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    Baseline Demographic and Clinical Characteristics of Patients with Adrenal Incidentaloma from a Single Center in China: A Survey. Li Lele,Yang Guoqing,Zhao Ling,Dou Jingtao,Gu Weijun,Lv Zhaohui,Lu Juming,Mu Yiming International journal of endocrinology AIM:To investigate the clinical and endocrinological characteristics of patients with adrenal incidentaloma (AI). MATERIALS AND METHODS:This retrospective study enrolled 1941 AI patients hospitalized at the Department of Endocrinology, Chinese PLA General Hospital, Beijing, China, between January 1997 and December 2016. The patient gender, age at visits, imaging features, functional status, and histological results were analyzed. RESULTS:Of the 1941 patients, 984 (50.70%) were men. The median age was 52 years (interquartile range: 44-69 years). 140 cases had bilateral AI. Endocrine evaluation showed that 1411 (72.69%) patients had nonfunctional tumor, 152 (7.83%) had subclinical Cushing syndrome (SCS), and 82 (4.33%) had primary hyperaldosteronism. A total of 925 patients underwent operation for removal of 496 cortical adenomas (53.62%), 15 adrenal cortical carcinomas (1.62%), and 172 pheochromocytomas (18.59%). The bilateral group had a higher proportion of SCS (18.57% versus 7.10%, < 0.001, = 0.006). A mass size of 46 mm was of great value in distinguishing malignant tumors from the benign tumors, with sensitivity of 88.2% and specificity of 95.5%. CONCLUSIONS:We reported the baseline demographic and clinical characteristics of patients with AI in a large series from a single center in China. 10.1155/2017/3093290
    Increased mortality in patients with adrenal incidentalomas and autonomous cortisol secretion: a 13-year retrospective study from one center. Patrova Jekaterina,Kjellman Magnus,Wahrenberg Hans,Falhammar Henrik Endocrine PURPOSE:To compare long-term outcomes in patients with adrenal incidentalomas (AIs) with the response to a 1 mg overnight dexamethasone suppression test (DST). METHODS:Consecutive patients with "non-functional" AIs (n = 365) were examined. Patients with overt hormone excess, adrenocortical cancer and known malignancy had been excluded. Patients were classified to normal cortisol secretion group (n = 204, DST ≤ 50 nmol/l), possible autonomous cortisol secretion group (n = 128, DST 51-138 nmol/l) and autonomous cortisol secretion group (n = 33, DST ≥ 138 nmol/l). RESULTS:Thirty-seven patients (10.1%) deceased during the follow-up period (5.2 ± 2.3 years): 16(7.8%) in the non-secreting group (time from diagnosis to death: 3.9 ± 2.9 years), 15 in the possible autonomous cortisol secretion group (11.7%, 3.2 ± 1.8 years) and 6 in the autonomous cortisol secretion group (18.2%, 2.3 ± 1.5 years), respectively (P = 0.019). Multivariate analysis only found significant association with age and the tumour size but if cortisol levels post-DST were analysed as a continuous variable it was significant as well. All deaths in autonomous cortisol secretion group were due to cancer not related to adrenal glands. Hypertension, cardiovascular disease and medications were more common in the possible and autonomous cortisol secretion group, especially in the former. More bilateral AIs and larger AI size were found in the two latter groups. CONCLUSIONS:Patients with autonomous cortisol secretion had higher mortality than those with non-functioning AIs though cortisol levels post-DST as a continuous variable, age and tumour size were better predictor of mortality. Cardiovascular disease and osteoporosis medication seemed more prevalent in the possible and autonomous cortisol secretion groups, especially in the former. 10.1007/s12020-017-1400-8
    Mental Health in Patients With Adrenal Incidentalomas: Is There a Relation With Different Degrees of Cortisol Secretion? Morelli Valentina,Ghielmetti Alberto,Caldiroli Alice,Grassi Silvia,Siri Francesca Marzia,Caletti Elisabetta,Mucci Francesco,Aresta Carmen,Passeri Elena,Pugliese Flavia,Di Giorgio Annabella,Corbetta Sabrina,Scillitani Alfredo,Arosio Maura,Buoli Massimiliano,Chiodini Iacopo The Journal of clinical endocrinology and metabolism CONTEXT:Cushing's syndrome frequently causes mental health impairment. Data in patients with adrenal incidentaloma (AI) are lacking. OBJECTIVE:We aimed to evaluate psychiatric and neurocognitive functions in AI patients, in relation to the presence of subclinical hypercortisolism (SH), and the effect of adrenalectomy on mental health. DESIGN:We enrolled 62 AI patients (64.8 ± 8.9 years) referred to our centers. Subclinical hypercortisolism was diagnosed when cortisol after 1mg-dexamethasone suppression test was >50 nmol/L, in the absence of signs of overt hypercortisolism, in 43 patients (SH+). INTERVENTIONS:The structured clinical interview for the Diagnostic and Statistical Manual of Mental Disorders-5, and 5 psychiatric scales were performed. The Brief Assessment of Cognition in Schizophrenia (Verbal and Working Memory, Token and Symbol Task, Verbal Fluency, Tower of London) was explored in 26 patients (≤65 years). RESULTS:The prevalence of psychiatric disorders was 27.4% (SH+ 30.2% vs SH- 21.1%, P = 0.45). SH+ showed a higher prevalence of middle insomnia (by the Hamilton Depression Rating Scale) compared with SH- (51% vs 22%, P = 0.039). Considering the Sheehan Disability Scale, SH+ showed a higher disability score (7 vs 3, P = 0.019), higher perceived stress (4.2 ± 1.9 vs 2.9 ± 1.9, P = 0.015), and lower perceived social support (75 vs 80, P = 0.036) than SH-. High perceived stress was independently associated with SH (odds ratio [OR] = 5.46, confidence interval 95% 1.4-21.8, P = 0.016). Interestingly, SH+ performed better in verbal fluency (49.5 ± 38.9 vs 38.9 ± 9.0, P = 0.012), symbol coding (54.1 ± 6.7 vs 42.3 ± 15.5, P = 0.013), and Tower of London (15.1 vs 10.9, P = 0.009) than SH-. In 8 operated SH+, no significant changes were found. CONCLUSIONS:Subclinical hypercortisolism may influence patients' mental health and cognitive performances, requiring an integrated treatment. 10.1210/clinem/dgaa695
    Bone loss determined by quantitative ultrasonometry correlates inversely with disease activity in patients with endogenous glucocorticoid excess due to adrenal mass. Tauchmanovà L,Rossi R,Nuzzo V,del Puente A,Esposito-del Puente A,Pizzi C,Fonderico F,Lupoli G,Lombardi G European journal of endocrinology OBJECTIVE:Glucocorticoid excess is widely recognized as one of the most important causes of bone loss. The mechanism of glucocorticoid-induced osteoporosis is presumably multifactorial, and consists of the loss of organic and non-organic compounds. Efforts have been made to develop simple physical methods for the assessment of bone tissue for the screening of subjects at high risk of osteoporosis, without the use of radioactive sources or ionizing radiation. Quantitative ultrasonometry (QUS) has been suggested as a useful method for monitoring patients undergoing glucocorticoid therapy, which is the most common cause of glucocorticoid excess. QUS appears to detect more structural bone changes than the traditional methods and allows assessment of bone density and elasticity, both characteristics influenced by organic and non-organic bone compounds. However, the use of QUS has not yet been extensively investigated in subjects with endogenous cortisol excess. The aim of this study was to evaluate the usefulness and predictive power of QUS in assessing bone loss in subjects with differing degrees of endogenous cortisol excess due to adrenal mass. DESIGN:Thirty-four patients (20 women and 14 men) aged between 21 and 59 years were evaluated; fifteen (9 women and 6 men; median age, 42 years) were affected by overt Cushing's syndrome (CS) and nineteen (11 women and 8 men; median age, 44 years) by subclinical CS, defined as lacking clinical signs of hormone excess despite the presence of at least two abnormalities in hypothalamic-pituitary-adrenal axis function, as assessed by routine endocrine tests. All women included were eumenorrhoic. METHODS:QUS measurement of amplitude-dependent speed of sound was performed on the 2nd to 5th proximal phalanges of the non-dominant hand using a DBM Sonic 1200R bone profiler (Igea S.r.l, Italy). The results were compared with bone density assessed on lumbar vertebrae (L1-L4) and femoral neck sites by dual-energy X-ray absorptiometry (DEXA). RESULTS:A strongly significant bone loss was detected by finger QUS measurement when the patients were considered either all together or as two subgroups (P<0.001, all). The bone density decrease in the fingers was similar to that found at the lumbar spine and femoral neck by the DEXA technique. Lumbar and finger Z-scores correlated inversely with 24 h urinary free cortisol (UFF) excretion (P<0.01, both). Finger Z-scores also correlated inversely with the estimated duration of subclinical CS (P<0.05). Concerning disease activity, only UFF was confirmed by multivariate analysis to be an independent factor influencing bone loss (P<0.05). A positive correlation between the results of the two techniques was found in controls (P<0.05) but not in patients. The lack of correlation between the two techniques in patients can probably be attributed to the different parameters of bone alteration measured by the techniques. CONCLUSIONS:The detection of bone loss in subclinical CS similar to that in overt CS suggests that all subjects with endogenous cortisol excess should be evaluated for bone mass. QUS measurement appears to be a reliable, radiation-free, simple and fast tool for the identification of bone alteration in subjects with endogenous cortisol excess.
