochemiluminescence immunoassay GC = glucocorticoid HPA = hypothalamic-pituitary-adrenal ITT = insulin tolerance test POD = postoperative day TSS = transsphenoidal surgery     

Identifying Probable Diabetes Mellitus Among Hispanics/Latinos from Four U.S. Cities: Findings from the Hispanic Community Health Study/Study of Latinos

Objective: The aim of this study was to compare the ability of American Diabetes Association (ADA) diagnostic criteria to identify U.S. Hispanics/Latinos from diverse heritage groups with probable diabetes mellitus and assess cardiovascular risk factor correlates of those criteria.Methods: Cross-sectional analysis of data from 15,507 adults from 6 Hispanic/Latino heritage groups, enrolled in the Hispanic Community Health Study/Study of Latinos. The prevalence of probable diabetes mellitus was estimated using individual or combinations of ADA-defined cut points. The sensitivity and specificity of these criteria at identifying diabetes mellitus from ADA-defined prediabetes and normoglycemia were evaluated. Prevalence ratios of hypertension, abnormal lipids, and elevated urinary albumin-creatinine ratio for unrecognized diabetes mellitus—versus prediabetes and normoglycemia—were calculated.Results: Among Hispanics/Latinos (mean age, 43 years) with diabetes mellitus, 39.4% met laboratory test criteria for probable diabetes, and the prevalence varied by heritage group. Using the oral glucose tolerance test as the gold standard, the sensitivity of fasting plasma glucose (FPG) and hemoglobin A1c—alone or in combination—was low (18, 23, and 33%, respectively) at identifying probable diabetes mellitus. Individuals who met any criterion for probable diabetes mellitus had significantly higher (P<.05) prevalence of most cardiovascular risk factors than those with normoglycemia or prediabetes, and this association was not modified by Hispanic/Latino heritage group.Conclusion: FPG and hemoglobin A1c are not sensitive (but are highly specific) at detecting probable diabetes mellitus among Hispanics/Latinos, independent of heritage group. Assessing cardiovascular risk factors at diagnosis might prompt multitarget interventions and reduce health complications in this young population.Abbreviations:2hPG = 2-hour post–glucose load plasma glucoseADA = American Diabetes AssociationBMI = body mass indexCV = cardiovascularFPG = fasting plasma glucoseHbA1c = hemoglobin A1cHCHS/SOL = Hispanic Community Health Study/Study of LatinosHDL-C = high-density-lipoprotein cholesterolNGT = normal glucose toleranceNHANES = National Health and Nutrition Examination SurveyOGTT = oral glucose tolerance testTG = triglycerideUACR = urine albumin-creatinine ratio     

The Low-Dose Acth Stimulation Test: is 30 Minutes Long Enough?

Objective: Controversy persists regarding the use of the low-dose adrenocorticotropic hormone (ACTH) stimulation test (LDST) for the diagnosis of adrenal insufficiency (AI) and optimal test result interpretation. However, many centers are now using the LDST to assess cortisol secretion adequacy, and some only use a 30-minute cortisol level to determine adrenal sufficiency or AI. This study examined both 30- and 60-minute cortisol levels to assess whether the interpretation of the test was affected when both cortisol levels were taken into consideration.Methods: Data were obtained by retrospective chart review from a single pediatric endocrinology unit over a 7-year period. We identified 82 patients who completed the LDST. Their mean age was 11.7 years, and 37% were female. Cortisol levels were evaluated at baseline and 30 and 60 minutes after cosyntropin administration. A cutoff value ≥18 μg/dL was used to define adrenal sufficiency.Results: We found that 54% of patients reached peak cortisol levels at 60 minutes, and 11 patients who did not pass the test at 30 minutes did so at 60 minutes. The only predictive characteristic was weight status; overweight and obese individuals tended to peak at 30 minutes, and normal and underweight individuals tended to peak at 60 minutes.Conclusion: Although further studies are necessary to confirm our findings, it appears that measuring cortisol both 30 and 60 minutes following synthetic ACTH administration may be necessary to avoid overdiagnosing AI.Abbreviations: ACTH = adrenocorticotropic hormone AI = adrenal insufficiency BMI = body mass index LDST = low-dose ACTH stimulation test MRI = magnetic resonance imaging     