    Cardiovascular Outcomes in Autonomous Cortisol Secretion and Nonfunctioning Adrenal Adenoma: A Systematic Review. Park Jane,De Luca Alyssa,Dutton Heidi,Malcolm Janine C,Doyle Mary-Anne Journal of the Endocrine Society There is growing evidence that autonomous cortisol secretion (ACS), previously known as subclinical Cushing syndrome, is associated with greater prevalence of cardiovascular (CV) risk factors. However, it is unclear whether ACS is associated with greater prevalence of CV outcomes compared with nonfunctioning adrenal adenomas (NFAAs). The objective of this study is to evaluate CV outcomes and CV risk factors in patients with adrenal adenoma with ACS compared with NFAA. A literature review was performed in Embase, Medline, Cochrane Library, and reference lists within selected articles. The study protocol was registered with PROSPERO. A literature search yielded six studies that met the inclusion criteria. Studies varied in their definitions of ACS and CV outcomes. Two retrospective longitudinal studies further demonstrated higher incidence of new CV events (ACS 16.7% vs NFAA 6.7%, = 0.04) and higher CV mortality in patients with ACS (ACS 22.6% vs 2.5%, = 0.02). The prevalence of CV outcomes in ACS was more than three times greater than in patients with NFAA. Three of five studies found that ACS was associated with higher prevalence of diabetes and hypertension. There was no difference in dyslipidemia or body mass index demonstrated in any study. There is heterogeneity among the few studies evaluating the association between ACS and CV outcomes. Although these studies suggest a higher risk of CV outcomes in patients with ACS, many did not adjust for known confounders. Larger, high quality, prospective studies are needed to evaluate this association and to identify modifiable risk factors. 10.1210/js.2019-00090
    Association of subclinical hypercortisolism with type 2 diabetes mellitus: a case-control study in hospitalized patients. Chiodini Iacopo,Torlontano Massimo,Scillitani Alfredo,Arosio Maura,Bacci Simonetta,Di Lembo Sergio,Epaminonda Paolo,Augello Giovanni,Enrini Riccardo,Ambrosi Bruno,Adda Guido,Trischitta Vincenzo European journal of endocrinology OBJECTIVE:Subclinical hypercortisolism (SH) may play a role in several metabolic disorders, including diabetes. No data are available on the relative prevalence of SH in type 2 diabetes (T2D). In order to compare the prevalence of SH in T2D and matched non-diabetic control individuals, we performed a case-controlled, multicenter, 12-month study, enrolling 294 consecutive T2D inpatients (1.7% dropped out the study) with no evidence of clinical hypercortisolism and 189 consecutive age- and body mass index-matched non-diabetic inpatients (none of whom dropped out). DESIGN AND METHODS:Ascertained SH (ASH) was diagnosed in individuals (i) with plasma cortisol after 1 mg overnight dexamethasone suppression >1.8 microg/dl (50 nmol/l), (ii) with more than one of the following: (a) urinary free cortisol >60.0 microg/24 h (165.6 nmol/24 h), (b) plasma ACTH <10.0 pg/ml (2.2 pmol/l) or (c) plasma cortisol >7.5 microg/dl (207 nmol/l) at 24:00 h or >1.4 microg/dl (38.6 nmol/l) after dexamethasone-CRH (serum cortisol after corticotrophin-releasing hormone stimulus during dexamethasone administration) test, and (iii) in whom the source of glucocorticoid excess was suggested by imaging and by additional biochemical tests (for ACTH-dependent ASH). RESULTS:Prevalence of ASH was higher in diabetic individuals than in controls (9.4 versus 2.1%; adjusted odds ratio, 4.8; 95% confidence interval, 1.6-14.1; P = 0.004). In our population the proportion of T2D which is statistically attributable to ASH was approx. 7%. Among diabetic patients, the presence of severe diabetes (as defined by the coexistence of hypertension, dyslipidaemia and insulin treatment) was significantly associated with SH (adjusted odds ratio, 3.8; 95% confidence interval, 1.4-10.2; P = 0.017). CONCLUSIONS:In hospitalized patients, SH is associated with T2D. 10.1530/eje.1.02045
    Bone mineral density, prevalence of vertebral fractures, and bone quality in patients with adrenal incidentalomas with and without subclinical hypercortisolism: an Italian multicenter study. Chiodini Iacopo,Morelli Valentina,Masserini Benedetta,Salcuni Antonio Stefano,Eller-Vainicher Cristina,Viti Raffaella,Coletti Francesca,Guglielmi Giuseppe,Battista Claudia,Carnevale Vincenzo,Iorio Laura,Beck-Peccoz Paolo,Arosio Maura,Ambrosi Bruno,Scillitani Alfredo The Journal of clinical endocrinology and metabolism CONTEXT:In patients with adrenal incidentalomas and subclinical hypercortisolism (SH), the factors influencing bone and the prevalence of vertebral fractures are debated. Spinal deformity index (SDI), which reflects bone quality, has never been evaluated. OBJECTIVE:The objective of the study was to investigate in these patients SDI and factors influencing the prevalence of fractures. DESIGN:This was a retrospective, multicenter study. SETTING:The study was conducted on an in- and outpatient basis. PATIENTS:Patients included 287 adrenal incidentaloma patients (111 eugonadal males, 31 premenopausal, 145 postmenopausal females) and 194 controls (90 eugonadal males, 29 premenopausal, 75 postmenopausal females). MAIN OUTCOME MEASURE:Bone mineral density (BMD) was measured by dual X-ray absorptiometry at lumbar spine and femoral neck. By radiograph each vertebra was assessed as intact (grade 0) or grade 1 (20-25%), 2 (25-40%), or 3 (>40%) deformity; SDI was calculated by summing the grade of deformity for each vertebra. SH was diagnosed in the presence of at least two of the following: urinary free cortisol greater than 70 microg per 24 h (193.1 nmol/liter), cortisol after 1-mg dexamethasone test greater than 3.0 microg/dl (>82.8 nmol/liter), ACTH less than 10 pg/ml (<2.2 pmol/liter). RESULTS:BMD was significantly lower in SH+ than SH- patients and controls (lumbar spine -0.73 +/- 1.43, 0.17 +/- 1.33, 0.12 +/- 1.21, respectively; femoral neck -0.37 +/- 1.06, 0.07 +/- 1.09, 0.17 +/- 1.02). Patients with SH had higher fracture prevalence and SDI than those without SH and controls (70.6, 22.2, 21.8%, respectively, P < 0.0001; 0.31 +/- 0.68, 0.39 +/- 0.93, 1.35 +/- 1.27, respectively, P < 0.0001). Fractures and SDI were associated with SH (odds ratio 7.27, 95% confidence interval 3.94-13.41, P = 0.0001; beta = 0.352, t = 6.241, P = 0.0001, respectively) regardless of age, BMD, menopause, and gender. CONCLUSION:SH is associated with low BMD, high fracture prevalence, and reduced bone quality as measured by SDI. 10.1210/jc.2009-0468
    Subclinical hypercortisolism: debatable or visible on the lightbox? Vassiliadi Dimitra A,Tsagarakis Stylianos Endocrine 10.1007/s12020-012-9689-9
    Preclinical Cushing's syndrome in adrenal "incidentalomas": comparison with adrenal Cushing's syndrome. Reincke M,Nieke J,Krestin G P,Saeger W,Allolio B,Winkelmann W The Journal of clinical endocrinology and metabolism Adrenal tumors are usually diagnosed by clinical symptoms of hormone excess. The increasing use of ultrasound and computed tomography results in the detection of a substantial number of incidentally discovered adrenal tumors. Most of these tumors are nonfunctional adrenocortical adenomas, but a few cases of subclinical cortisol production in "incidentalomas" have been reported. We investigated prospectively the prevalence of autonomous cortisol production in 68 patients (44 females and 24 males, aged 25-90 yr) with adrenal incidentalomas at our institution. As a screening procedure all patients with incidentalomas underwent an overnight dexamethasone suppression test (1 mg). Patients who failed to suppress serum cortisol below 140 nmol/L (5 micrograms/dL) underwent more comprehensive studies (prolonged dexamethasone suppression test, determination of the diurnal rhythm of cortisol secretion in saliva, and CRH stimulation test). Eight patients (12% of all patients with incidentalomas; 5 females and 3 males, aged 25-71 yr) were finally identified as having cortisol-producing tumors, and the findings in these patients were compared with those of overt Cushing's syndrome in 8 patients (8 females, aged 26-50 yr) suffering from cortisol-producing adrenal adenomas. The tumor size of patients with cortisol-producing incidentalomas ranged from 2-5 cm. No specific signs and symptoms of hypercortisolism were present, but arterial hypertension (seven of eight subjects), diffuse obesity (four of eight subjects), and noninsulin-dependent diabetes mellitus (NIDDM; two of eight subjects) were frequently observed. Baseline cortisol levels were in the normal to upper normal range, whereas baseline ACTH levels were suppressed in five of the eight patients. In none of the patients was serum cortisol suppressible by low dose or high dose dexamethasone. The ACTH and cortisol responses to CRH were normal in two, blunted in one, and suppressed in four patients. Unilateral adrenalectomy was performed in seven patients and resulted in temporary adrenal insufficiency in four of them. After surgery, improvement of arterial hypertension, a permanent weight loss in obese subjects, and a better metabolic control of NIDDM were noted in the majority of patients. The following conclusions were reached. Incidentally diagnosed adrenal tumors with pathological cortisol secretion in otherwise clinically asymptomatic patients are more frequently observed than previously assumed. Adrenocortical insufficiency is a major risk in these patients after adrenalectomy. After surgery, hypertension, obesity, and NIDDM may improve. Patients with asymptomatic adrenal incidentalomas, therefore, should be screened for cortisol production by means of an overnight dexamethasone suppression test. 10.1210/jcem.75.3.1517373
    Risk of new vertebral fractures in patients with adrenal incidentaloma with and without subclinical hypercortisolism: a multicenter longitudinal study. Morelli Valentina,Eller-Vainicher Cristina,Salcuni Antonio Stefano,Coletti Francesca,Iorio Laura,Muscogiuri Giovanna,Della Casa Silvia,Arosio Maura,Ambrosi Bruno,Beck-Peccoz Paolo,Chiodini Iacopo Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research In patients with adrenal incidentalomas (AIs), cross-sectional studies suggested the presence of an association between subclinical hypercortisolism (SH) and an increased prevalence of vertebral fractures (VFx) and spinal deformity index (SDI), which is a clinical index of bone quality. No longitudinal studies investigated the incidence of VFx and SDI changes over time in SH. The aim of this study was to evaluate VFx risk and SDI changes in SH over time. One-hundred-three consecutive AI patients were studied at baseline and after 12 and 24 months. Patients were divided into SH(+) (n = 27) and SH(-) (n = 76) groups on the basis of the presence of two or more among urinary free cortisol greater than 70 µg/24 hours, serum cortisol after 1-mg dexamethasone suppression test greater than 3.0 µg/dL, and adrenocorticotropic hormone (ACTH) less than 10 pg/mL in 2 or more of the 3 evaluations. At baseline and after 24 months, bone mineral density (BMD) by dual-energy X-ray absorptiometry and the presence of VFx and SDI by summing the grade of deformity for each vertebra were evaluated. At the end of follow-up, the SH(+) group showed a higher prevalence of VFx (81.5%) as compared with baseline (55.6%, p = .04) and a worsening of SDI (2.11 ± 1.85 versus 1.11 ± 1.47, p = .032) associated with SH regardless of age, gender, body mass index , BMD, baseline SDI, menopause duration [odds ratio (OR) = 12.3, 95% confidence interval (CI) 4.1-36.5, p = .001]. The incidence of new vertebral fractures was higher in the SH(+) group (48%) than in the SH(-) group (13%; p = .001). It is concluded that subclinical hypercortisolism is associated with an increased risk of VFx and a possible deterioration of bone quality. 10.1002/jbmr.398
    Endogenous subclinical hypercortisolism: Diagnostic uncertainties and clinical implications. Tsagarakis S,Vassiliadi D,Thalassinos N Journal of endocrinological investigation Subclinical hypercortisolism (SH) is a newly characterized hormonal disorder that is almost exclusively detected in the context of incidentally discovered adrenal masses. The diagnostic criteria used for the definition of this condition are at present controversial. Amongst the various tests used for the detection of this abnormality (dexamethasone suppression, urinary free cortisol, ACTH levels, midnight serum or salivary cortisol concentrations, ACTH responses to CRH stimulation), the dexamethasone suppression tests (DST) seem to better accomplish the task of unmasking subtle abnormalities of cortisol secretion. Several versions of DST have been used: the 1-mg overnight, the 3-mg overnight and the classical 2-day low-dose DST. This latter test has the theoretical advantage that, by more efficiently suppressing pituitary ACTH secretion, it may provide a measure of the residual (ie non- ACTH-dependent) cortisol secretion from the adrenal mass. In this way, post-dexamethasone cortisol concentrations may quantify the degree of autonomous cortisol hypersecretion. In fact, post-dexamethasone cortisol concentrations have a negative correlation with basal ACTH levels and a positive correlation with midnight cortisol concentrations as well as the size of the incidentally discovered adrenal mass. Most of the existing data indicate that SH detected in the context of adrenal incidentalomas may have some clinically significant implications. In fact, patients with higher post-dexamethasone cortisol concentrations demonstrate higher lipid levels and lower bone mass densities. It has also been suggested that SH may be responsible for biochemical and phenotypic changes reminiscent of the metabolic syndrome. In summary, SH does exist and is associated with a negative impact in patients' health; however, hormonal cut-off criteria for decision-making remain to be defined. 10.1007/BF03344133
    Clinical and subclinical ACTH-independent macronodular adrenal hyperplasia and aberrant hormone receptors. Christopoulos Stavroula,Bourdeau Isabelle,Lacroix André Hormone research ACTH-independent macronodular adrenal hyperplasia (AIMAH) is a very rare cause of endogenous Cushing's syndrome (CS). In this review, the clinical characteristics, the pathophysiology, and the management of AIMAH are described. AIMAH typically presents with overt CS, but subclinical oversecretion of cortisol has been increasingly described. The diagnosis is suspected by adrenal nodular enlargement on conventional imaging following the demonstration of ACTH-independent hypercortisolism. Final diagnosis is established by histological examination of the adrenal tissue. Bilateral adrenalectomy is the treatment of choice but unilateral adrenalectomy has been proposed in selected cases. In patients with subclinical CS, the decision to treat should be individualized. The pathophysiology of this condition has begun to be elucidated in recent years. Diverse aberrant membrane-bound receptors expressed in a non-mutated form in the adrenal gland have been found to be implicated in the regulation of steroidogenesis in AIMAH. When systematically screened, most patients with AIMAH and CS or subclinical CS exhibit an in vivo aberrant cortisol response to one or various ligands suggesting the presence of aberrant adrenal receptors. A protocol designed to screen patients for the presence of these aberrant receptors should be undertaken in all patients with AIMAH. The identification of these receptors provides the potential for novel pharmacological therapies by suppressing the endogenous ligands or blocking the receptor with specific antagonists. 10.1159/000088818
    Adrenal incidentaloma: subclinical Cushing's syndrome. Newell-Price J,Grossman A Postgraduate medical journal Adrenal incidentalomas present a significant differential diagnostic challenge. All patients with an incidentally discovered adrenal lesion should be carefully considered and re-evaluated to exclude extra-adrenal malignancy. Tumours with hypersecretory syndromes require excision, whilst those tumours more than 6 cm in size, particularly if they exhibit other features of malignancy on computed tomography (CT), magnetic resonance imaging (MRI) or scintigraphy, should also be excised. In all cases screening for phaeochromocytomas should be performed, and in the context of hypertension and spontaneous hypokalaemia, a primary aldosterone-secreting tumour requires exclusion. However, the natural history and treatment regimens for those individuals demonstrating 'subclinical Cushing's syndrome' is far from clear. Size, as determined by CT or MR scanning, does not in itself reliably distinguish benign from malignant disease. Scintigraphy may be a useful adjunct, with discordant patterns suggesting malignant disease. Fine needle aspiration should not routinely be used but may be useful in cases of doubt about other extra adrenal malignancy. 10.1136/pgmj.72.846.207
    The landscape of bilateral adrenal incidentalomas associated with subclinical hypercortisolism. Di Dalmazi Guido Endocrine 10.1007/s12020-016-1004-8
    Low dehydroepiandrosterone sulphate: a sensitive and specific test for the detection of subclinical hypercortisolism in adrenal incidentalomas. Stoddart Heather Annals of clinical biochemistry 10.1177/0004563217704738
    Subclinical hypercortisolism in hospitalized patients with type 2 diabetes mellitus. Taniguchi Takao,Hamasaki Akihiro,Okamoto Motozumi Endocrine journal Pre(sub)clinical Cushing's disease is a recently described entity defined by the autonomous secretion of ACTH and the absence of a cushingoid appearance. We screened 77 hospitalized patients with diabetes mellitus for subclinical hypercortisolism and detected pre(sub)clinical Cushing's disease in 2 (2.6%) of them. In both patients, transsphenoidal surgery was performed and a microadenoma was removed. Their metabolic clearance rate of glucose measured by a glucose clamp study, an index of insulin sensitivity, significantly improved after surgery. Our results indicate that screening for subclinical hypercortisolism in diabetic patients might be useful, as surgery improves glucose tolerance and insulin sensitivity.