Serum Morning Cortisol as A Screening Test for Adrenal Insufficiency

Objective: To evaluate the performance of morning serum cortisol (MSC) compared to a 10 mg adrenocortico-tropic hormone (ACTH) stimulation test in the diagnosis of adrenal insufficiency (AI).Methods: A retrospective, cross-sectional analysis of ACTH stimulation tests were conducted. From a total of 312 potentially eligible ACTH stimulation tests, 306 met the inclusion criteria. The population was randomized into 2 groups: test (n = 159) and validation (n = 147). In the test group, the receiver operating characteristics curve test evaluated the diagnostic performance of MSC.Results: A subnormal cortisol response to ACTH was found in 25.8% of the test group. The area under the curve values of MSC to predict AI at +30 minutes, +60 minutes, or at maximal cortisol response were 0.874, 0.897, and 0.925 (95% confidence interval &lsqb;CI] 0.81 to 0.92, 0.83 to 0.93, and 0.87 to 0.96). The Youden index was 234.2 mmol/L with a sensitivity of 83.3% (95% CI 65.2 to 94.3%), and a specificity of 89.1% (95% CI 82.4 to 93.9%). Positive and negative predictive values were 64.1% (95% CI 47.1 to 78.8%) and 95.8% (95% CI 90.5 to 98.6%). There was no difference in age, gender, AI prevalence, or mean serum cortisol at +30 or +60 minutes in the validation group; however, a lower mean MSC value was found. Lower sensitivity and specificity values (88.3% and 60%, respectively) were found for the 234.2 mmol/L cutoff value.Conclusion: This study supports the role of MSC as a first-step diagnostic test in patients with clinically suspected AI. The short stimulation test could be omitted in almost half of the cases. Prospective and longitudinal studies to reproduce and confirm the cutoff values proposed are warranted.Abbreviations: ACTH = adrenocorticotropic hormone; AI = adrenal insufficiency; AUC = area under the curve; CI = confidence interval; HPA = hypothalamic pituitary adrenal; ITT = insulin tolerance test; MSC = morning serum cortisol     

The Association Between First-Degree Family History of Diabetes and Metabolic Syndrome

Objective: Because they share genetic and environmental factors with patients with diabetes, the first-degree relatives (FDRs) of patients with diabetes exhibit early signs of metabolic abnormalities. The present study aimed to investigate the correlation between family history of diabetes in FDRs and metabolic syndrome (MS), as well as changes in related risk factors.Methods: The present study population was a part of the baseline survey from the REACTION study. FDRs were defined as individuals having one or more FDRs with diabetes. MS and its components were defined according to the 2007 Joint Committee for Developing Chinese Guidelines.Results: A total of 2,692 individuals with an average age of 57.24 ± 8.35 years were enrolled in the present study. The prevalence of MS in FDRs (36.44%) was significantly higher than that in non-FDRs (25.28%; P<.001). FDRs accounted for 13.37%, 14.32%, 16.67%, 22.47%, 23.53%, and 25.58% of subjects with 0 to 5 MS components, showing an increasing trend (P for trend <.001). After adjusting for gender and age, partial correlation analyses showed significant associations of first-degree family history of diabetes with MS-related indexes (all P<.05). After adjusting for gender, age, lifestyle habits, and total metabolic traits, the first-degree family history of diabetes remained an independent factor that was positively associated with MS (odds ratio, 1.765; P<.001).Conclusion: A first-degree family history of diabetes predisposes individuals to developing MS and stands out as an independent risk factor for MS even without considering the subsequent effects of hyperglycemia.Abbreviations: BMI = body mass index; DBP = diastolic blood pressure; FDR = first-degree relative; FPG = fasting plasma glucose; HbA1c = glycated hemoglobin A1c; HDL-c = high-density-lipoprotein cholesterol; LDL-c = low-density-lipoprotein cholesterol; MAP = mean arterial pressure; MS = metabolic syndrome; OR = odds ratio; SBP = systolic blood pressure; TC = total cholesterol; TG = triglyceride; WC = waist circumference; WHR = waist-to-hip ratio; 2hPG = 2-hour plasma glucose     