    Adrenal adenomas, subclinical hypercortisolism, and cardiovascular outcomes. Di Dalmazi Guido,Pasquali Renato Current opinion in endocrinology, diabetes, and obesity PURPOSE OF REVIEW:Recent evidence has highlighted the link between cardiovascular outcomes and incidentally discovered adrenal masses. The purpose of this review is to summarize the most recent findings on the cardiovascular profile of patients with nonfunctional adrenal adenomas. RECENT FINDINGS:Nonsecreting adrenal tumors, defined mostly by cortisol levels after dexamethasone suppression test below 1.8 μg/dl, are associated with impairment of markers of subclinical atherosclerosis such as intima-media thickness and flow-mediated vasodilation. The presence of impaired indices of insulin resistance could represent an additional factor that contributes to the worsening of the cardiovascular profile of those patients. No evidence of increased cardiovascular outcomes was found in this group of patients. On the contrary, according to the findings of recent long-term retrospective studies, patients with subclinical hypercortisolism have an increased incidence of cardiovascular outcomes and related mortality with respect to nonsecreting adrenal masses and to the general population. SUMMARY:An impaired cardiovascular profile is a common finding in patients with apparently nonfunctional adrenal masses. However, the incidence of cardiovascular outcomes and related mortality seems to be increased only in patients with mild cortisol hypersecretion. 10.1097/MED.0000000000000153
    High prevalence of subclinical hypercortisolism in patients with bilateral adrenal incidentalomas: a challenge to management. Vassiliadi Dimitra A,Ntali Georgia,Vicha Eirini,Tsagarakis Stylianos Clinical endocrinology OBJECTIVE:The prevalence of subclinical hypercortisolism (SH) in unilateral incidentalomas (UI) has been extensively studied; however, patients with bilateral incidentalomas (BI) have not been thoroughly investigated. We therefore aimed to describe the characteristics of patients with BI compared to their unilateral counterparts. The surgical outcome in a small number of patients is reported. DESIGN:Observational retrospective study in a single secondary/tertiary centre. PATIENTS:One hundred and seventy-two patients with adrenal incidentalomas (41 with BI). MEASUREMENTS:Morning cortisol (F), ACTH, dehydroepiandrosterone sulphate (DHEA-S), midnight F, 24-h urine collection for cortisol (UFC), low-dose dexamethasone suppression test (LDDST), fasting glucose, insulin, and oral glucose tolerance test (OGTT). Primarily, SH was defined as F-post-LDDST>70 nmol/l and one more abnormality; several diverse cut-offs were also examined. RESULTS:No difference was noted in age, body mass index, or prevalence of diabetes and impaired glucose tolerance between patients with UI and those with BI. Patients with BI had higher F-post-LDDST (119·3 ± 112·8 vs 54·3 ± 71·5 nmol/l, P<0·001) and lower DHEA-S (1·6 ± 1·5 vs 2·5 ± 2·3 μmol/l, P=0·003) but similar UFC, ACTH and midnight F levels, compared to UI. SH was significantly more prevalent in BI (41·5%vs 12·2%, P<0·001). Fourteen patients were operated on; four underwent bilateral interventions. In 10 patients, unilateral adrenalectomy on the side of the largest lesion resulted in significant improvement in F-post-LDDST (P=0·008) and a decrease in midnight F (P=0·015) levels. CONCLUSIONS:Subclinical hypercortisolism is significantly more prevalent in bilateral incidentaloma patients, posing great dilemmas for its optimum management. 10.1111/j.1365-2265.2010.03963.x
    Subclinical hypercortisolism: correlation between biochemical diagnostic criteria and clinical aspects. Morelli V,Masserini B,Salcuni A S,Eller-Vainicher C,Savoca C,Viti R,Coletti F,Guglielmi G,Battista C,Iorio L,Beck-Peccoz P,Ambrosi B,Arosio M,Scillitani A,Chiodini I Clinical endocrinology OBJECTIVE:Subclinical hypercortisolism (SH) has been associated with increased prevalence of hypertension, type 2 diabetes mellitus, dyslipidaemia, central obesity, osteoporosis and vertebral fractures. We aimed to investigate the accuracy of different SH diagnostic criteria in predicting the presence of complications. DESIGN:This was a retrospective study. PATIENTS:We evaluated data from 231 patients (120 women and 111 men) affected with adrenal incidentalomas (AI). MEASUREMENTS:We studied the accuracy of different SH diagnostic criteria (cortisol after 1 mg overnight dexamethasone suppression test - 1mg-DST - at different cut-off such as 49.7, 82.8, 137.9 nmol/l, elevated urinary free cortisol, reduced adrenal corticotroph hormone (ACTH) levels alone or various combination of these parameters) in predicting the concomitant presence of the following three complications: hypertension, type 2 diabetes and vertebral fractures. RESULTS:The criterion characterized by the presence of two of 1mg-DST >82.8 nmol/l, elevated UFC and reduced ACTH struck the best balance between sensitivity and specificity, reaching a good accuracy in predicting the cluster of complications (61.9%; 77.1% and 75.8%, respectively). The presence of this cluster was associated with this criterion (OR 4.75, 95%CI 1.8-12.7, P = 0.002) regardless of gonadal status, body mass index (BMI) and age. CONCLUSIONS:The SH criterion characterized by the presence of two of 1mg-DST >82.8 nmol/l, elevated UFC and reduced ACTH seems the best in predicting the presence of chronic manifestations of subtle cortisol excess. 10.1111/j.1365-2265.2010.03794.x
    Subclinical Cushing syndrome due to adrenocorticotropic hormone-independent macronodular adrenocortical hyperplasia: changes in plasma cortisol levels during long-term follow-up. Sasao T,Itoh N,Sato Y,Takahashi A,Tsukamoto T Urology A 63-year-old man with bilateral adrenal tumors was treated for hypertension and diabetes mellitus. Endocrinologic examination during follow-up revealed the production of cortisol to be independent of the regulation of the hypothalamo-pituitary-adrenal axis. Therefore, he was diagnosed as having subclinical Cushing syndrome, and these tumors were removed. Adrenocorticotropic hormone-independent macronodular adrenal hyperplasia (AIMAH) was endocrinologically and histopathologically diagnosed. This is the first report demonstrating that endocrinologic changes of AIMAH can be observed during long-term follow-up. 10.1016/s0090-4295(99)00381-7
    Subclinical hypercortisolism and CT appearance in adrenal incidentalomas: a multicenter study from Southern Sweden. Olsen Henrik,Nordenström Erik,Bergenfelz Anders,Nyman Ulf,Valdemarsson Stig,Palmqvist Erik Endocrine Evaluation of subclinical hypercortisolism (SH) in patients with adrenal incidentaloma (AI) including its correlation to size, attenuation at unenhanced computed tomography (CT) and unilateral or bilateral adrenal disease. Nine hospitals in Southern Sweden investigated during 2005-2007 consecutively patients with AI with hormonal and CT examinations according a regional protocol. Two hundred and twenty-eight patients with AI with median size 2.0 cm were included. One mg overnight dexamethasone suppression test (DST) was performed in 223 patients and basal P-ACTH measured in 146 patients. SH was defined as cortisol ≥ 50 nmol/l at DST in combination with basal ACTH <2 pmol/l. In patients with unilateral AI 42% (76/180) had inadequate suppression at DST and 23% (27/115) had SH. The probability for SH and inadequate suppression at DST correlated positively to size and inversely to attenuation at CT. Bilateral AI were found in 43 patients and of these 70% (30/43) had inadequate suppression at DST and 42% (13/31) SH. The patients with SH or inadequate suppression at DST had increased frequency of hypertension which increased further in patients with post-DST cortisol ≥ 140 nmol/l. The applied criterion for SH is useful for initial evaluation of patients with AI. SH is common in patients with AI, particular in bilateral disease. In patients with unilateral AI the probability for SH correlated positively to size and inversely to attenuation at CT. Furthermore, SH and the post-DST cortisol concentration was associated with hypertension. 10.1007/s12020-012-9622-2
    Alteration in skeletal muscle mass in women with subclinical hypercortisolism. Kim Jae Hyeon,Kwak Mi Kyung,Ahn Seong Hee,Kim Hyeonmok,Cho Yoon Young,Suh Sunghwan,Kim Beom-Jun,Song Kee-Ho,Lee Seung Hun,Koh Jung-Min Endocrine PURPOSE:Despite the well-known deleterious effects of cortisol on skeletal muscle, whether subtle cortisol excess in subclinical hypercortisolism (SH) affects skeletal muscle mass is unknown. Our objective was to understand the effects of the cortisol level on skeletal muscle mass in patients with SH. METHODS:We compared skeletal muscle mass and fat mass (FM) between 21 patients with SH (12 women and 9 men) and 224 controls (67 women and 157 men) with nonfunctioning adrenal incidentaloma (NFAI). Medical records were reviewed, and we measured body composition parameters using bioelectrical impedance analysis and serum cortisol levels after the overnight 1-mg dexamethasone suppression test (DST). RESULTS:After adjusting for confounding factors, 1-mg DST levels were inversely correlated with appendicular skeletal muscle mass (ASM) (γ = -0.245, P = 0.040), lower limb ASM (γ = -0.244, P = 0.040), and appendicular skeletal muscle index (ASMI; height-adjusted ASM) (γ = -0.229, P = 0.048) in all women, but not men. ASM and ASMI were significantly lower by 6.2% (P = 0.033) and 5.9% (P = 0.046), respectively, in women with SH compared with those with NFAI, but not men. Conversely, FM and percent fat mass were similar between the two groups. Compared with women with NFAI, among those with SH, lower limb, but not upper limb, ASM was lower by 6.8% (P = 0.020). CONCLUSIONS:This study showed that women with SH had lower skeletal muscle mass, especially of the lower limb, and suggested that subtle cortisol excess also has adverse effects on skeletal muscle metabolism. 10.1007/s12020-018-1598-0
    Epidemiology of Cushing's syndrome and subclinical disease. Ross N S Endocrinology and metabolism clinics of North America Adenomatous lesions of the adrenal are commonplace. Advances in imaging technology have resulted in the discovery of increasing numbers of these lesions. A variety of hormonal and anatomic evaluations have been suggested to distinguish between the benign and potentially harmful of these lesions. Among the suggested evaluations is assessment of the feedback regulation of cortisol secretion. Several studies have confirmed that approximately 10% of the adenomas secrete cortisol in at least a partially unregulated manner. These patients, defined as having either subclinical or preclinical Cushing's syndrome, frequently undergo extensive diagnostic testing and on occasion, adrenalectomy. The relative infrequency of Cushing's syndrome in the general population suggests strongly that the vast majority of individuals identified by subjecting all patients with incidentally discovered adrenal masses to screening tests for excess cortisol secretion will never progress to clinically significant disease (clinical Cushing's syndrome). Thus, testing of this nature in the absence of clinical findings consistent with Cushing's syndrome is counterproductive and should generally not be performed. Individuals with these masses should, however, receive close clinical follow-up and testing initiated if any findings suggestive of Cushing's syndrome develop. The application of screening tests in a relatively unselected population is clinically ineffective and can be deleterious when patients without disease undergo subsequent invasive procedures. The clinical epidemiology af adrenal Cushing's syndrome, the natural history of incidentally discovered adrenal lesions, and the lack of clearly documented benefits in removing lesions from patients with subclinical disease argue strongly against use of a biochemical screen ion the decision to operate.(ABSTRACT TRUNCATED AT 250 WORDS)
    Clinical review: Diagnosis and treatment of subclinical hypercortisolism. Chiodini Iacopo The Journal of clinical endocrinology and metabolism CONTEXT:Subclinical hypercortisolism (SH) is a condition of biochemical cortisol excess without the classical signs or symptoms of overt hypercortisolism. It is thought to be present in the 5-30% of patients with incidentally discovered adrenal mass (adrenal incidentalomas), which in turn are found in 4-7% of the adult population. Therefore, SH has been suggested to be present in 0.2-2.0% of the adult population. Some studies suggested that this condition is present in 1-10% of patients with diabetes or established osteoporosis. The present manuscript reviews the literature on diagnostic procedures and the metabolic effect of the recovery from SH. EVIDENCE ACQUISITION:A PubMed search was used to identify the available studies. The most relevant studies from 1992 to November 2010 have been included in the review. EVIDENCE SYNTHESIS:The available data suggest that SH may be associated with chronic complications, such as hypertension, diabetes mellitus, overweight/obesity, and osteoporosis. The available intervention studies suggest that the recovery from SH may lead to the improvement of hypertension and diabetes mellitus. A retrospective study suggests that this beneficial effect could be predicted before surgery. CONCLUSIONS:SH is suggested to be associated with some chronic complications of overt cortisol excess. Recovery from this condition seems to improve these complications. However, a large, prospective, randomized study is needed to confirm this hypothesis and to establish the best diagnostic approach to identify patients with adrenal incidentalomas who can benefit from surgery. 10.1210/jc.2010-2722
    Biochemical and clinical benefits of unilateral adrenalectomy in patients with subclinical hypercortisolism and bilateral adrenal incidentalomas. Perogamvros I,Vassiliadi D A,Karapanou O,Botoula E,Tzanela M,Tsagarakis S European journal of endocrinology OBJECTIVE:The treatment of subclinical hypercortisolism in patients with bilateral adrenal incidentalomas (AI) is debatable. We aimed to compare the biochemical and clinical outcome of unilateral adrenalectomy vs a conservative approach in these patients. DESIGN:Retrospective study. METHODS:The study included 33 patients with bilateral AI; 14 patients underwent unilateral adrenalectomy of the largest lesion (surgical group), whereas 19 patients were followed up (follow-up group). At baseline and at each follow-up visit, we measured 0800 h plasma ACTH, midnight serum cortisol (MSF), 24-h urinary-free cortisol (UFC) and serum cortisol following a standard 2-day low-dose-dexamethasone-suppression test (LDDST). We evaluated the following comorbidities: arterial hypertension, impaired glucose tolerance or diabetes mellitus, dyslipidemia and osteoporosis. RESULTS:Baseline demographic, clinical characteristics and the duration of follow-up (53.9±21.3 vs 51.8±20.1 months, for the surgical vs the follow-up group) were similar between groups. At the last follow-up visit the surgical group had a significant reduction in post-LDDST cortisol (2.4±1.6 vs 6.7±3.9 μg/dl, P=0.002), MSF (4.3±2 vs 8.8±4.6 μg/dl, P=0.006) and 24-h UFC (50.1±21.1 vs 117.9±42.4 μg/24 h, P=0.0007) and a significant rise in mean±s.d. morning plasma ACTH levels (22.2±9.6 vs 6.9±4.8 pg/ml, P=0.002). Improvement in co-morbidities was seen only in the surgical group, whereas no changes were noted in the follow-up group. CONCLUSIONS:Our early results show that removal of the largest lesion offers significant improvement both to cortisol excess and its metabolic consequences, without the debilitating effects of bilateral adrenalectomy. A larger number of patients, as well as a longer follow-up, are required before drawing solid conclusions. 10.1530/EJE-15-0566
    Adrenalectomy reduces the risk of vertebral fractures in patients with monolateral adrenal incidentalomas and subclinical hypercortisolism. Salcuni Antonio Stefano,Morelli Valentina,Eller Vainicher Cristina,Palmieri Serena,Cairoli Elisa,Spada Anna,Scillitani Alfredo,Chiodini Iacopo European journal of endocrinology OBJECTIVE:Subclinical hypercortisolism (SH) is associated with increased risk of vertebral fractures (VFx). The effect on bone following recovery from SH is unknown. DESIGN:Of the 605 subjects consecutively referred for monolateral adrenal incidentalomas (AIs) to our outpatient clinics, 55 SH patients (recruited on the basis of the exclusion criteria) were enrolled. We suggested to all patients to undergo adrenalectomy, which was accepted by 32 patients (surgical group, age 61.3±8.1 years) and refused by 23 patients, who were followed with a conservative management (non-surgical group, age 65.4±7.1 years). METHODS:We diagnosed SH in patients with serum cortisol after 1  mg dexamethasone suppression test (1  mg-DST) >5.0  μg/dl or with greater than or equal to two criteria among 1  mg-DST >3.0  μg/dl, urinary free cortisol >70  μg/24  h and ACTH <10  pg/ml. We assessed: bone mineral density (BMD) at lumbar spine (LS) and femoral neck (as Z-score) by dual-energy X-ray absorptiometry and the VFx presence by X-ray at baseline and at the end of follow up (surgical group 39.9±20.9 months and non-surgical group 27.7±11.1 months). RESULTS:The LS Z-score (ΔZ-score/year) tended to increase in the surgical group (0.10±0.20) compared with the non-surgical group (-0.01±0.27, P=0.08) and in the former, the percentage of patients with new VFx was lower (9.4%) than in the latter (52.2%, P<0.0001). Surgery in AI patients with SH was associated with a 30% VFx risk reduction (odds ratio 0.7, 95% CI 0.01-0.05, P=0.008) regardless of age, gender, follow up duration, 1  mg-DST, LS BMD, and presence of VFx at baseline. CONCLUSION:In patients with monolateral AI and SH, adrenalectomy reduces the risk of VFx. 10.1530/EJE-15-0977