The Classic and Nonclassic Concenital Adrenal Hyperplasias

Objective: The American Association of Clinical Endocrinologists Adrenal Scientific Committee has developed a series of articles to update members on the genetics of adrenal diseases.Methods: Case presentation, discussion of literature, table, and bullet point conclusions.Results: The congenital adrenal hyperplasia (CAH) syndromes are autosomal recessive defects in cortisol biosynthesis. The phenotype of each CAH patient depends on the defective enzyme and the severity of the defect. Clinical manifestations derive from both failure to synthesize hormones distal to the enzymatic block, as well as consequences from cortisol precursor accumulation proximal to the block, often with diversion to other biologically active steroids. The most common form of CAH is 21-hydroxylase deficiency, which occurs in the classic form in 1 in 16,000 newborns and in a milder or nonclassic form in at least 1 in 1,000 people.Conclusion: This article reviews the various forms of CAH and pitfalls in the diagnosis and treatment of these conditions.Abbreviations: 11OHD = 11-hydroxylase deficiency 17OHD = 17-hydroxylase deficiency 17OHP = 17-hydroxyprogesterone 21OHD = 21-hydroxylase deficiency 3βHSD = 3β-hydroxysteroid dehydrogenase CAH = congenital adrenal hyperplasia CST = cosyntropin stimulation test CYP17A1 = cytochrome P450 17A1 (steroid 17-hydroxylase/17,20-lyase) DHEAS = dehydroepiandrosterone sulfate DSD = disorder of sex development LCAH = lipoid congenital adrenal hyperplasia NBS = newborn screening NCAH = nonclassic CAH PCOS = polycystic ovary syndrome PORD = P450-oxidoreductase deficiency     

Risk Factors for Hearing Impairment in Type 1 Diabetes

Objective: Studies have demonstrated that glycated hemoglobin (HbA1c) is a significant predictor of hearing impairment in type 1 diabetes. We identified additional factors associated with hearing impairment in participants with type 1 diabetes from the Diabetes Control and Complications Trial and its observational follow-up, the Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study.Methods: A total of 1,150 DCCT/EDIC participants were recruited for the Hearing Study. A medical history, physical measurements, and a self-administered hearing questionnaire were obtained. Audiometry was performed by study-certified personnel and assessed centrally. Logistic regression models assessed the association of risk factors and comorbidities with speech- and high-frequency hearing impairment.Results: Mean age was 55 ± 7 years, duration of diabetes 34 ± 5 years, and DCCT/EDIC HbA1c 7.9 ± 0.9% (63 mmol/mol). In multivariable models, higher odds of speech-frequency impairment were significantly associated with older age, higher HbA1c, history of noise exposure, male sex, and higher triglycerides. Higher odds of high-frequency impairment were associated with older age, male sex, history of noise exposure, higher skin intrinsic florescence (SIF) as a marker of tissue glycation, higher HbA1c, nonprofessional/nontechnical occupations, sedentary activity, and lower low-density-lipoprotein cholesterol. Among participants who previously completed computed tomography and carotid ultrasonography, coronary artery calcification (CAC) >0 and carotid intima-medial thickness were significantly associated with high-but not speech-frequency impairment.Conclusion: Consistent with previous reports, male sex, age, several metabolic factors, and noise exposure are independently associated with hearing impairment. The association with SIF further emphasizes the importance of glycemia—as a modifiable risk factor—over time. In addition, the macrovascular contribution of CAC is novel and important.Abbreviations: AER = albumin excretion rate; CAC = coronary artery calcification; CVD = cardiovascular disease; DCCT/EDIC = Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications; eGFR = estimated glomerular filtration rate; ETDRS = Early Treatment Diabetic Retinopathy Study; HbA1c = glycated hemoglobin; HDL = high-density lipoprotein; IMT = intima-media thickness; LDL = low-density lipoprotein; NHANES = National Health and Nutrition Examination Survey; OR = odds ratio; SIF = skin intrinsic fluorescence; T1D = type 1 diabetes     