    Bilateral adrenal incidentaloma with subclinical hypercortisolemia: indications for surgery. Papierska Lucyna,Ćwikła Jarosław,Rabijewski Michał,Glinicki Piotr,Otto Maciej,Kasperlik-Załuska Anna Polskie Archiwum Medycyny Wewnetrznej INTRODUCTION:According to some authors, a higher incidence of subclinical hypercortisolemia is found among patients with bilateral benign adrenal tumors than in those with unilateral tumors. It is still unknown whether all patients with bilateral adrenal tumors and subclinical hypercortisolemia should undergo surgery, and, if so, which tumor should be removed first. OBJECTIVES:The aim of the study was to investigate whether unilateral adrenalectomy can lead to resolution of hypercortisolemia in patients with bilateral adrenal tumors and to improvement of their clinical status. PATIENTS AND METHODS:The study group consisted of 25 patients with bilateral benign adrenal tumors and subclinical hypercortisolemia. In 24 patients, unilateral adrenalectomy was performed. The adrenal gland was selected for removal on the basis of scintigraphy and/or tumor diameter. Cortisol concentrations were measured before the surgery and at 1 and 6 months after the surgery at 8:00 AM, 10:00 PM, and after dexamethasone suppression. The morning blood levels of adrenocorticotropic hormone, dehydroepiandrosterone, 17‑hydroxyprogesterone, glycated hemoglobin, and lipid profile were determined. RESULTS:In all surgical patients, hypercortisolemia resolved after the surgery. However, only in 14 patients (58%), the clinical improvement was evident (improved control of diabetes and hypertension, body mass loss). CONCLUSIONS:Although subclinical hypercortisolemia resolved after surgery in all patients with bilateral adrenal tumors, only patients with poorly controlled diabetes and hypertension and a rapid increase in body mass benefited from the surgery. 10.20452/pamw.2347
    MECHANISMS IN ENDOCRINOLOGY: Endogenous subclinical hypercortisolism and bone: a clinical review. Chiodini I,Vainicher C Eller,Morelli V,Palmieri S,Cairoli E,Salcuni A S,Copetti M,Scillitani A European journal of endocrinology In recent years, the condition of subclinical hypercortisolism (SH) has become a topic of growing interest. This is due to the fact that SH prevalence is not negligible (0.8-2% in the general population) and that, although asymptomatic, this subtle cortisol excess is not harmless, being associated with an increased risk of complications, in particular of osteoporosis and fragility fractures. As specific symptoms of hypercortisolism are absent in SH, the SH diagnosis relies only on biochemical tests and it is a challenge for physicians. As a consequence, even the indications for the evaluation of bone involvement in SH patients are debatable and guidelines are not available. Finally, the relative importance of bone density, bone quality and glucocorticoid sensitivity in SH is a recent field of research. On the other hand, SH prevalence seems to be increased in osteoporotic patients, in whom a vertebral fracture may be the presenting symptom of an otherwise asymptomatic cortisol excess. Therefore, the issue of who and how to screen for SH among the osteoporotic patients is widely debated. The present review will summarize the available data regarding the bone turnover, bone mineral density, bone quality and risk of fracture in patients with endogenous SH. In addition, the role of the individual glucocorticoid sensitivity in SH-related bone damage and the problem of diagnosing and managing the bone consequences of SH will be reviewed. Finally, the issue of suspecting and screening for SH patients with apparent primary osteoporosis will be addressed. 10.1530/EJE-16-0289
    Low DHEAS: A Sensitive and Specific Test for the Detection of Subclinical Hypercortisolism in Adrenal Incidentalomas. Dennedy M Conall,Annamalai Anand K,Prankerd-Smith Olivia,Freeman Natalie,Vengopal Kuhan,Graggaber Johann,Koulouri Olympia,Powlson Andrew S,Shaw Ashley,Halsall David J,Gurnell Mark The Journal of clinical endocrinology and metabolism CONTEXT:Subclinical hypercortisolism (SH) occurs in 5% to 30% of adrenal incidentalomas (AIs). Common screening tests for adrenocorticotropin-independent hypercortisolism have substantial false-positive rates, mandating further time and resource-intensive investigations. OBJECTIVE:To determine whether low basal dehydroepiandrosterone sulfate (DHEAS) is a sensitive and specific screening test for SH in AI. SETTING AND PATIENTS:In total, 185 patients with AI were screened for adrenal medullary (plasma metanephrines) and cortical [1 mg overnight dexamethasone suppression test (ONDST), 24-hour urinary free cortisol (UFC), serum DHEAS, plasma renin, and aldosterone] hyperfunction. Positive ONDST [≥1.8 mcg/dL (≥50 nmol/L)] and/or UFC (more than the upper limit of reference range) results were further investigated. We diagnosed SH when at least 2 of the following were met: raised UFC, raised midnight serum cortisol, 48-hour dexamethasone suppression test (DST) cortisol ≥1.8 mcg/dL (≥50 nmol/L). RESULTS:29 patients (16%) were diagnosed with SH. Adrenocorticotropin was <10 pg/mL (<2.2 pmol/L) in all patients with SH. We calculated age- and sex-specific DHEAS ratios (derived by dividing the DHEAS by the lower limit of the respective reference range) for all patients. Receiver operating characteristic curve analyses demonstrated that a ratio of 1.12 was sensitive (>99%) and specific (91.9%) for the diagnosis of SH. Cortisol following 1 mg ONDST of 1.9 mcg/dL (53 nmol/L) was a sensitive (>99%) screening test for SH but had lower specificity (82.9%). The 24-hour UFC lacked sensitivity (69%) and specificity (72%). CONCLUSION:A single basal measurement of DHEAS offers comparable sensitivity and greater specificity to the existing gold-standard 1 mg DST for the detection of SH in patients with AIs. 10.1210/jc.2016-2718
    [Surgical excision of subclinical cortisol secreting incidentalomas: Impact on blood pressure, BMI and glucose metabolism]. Mauclère-Denost S,Duron-Martinaud S,Nunes M -L,Gatta B,Fagour C,Rault A,Gosse P,Tabarin A Annales d'endocrinologie OBJECTIVES:To compare clinical, vascular and metabolic parameters before and after surgery in patients with subclinical cortisol secreting incidentalomas. PATIENTS AND METHODS:Eight patients were investigated before and 12 months after removal of the mass on hemodynamic (blood pressure by MAPA procedure), anthropometric (body weight, body mass index), and metabolic parameters (glucose level, HbA(1c)). RESULTS:In the whole group, 75% of patients displayed decrease in blood pressure (cessation of at least one hypotensive medication) and 33% of them were definitely cured of hypertension. Seventy-one percent of patients lost body weight and 37.5% lost more than 5%. In the whole group of patients, glucose level decreased by 1.1% and medical treatment was discontinuated in two of three diabetic patients. CONCLUSION:Subclinical cortisol secreting adrenal incidentalomas are associated with cardiovascular risk factors that may be corrected after removal of the mass. Therefore, surgery may be an appropriate choice in patients with subclinical Cushing's syndrome to improve hypertension, body weight and impaired glucose level. Controlled studies comparing surgical treatment to a medical follow-up including optimal cardiovascular risk factors treatment are needed to define the usefulness of surgery in hypertensive patients with subclinical cortisol secreting incidentalomas. 10.1016/j.ando.2009.03.005