Genetic Basis of Bilateral Macronodular Hyperplasia

Objective: To review the genetic basis of bilateral macronodular hyperplasia (BMAH).Methods: Case presentation, review of literature, table, and bullet point conclusions.Results: BMAH, also known as adrenocorticotropic hormone (ACTH)-independent macronodular hyperplasia (AIMH), can cause Cushing syndrome or mild hypercortisolism. Recent studies have demonstrated that hyperplastic tissue reproduces ectopic ACTH, implying that BMAH is the more proper term, as the syndrome is not ACTH-independent. BMAH was thought to be sporadic, but recent data have shown that there is likely a genetic component in the majority of cases. Mutations in ARMC5, a putative suppressor gene, have been found in many familial cases of BMAH and are thought to be responsible for the disorder. As these nodules inefficiently produce cortisol, large nodules are required to produce a clinical syndrome. ARMC5 likely requires a second somatic mutation to become clinically apparent. Clinical manifestations are not generally noted until the fifth to sixth decades of life.Conclusion: BMAH is an underrecognized genetic condition that can lead to Cushing syndrome and should be screened for in patients and susceptible family members.Abbreviations: ACTH = adrenocorticotropic hormone AIMAH = ACTH-independent macronodular adrenal hyperplasia ARMC5 = armadillo-repeat containing 5 BMAH = bilateral macronodular adrenal hyperplasia CAH = congenital adrenal hyperplasia CT = computed tomography MEN1 = multiple endocrine neoplasia 1 UFC = urinary free cortisol     

EXOGENOUS TESTOSTERONE DOES NOT INDUCE OR EXACERBATE THE METABOLIC FEATURES ASSOCIATED WITH PCOS AMONG TRANSGENDER MEN

Objective: Polycystic ovary syndrome (PCOS) is a complex condition which can include menstrual irregularity, metabolic derangement, and increased androgen levels. The mechanism of PCOS is unknown. Some suggest that excess production of androgens by the ovaries may cause or exacerbate the metabolic findings. The purpose of this study was to assess the role of increased testosterone on metabolic parameters for individuals presumed to be chromosomally female by examination of these parameters in hormone-treated transgender men.Methods: In 2015 and 2016, we asked all transgender men who visited the Endocrinology Clinic at Boston Medical Center treated with testosterone for consent for a retrospective anonymous chart review. Of the 36 men, 34 agreed (94%). Serum metabolic factors and body mass index (BMI) levels for each patient were graphed over time, from initiation of therapy through 6 years of treatment. Bivariate analyses were conducted to analyze the impact of added testosterone.Results: Regressions measuring the impact of testosterone demonstrated no significant changes in levels of glycated hemoglobin (HbA1c), triglycerides, or low-density-lipoprotein cholesterol. There was a statistically significant decrease in BMI with increasing testosterone. There was also a statistically significant decrease in high-density lipoprotein levels upon initiation of testosterone therapy.Conclusion: Testosterone therapy in transgender men across a wide range of doses and over many years did not result in the dyslipidemia or abnormalities in HbA1c seen with PCOS. Instead, treatment of transgender men with testosterone resulted only in a shift of metabolic biomarkers toward the average physiologic male body.Abbreviations: BMI = body mass index; HbA1c = glycated hemoglobin; HDL = high-density lipoprotein; LDL = low-density lipoprotein; PCOS = polycystic ovary syndrome     

Is Biochemical Assessment of Pheochromocytoma Necessary in Adrenal Incidentalomas with Magnetic Resonance Imaging Features not Suggestive of Pheochromocytoma?