    Hypercortisolism in obesity-associated hypertension. Varughese Amy G,Nimkevych Oksana,Uwaifo Gabriel I Current hypertension reports Obesity is prevalent worldwide and associated with co-morbidities that result in increased cardiovascular risk. Hypertension is the most prevalent obesity comorbidity associated with increased cardiovascular risk. Obesity hypertension is a distinct subtype of essential hypertension. While endogenous Cushing's syndrome is an uncommon cause of both obesity and hypertension, the recent recognition of other hypercortisolemic states has raised the profile of hypercortisolism as an important contributor in obesity hypertension. The high prevalence of exogenous, iatrogenic, pseudo, and subclinical Cushing's syndromes makes hypercortisolism an important diagnostic consideration in the evaluation and management of patients with obesity hypertension who are resistant to conventional management. Available data suggest that the renin-angiotensin-aldosterone system modulating antihypertensives have the best efficacy in hypercortisolism-mediated obesity hypertension. Strategies aimed at reducing cortisol production and action also have utility. This review provides a comprehensive overview of the epidemiology, etiopathogenesis and management options available for glucocorticoid-mediated obesity hypertension. 10.1007/s11906-014-0443-y
    Prevalence of subclinical hypercortisolism in type 2 diabetic patients from the Rio de Janeiro Type 2 Diabetes Cohort Study. Costa Denise S,Conceição Flavia L,Leite Nathalie C,Ferreira Marcel T,Salles Gil F,Cardoso Claudia R L Journal of diabetes and its complications AIMS:Subclinical hypercortisolism was reported to be more prevalent among diabetic, obese and hypertensive patients. Our primary aim was to investigate the prevalence of subclinical hypercortisolism in patients from the Rio de Janeiro Type 2 Diabetes (RIO-T2D) Cohort; and secondarily to assess its associated factors. METHODS:From May 2013 to August 2014, 393 diabetic outpatients underwent overnight 1mg dexamethasone suppression test (DST). Patients with non-suppressive morning cortisol (≥1.8μg/dl) were further evaluated with nocturnal salivary cortisol, two readings >0.35μg/dl were considered confirmatory for subclinical hypercortisolism. RESULTS:One-hundred twenty-eight patients (32.6%) failed to suppress morning cortisol, and in 33 patients (8.6%) subclinical hypercortisolism was confirmed. Independent correlates of a positive DST were older age (OR: 1.04; 95% CI: 1.01-1.07; p=0.007), number of anti-hypertensive drugs in use (OR: 1.26; 95% CI: 1.05-1.50; p=0.012), longer diabetes duration (OR: 1.03; 95% CI: 1.004-1.06; p=0.023), and presence of diabetic nephropathy (OR: 1.70; 95% CI: 1.01-2.87; p=0.047). Independent correlates of confirmed subclinical hypercortisolism were a greater number of anti-hypertensive medications (OR: 1.54; 95% CI: 1.14-2.06; p=0.004), shorter diabetes duration (OR: 0.92; 95% CI: 0.87-0.98; p=0.006), and increased aortic stiffness (OR: 2.81; 95% CI: 1.20-6.57; p=0.017); metformin use was protective (OR: 0.27; 95% CI: 0.10-0.73; p=0.010). CONCLUSION:Patients with type 2 diabetes had a high prevalence of subclinical hypercortisolism, and its presence was associated with more severe hypertension and increased aortic stiffness. 10.1016/j.jdiacomp.2016.05.006
    Assessment of platelet function in endogenous hypercortisolism. Świątkowska-Stodulska Renata,Mital Andrzej,Wiśniewski Piotr,Babińska Anna,Skibowska-Bielińska Anna,Sworczak Krzysztof Endokrynologia Polska INTRODUCTION:It is commonly known that glucocorticoids exert a significant effect on haemostasis. Studies that have analysed the plasmatic coagulation system and fibrinolysis parameters in hypercortisolaemic patients are abundant. Platelet function, which plays a vital role in primary haemostasis, is much less clear in this context. We aimed at assessing platelet function in endogenous hypercortisolaemic patients. MATERIAL AND METHODS:Twenty-five hypercortisolaemic patients were included in the study. Twelve of them were diagnosed with overt Cushing's syndrome (OCS) and 13 had subclinical Cushing's syndrome (SCS). Thirty healthy volunteers comprised the control group. In all subjects platelet function parameters were examined: ADP- and collagen-induced platelet aggregation (ADP-IPA and Col-IPA, respectively), IMPACT R (expressed as percentage of surface covered (SC) by platelets and average size (AS) of the adhering particles in μm2), as well as closure time (CT) after platelet activation with agonists: ADP and Col or Col and epinephrine (EPI). The statistical significance level was set at 0.05. RESULTS:There was no significant difference in mean values of ADP-IPA, Col-IPA, Col/Epi CT, Col/ADP CT, SC, and AS between hypercortisolaemic subjects and controls. No statistically significant differences in means of examined parameters were found between overt and subclinical Cushing's syndrome patients. Furthermore, no statistically significant relationships were found between these parameters and hormonal indicators of hypercortisolism: 24-hour urinary cortisol excretion, morning and evening serum cortisol level, and overnight-test cortisol concentration. CONCLUSIONS:In hypercortisolaemic patients no primary haemostasis disorders are present, as reflected by platelet adhesion and ADP- and collagen-induced aggregation measurements. 10.5603/EP.2015.0014
    Clinical significance of screening for subclinical Cushing's disease in patients with pituitary tumors. Tamada Daisuke,Kitamura Tetsuhiro,Otsuki Michio,Oshino Satoru,Saitoh Youichi,Shimomura Iichiro Endocrine journal Cushing's syndrome (CS) is a clinical state caused by chronic excess of glucocorticoid, and results in hypertension, impaired glucose tolerance, and dyslipidemia. Recently, a mild state of pituitary CS without typical Cushingoid appearance (subclinical Cushing's disease; SCD) has been identified. However, the true prevalence of SCD and its effect on metabolic disorders remain obscure. The aim of this prospective study was to determine the prevalence of SCD according to the guideline proposed by the working group of the Japanese Ministry of Health, Welfare and Labor, and to assess the outcome of surgery on metabolic disorders. The prevalence of SCD was investigated in 105 consecutive patients diagnosed with pituitary adenomas by MRI. ACTH-dependent hypercortisolism was diagnosed based on the results of the 0.5 mg dexamethasone suppression test (serum cortisol >3.0 μg/dL) plus one positive finding of the following two tests: midnight serum cortisol level >5.0 μg/dL or ACTH increase >50% after 1-deamino-5-D-arginine vasopressin (DDAVP) challenge. The final diagnosis of SCD was established by positive staining for ACTH in surgically-excised pituitary adenoma. Three patients (4.8%) were diagnosed with SCD among 62 patients with pituitary adenoma. Transsphenoidal adenomectomy partially resulted in improvement of blood pressure and glucose metabolism in SCD patients. Our results emphasize the importance of SCD screening in patients with pituitary tumors, especially in those patients with metabolic disorders. 10.1507/endocrj.EJ15-0446
    Subclinical hypercortisolism: a state, a syndrome, or a disease? Di Dalmazi Guido,Pasquali Renato,Beuschlein Felix,Reincke Martin European journal of endocrinology Subclinical hypercortisolism (SH), defined as alterations of the hypothalamus-pituitary-adrenal axis in the absence of clinical signs or symptoms related to cortisol secretion, is a common finding in patients with adrenal incidentalomas. The clinical correlates of this pathological condition have become clearer over the last few years. The aim of this review is to summarize the co-morbidities and the clinical outcomes of patients with SH. According to the analysis of the results of the studies published within the last 15 years, hypertension and type 2 diabetes are a common finding in patients with SH, occurring roughly in 2/3 and 1/3 of the patients respectively. Moreover, several additional cardiovascular and metabolic complications, like endothelial damage, increased visceral fat accumulation and impaired lipid metabolism have been shown to increase the cardiovascular risk of those patients. Accordingly, recent independent reports investigating the natural history of the disease in a long-term follow-up setting have shown that patients with SH have a higher incidence of cardiovascular events and related mortality. Moreover, longitudinal studies have also shown increased incidence of osteoporotic vertebral fractures. Future research is needed to improve the diagnostic performance of hormonal tests, by assessment of the complete steroid profile with more accurate assays, and to define the efficacy of surgical vs medical treatment in a randomized-controlled setting. 10.1530/EJE-15-0272