Objective: Currently, it is unclear whether pheochromocytomas can be ruled out based on low intensity on T2-weighted sequences and signal loss on out-of-phase magnetic resonance imaging (MRI) sequences. Hence, in this study, we investigated whether biochemical screening for pheochromocytoma in patients with adrenal incidentalomas (AIs) showing MRI features not suggesting pheochromocytoma would prove beneficial.Methods: We performed MRI for 300 AIs in 278 consecutive patients. All patients were screened for pheochromocytoma with plasma metanephrine and normetanephrine. Patients with high plasma levels of metanephrine and/or normetanephrine were also assessed for pheochromocytoma by urinary metanephrines.Results: Hyperintensity was detected on T2-weighted MRI sequences in 28 (9.3%) of the 300 AIs. Among these 28 incidentalomas, pheochromocytoma was diagnosed in 13 (46.4%) of the cases by histopathologic analysis. Hyperintensity on T2-weighted MRI was significantly higher in pheochromocytomas compared to the remaining AIs (P<.001). All 13 pheochromocytomas were characterized by hyperintensity on T2-weighted sequences and the absence of signal loss on out-of-phase MRI sequences. Pheochromocytoma was not detected in any of the 272 AIs that appeared hypointense or isointense on T2-weighted MRI sequences or in the 250 cases with signal loss on out-of-phase sequences.Conclusion: The results of this study suggest that AIs that appear hypointense or isointense on T2-weighted MRI sequences and those with signal loss on out-of-phase sequences may not require routine biochemical screening for pheochromocytoma. Further studies including a higher number of pheochromocytomas are required to confirm our results.Abbreviations:AI = adrenal incidentalomaCT = computed tomographyMRI = magnetic resonance imaging     

Performance of Free Versus Total Cortisol Following Cosyntropin Stimulation Testing in an Outpatient Setting

Objective: Free cortisol (FC) is potentially superior to total cortisol (TC) measurements in selected clinical settings; however, the advantages of uniform use of FC in outpatient settings are unclear. The objectives of this study were to describe the dynamic response of FC during cosyntropin stimulation testing (CST) compared to TC and to determine the rates of discordance.Methods: This is a cross-sectional study of 295 stable patients who underwent CST in an outpatient Endocrine Testing Center. The main outcome measures were TC and FC measurements during CST.Results: The mean age of the 295 subjects was 49.1 (16.9) years. Of 218 females, 43 were taking estrogen therapy (ET) at the time of testing. Adrenal insufficiency (AI) was diagnosed in 41/295 (14%) patients. The FC concentrations were associated with TC concentrations at baseline (R² = 0.77, P<.001), 30 minutes (R² = 0.87, P<.001), and 60 minutes (R² = 0.90, P<.001). The FC cutoffs for AI were 873 and 1,170 ng/dL at 30 and 60 minutes, respectively. The FC had a more pronounced fold change from baseline to peak than TC (median 3.2 vs. 1.7, P<.001). Both TC and FC at baseline were higher in females on ET compared to those who were not and to males; however, peak TC and FC values were similar. In 3/43 females on ET, FC, and TC results were discordant (P = .003).Conclusion: We report 99% concordance of TC and FC measurements in a large outpatient cohort. The discordant rates were high in females treated with ET (7%). The FC measurements during CST in females on ET may provide a more rapid and accurate diagnosis of AI.Abbreviations:ACTH = adrenocorticotropic hormoneAI = adrenal insufficiencyCBG = corticosteroid-binding proteinCST = cosyntropin stimulation testingET = estrogen therapyFC = free cortisolfΔ = fold changeROC = receiver operating characteristicTC = total cortisol     

Utility of a Glucocorticoid Sparing Strategy in the Management of Patients Following Transsphenoidal Surgery

Objective: Following transsphenoidal surgery (TSS), it is important to assess for and manage adrenal insufficiency (AI). The goal of this study is to assess the efficacy and safety of a glucocorticoid (GC) sparing protocol to limit GC exposure in patients undergoing TSS.Methods: Adult patients undergoing TSS (excluding Cushing disease) with adequate adrenal function prior to surgery underwent TSS without perioperative GC coverage. Following TSS, daily morning fasting serum cortisol levels were tested. GCs were administered at stress doses for serum cortisol <5 mcg/dL, between 5 and 12 mcg/dL in the presence of clinically significant symptoms of AI, or >12 mcg/dL with severe headache, nausea or vomiting, fatigue, anorexia, or hyponatremia. The primary endpoint was the use of GCs in the immediate postoperative period.Results: Of 178 subjects, GCs were administered to 80 (45%) patients for the following indications: 31.3% for serum cortisol <5 mcg/dL; 36.3% for cortisol between 5 and 12 mcg/dL accompanied by symptoms or signs of AI; 8.8% for moderate to severe postoperative hyponatremia; and 7.5% for severe headache, nausea and vomiting, fatigue, or anorexia with cortisol >12 mcg/dL. Logistic regression analysis showed that longer length of hospital stay (odds ratio [OR] 1.22, confidence interval [CI] 1.02–1.45) and the presence of new postoperative anterior pituitary hormone deficiency (OR 3.3, CI 1.26–8.67) were associated with postoperative GC use. By 12 weeks, only 14% of subjects remained on GCs. There were no adverse events related to withholding GCs.Conclusion: Our protocol for managing GC replacement is both safe and effective for limiting GC exposure in patients undergoing TSS.Abbreviations:AI = adrenal insufficiencyCI = confidence intervalFSH = follicle-stimulating hormoneGC = glucocorticoidGH = growth hormoneIGF-1 = insulin-like growth factor-1IV = intravenousLH = luteinizing hormoneLOS = length of hospital stayOR = odds ratioTSS = transsphenoidal surgery     

Adrenal Incidentalomas, 2003 to 2005: Experience After Publication of the National Institutes of Health Consensus Statement

ObjectiveTo determine the clinical outcomes and follow-up imaging characteristics for incidentally discovered adrenal nodules at a large metropolitan health care center, as well as compliance with National Institutes of Health guidelines for the evaluation of these lesions.MethodsBetween October 2003 and June 2005, computed tomographic (CT) scanning performed at Harvard Vanguard Medical Associates detected 165 adrenal nodules (incidentalomas) in 129 patients without extra-adrenal malignant lesions or evidence of adrenal hyperfunction. Nodule characteristics, including size at baseline, change in size at follow-up, CT attenuation values, biochemical data, and clinical outcomes, were analyzed.ResultsOf the 165 adrenal incidentalomas, 96% were smaller than 4 cm. When attenuation values were determined, 65% were low (< 10 Housfield units). Ninetyeight patients (76%) with 142 nodules (86% of all incidentalomas) had at least 1 follow-up CT scan. Of these 142 lesions, 20 (14%) changed significantly in size (grew or became smaller by 0.5 cm or more). Growth was detected within 12 months in 5 of the 7 lesions (71%) that grew. For 95% of patients, the adrenal nodule did not necessitate intervention, including change in medication or surgical treatment. Biochemical studies for adrenal hyperfunction were done in 39 of the overall 129 patients (30%), but in only 20 of 109 patients (18%) not seen by endocrinologists.ConclusionMost adrenal incidentalomas are benign, nonfunctional tumors. Growth typically occurs within 12 months after detection. Despite the 2002 National Institutes of Health guidelines, 82% of patients at our medical center with adrenal nodules who were not seen by endocrinologists did not have hormonal testing. More physician education about the evaluation of incidentalomas should be provided, and prospective studies to establish the appropriate duration of follow-up should be conducted. (Endocr Pract. 2008;14:279-284)     

Association Of Peripheral 5-Hydroxyindole-3-Acetic Acid,A Serotonin Derivative,with Metabolic Syndrome and Low-Grade Inflammation

Objective: The constellation of metabolic abnormalities seen in metabolic syndrome (MetS) has been linked to atherosclerosis and adverse cardiovascular outcomes due to heightened inflammation. Accumulating evidence suggests that peripheral 5-hydroxyindole-3-acetic acid (5-HIAA), the derivative end-product of serotonin (5-HT), might be involved in the pathogenesis of obesity, and abnormal lipid and glucose metabolism. We examined the association between serum 5-HIAA concentrations and MetS and also highly sensitive C-reactive protein (hsCRP).Methods: We assessed 180 healthy adults (110 males and 70 females) in a cross-sectional setting. Anthropometric indices and blood pressure were measured, as were laboratory parameters including fasting 5-HIAA concentrations. The associations between 5-HIAA and individual components of MetS, as well as MetS as a single entity, were investigated with bivariate correlation and logistic regression analyses.Results: Eighty-nine individuals (49.4%) were diagnosed with MetS. Significant correlations were found between 5-HIAA concentrations and age (r = 0.184), waist circumference (r = 0.415), high-density lipoprotein (HDL) cholesterol (r = -0.148), systolic blood pressure (r = 0.374), diastolic blood pressure (r = 0.355), homeostasis model assessment of insulin resistance (r = 0.201), and hsCRP (r = 0.453) were found (P<.05 in all tests). In logistic regression, 5-HIAA was significantly associated with 4 MetS components including central obesity, raised triglycerides, raised blood pressure, and raised fasting plasma glucose (FPG) (P<.05). Moreover, 5-HIAA was a predictor of MetS as a single entity, and the relationship persisted after adjusting for hsCRP (odds ratio [OR] = 4.41, 95% confidence interval [CI]: 2.58-7.67, P<.001).Conclusion: Elevated concentrations of 5-HIAA are seen in individuals with MetS. Increased 5-HIAA is also associated with hsCRP, a marker of chronic lowgrade inflammation underlying MetS.Abbreviations: BMI = body mass index CI = confidence interval FI = fasting insulin FPG = fasting plasma glucose HbA1c = glycated hemoglobin HDL = high-density lipoprotein 5-HIAA = 5-hydroxyindole-3-acetic acid 5-HT = 5-hydroxytryptamine HOMA-IR = homeostatic model assessment of insulin resistance hsCRP = highly sensitive C-reactive protein LDL = low-density lipoprotein MetS = metabolic syndrome OR = odds ratio     

A Cross-Sectional Study of the Association between the 1-Hour Oral Glucose Tolerance Test and the Metabolic Syndrome in a High-Risk Sample with Impaired Fasting Glucose

Objective: The aim of this study was to evaluate the association between the 1-hour oral glucose tolerance test (OGTT) (≥155 mg/dL) and metabolic syndrome (MS) in a sample with previous impaired fasting glucose (IFG).Methods: Three hundred and twenty four Peruvian subjects with a history of IFG ≥100 mg/dL were selected for a cross-sectional study. They underwent a 75 g OGTT and were assigned to different groups according to the result. We evaluated the association between 1-hour OGTT and MS.Results: The mean age was 56.5 ± 12.6 years and 191 (61.5%) were female. During the OGTT, we found 28 (8.6%) subjects with diabetes, 74 (22.8%) with IGT, and 222 (68.5%) with a normal glucose tolerance test with a 2-hour glucose <140 mg/dL (NGT). In the NGT group, 124 (38.3%) had 1-hour glucose levels <155 mg/dL, while 98 (30.2%) had 1-hour glucose levels ≥155 mg/dL. Evaluating the association between the 1-hour value in the OGTT and MS, we found that subjects with a 1-hour glucose ≥155 mg/dL were more than twice as likely to have MS as those with a 1-hour glucose <155 mg/dL (odds ratio = 2.64, 95% confidence interval: 1.52 to 4.57). In addition, body mass index, fasting glycemia, triglycerides, and waist circumferences were significantly higher in subjects with 1-hour glucose levels ≥155 mg/dL compared to those with 1-hour glucose levels <155 mg/dL (P<.05).Conclusion: Among subjects with IFG, performing an OGTT was helpful to identify subjects with 1-hour glucose levels ≥155 mg/dL and NGT who were significantly more likely to have MS and a worse cardiometabolic risk profile.Abbreviations: AST = aspartate aminotransferase; BMI = body mass index; CI = confidence interval; IFG = impaired fasting glucose; IGT = impaired glucose tolerance; LDL = low-density lipoprotein; MS = metabolic syndrome; NGT = normal glucose tolerance; OGTT = oral glucose tolerance test; OR = odds ratio; T2DM = type 2 diabetes; TG = triglycerides