    Prevalence and associated factors of subclinical hypercortisolism in patients with resistant hypertension. Martins Leonam C,Conceição Flavia L,Muxfeldt Elizabeth S,Salles Gil F Journal of hypertension BACKGROUND:Subclinical hypercortisolism is a secondary cause of hypertension that had never been evaluated in resistant hypertensive patients, a subgroup of general hypertensive individuals with an expected high prevalence of secondary hypertension. METHODS:Four hundred and twenty-three patients with resistant hypertension and ages up to 80 years were screened for the presence of subclinical hypercortisolism by morning serum cortisol after a midnight 1 mg dexamethasone suppression test (DST). Those with morning cortisol of at least 50  nmol/l had hypercortisolism confirmed by two salivary cortisol of at least 3.6  nmol/l collected at 2300  h. Statistical analysis included bivariate tests between those with positive and negative screening test and with and without confirmed hypercortisolism, and logistic regressions to assess their independent correlates. RESULTS:One hundred and twelve patients (prevalence 26.5%, 95% confidence interval 22.0-31.9%) had the screening test positive for suspected hypercortisolism. None had overt Cushing syndrome. Patients with positive screening were older, more frequently males, had higher prevalences of diabetes and target-organ damage and higher nighttime SBPs than patients with normal screening test results. Thirty-four patients (total prevalence 8.0%, 95% confidence interval: 5.7-11.2%) had confirmed hypercortisolism. Independent correlates of a positive DST were older age (P = 0.007), male sex (P = 0.012) and presence of cardiovascular diseases (P = 0.002) and chronic kidney disease (P = 0.016). Correlates of confirmed subclinical hypercortisolism were older age (P = 0.020), diabetes (P = 0.06) and a nondipping pattern on ambulatory blood pressure monitoring (P = 0.04). CONCLUSION:Patients with resistant hypertension had a relatively high prevalence of subclinical hypercortisolism, and its presence is associated with several markers of worse cardiovascular prognosis. 10.1097/HJH.0b013e3283521484
    Bilateral adrenal incidentalomas differ from unilateral adrenal incidentalomas in subclinical cortisol hypersecretion but not in potential clinical implications. Vassilatou Evangeline,Vryonidou Andromachi,Ioannidis Dimitrios,Paschou Stavroula A,Panagou Maria,Tzavara Ioanna European journal of endocrinology OBJECTIVE:To investigate the possibility of a different prevalence of subclinical Cushing's syndrome (SCS) and potentially related morbidities between patients with unilateral adrenal incidentalomas (UAI) and bilateral adrenal incidentalomas (BAI), as existing data are few and controversial. DESIGN:Prospective observational study. METHODS:Clinical examination, biochemical tests, and hormonal evaluation were performed in 298 consecutive patients with adrenal incidentalomas, unilateral in 224 patients (75.2%), bilateral in 74 patients (24.8%), with apparently benign masses based on imaging characteristics and after exclusion of overt endocrine disease. The diagnosis of SCS was based on a post-dexamethasone suppression test (2 mg dexamethasone/24 h for 48 h), with serum cortisol level ≥1.8 μg/dl combined with at least one abnormal result of the other hormonal measurements. RESULTS:SCS was diagnosed in 66 out of 298 (22.1%) patients, being more frequent in patients with BAI (35.1 vs 17.9%, P=0.003, for BAI and UAI respectively). Hypertension, type 2 diabetes mellitus, impaired glucose tolerance, and dyslipidemia were of a similar frequency in both groups. SCS patients with UAI and BAI did not differ in age, gender, BMI, waist circumference, and mass size. Factors related to SCS were the presence of BAI (OR, 3.24; 95% CI, 2.31-4.54) and mass size (OR, 2.63; 95% CI, 1.31-5.26). CONCLUSION:BAI patients present more often with SCS when compared with UAI patients; however, morbidities potentially related to subtle cortisol hypersecretion were of a similar frequency in both groups. Further studies are needed to clarify whether this difference in hormonal activity may be related to different pathophysiologies. 10.1530/EJE-13-0848
    Adrenal mild hypercortisolism. Goddard Gillian M,Ravikumar Aarti,Levine Alice C Endocrinology and metabolism clinics of North America Adrenal incidentalomas have become detected more often as the use of abdominal imaging has increased. Up to one-third of these may be secreting low levels of cortisol, known as mild hypercortisolism or subclinical Cushing syndrome. These low levels of cortisol have been found to be associated with an increased in the metabolic syndrome, osteoporosis, cardiovascular events, and mortality. This article discusses in detail the epidemiology, diagnosis, clinical associations, and treatment options of mild hypercortisolism. 10.1016/j.ecl.2015.02.009
    Influence of adrenal subclinical hypercortisolism on hypertension in patients with adrenal incidentaloma. Oki K,Yamane K,Nakanishi S,Shiwa T,Kohno N Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association OBJECTIVE:The purpose of our study was to clarify whether subtle cortisol-producing tumors, such as not only subclinical Cushing's syndrome (SubCS) but also subclinical hypercortisolism (SH), influence the prevalence of hypertension, since numerous basic research studies have noted that glucocorticoid excess influences blood pressure. METHODS:80 patients with adrenocortical adenomas (39 women and 41 men; mean age 62.1 years) were enrolled. SubCS was diagnosed using a diagnostic criteria, and SH was diagnosed as the presence of a serum cortisol level greater than 50 nmol/L following 1-mg dexamethasone suppression test (DST). RESULTS:SubCS, SH, or non-functioning adrenocortical adenoma (NF) was diagnosed in 14, 13, or 53 patients, respectively. The prevalence of hypertension differed significantly among the diagnoses (SubCS, 78.6%; SH, 84.6%; NF, 39.6%; P=0.002), whereas no differences in other clinical characteristics such as age, sex, or waist girth were observed. The patients with SH had an 11.7-fold increased risk (95% confidence interval: 1.9-72.7, P=0.009) and those with SubCS had a 9.5-fold increased risk (95% confidence interval: 1.9-48.3, P=0.007) for hypertension compared to those with NF using a multivariate analysis. CONCLUSION:We demonstrated that subtle cortisol-producing tumors, such as SH as well as SubCS, were an independent risk factor for hypertension. The cut-off value of the 1-mg DST would be appropriate to predict the development of hypertension. 10.1055/s-0032-1301896
    Clinical Benefits of Unilateral Adrenalectomy in Patients with Subclinical Hypercortisolism Due to Adrenal Incidentaloma: Results from a Single Center. Petramala Luigi,Cavallaro Giuseppe,Galassi Matteo,Marinelli Cristiano,Tonnarini Gianfranco,Concistrè Antonio,Costi Umberto,Bufi Maurizio,Lucia Piernatale,De Vincentis Giuseppe,Iannucci Gino,De Toma Giorgio,Letizia Claudio High blood pressure & cardiovascular prevention : the official journal of the Italian Society of Hypertension INTRODUCTION:This study was designed to evaluate the results of unilateral laparoscopic adrenalectomy in patients with subclinical hypercortisolism (SH) due to adrenal incidentaloma (AI) concerning the main cardiometabolic disorders. METHODS:We have studied between January 2000 to December 2015, 645 patients with AI (283 males and 362 females; mean age 61.9 ± 10 years) and we found 70 patients with SH (27 males and 43 females; mean age 61.9 ± 8.4 years). Twenty-six (37%) SH patients (6 males and 20 females; mean age 58.7 ± 7.1 years) underwent unilateral laparoscopic adrenalectomy, whereas 44 SH patients (21 males and 23 females; mean age 63.9 ± 9.9 years) performed a conservative treatment. All SH patients were evaluated at diagnosis and after follow-up (mean 12 months; range 9-15 months). RESULTS:In only SH patients undergoing unilateral adrenalectomy we found a statistical significant reduction of the arterial hypertension and metabolic syndrome (p < 0.05, respectively). In particular we observed a reduction of 24-h systolic blood pressure and "non-dipper" pattern (p < 0.05, respectively) evaluated with ambulatory blood pressure monitoring (ABPM). CONCLUSIONS:Our study confirm the high prevalence of SH in AI, and the unilateral laparoscopic adrenalectomy seemed to have a beneficial effect on some cardiometabolic disorders. 10.1007/s40292-017-0182-7
    Cardiovascular and metabolic risk factors in patients with subclinical Cushing. Petramala Luigi,Olmati Federica,Concistrè Antonio,Russo Riccardo,Mezzadri Martina,Soldini Maurizio,De Vincentis Giuseppe,Iannucci Gino,De Toma Giorgio,Letizia Claudio Endocrine PURPOSE:Adrenal incidentalomas (AI) are discovered after work-up unrelated to adrenal gland diseases; up to 30% of AI show subclinical endogenous cortisol excess (SH), frequently associated to hypertension, obesity, metabolic disorders and increased incidence of cardiovascular events (CVEs). METHODS:We analysed 628 AI patients divided into two groups: 471 non-functional adrenal adenoma (NFA) and 157 SH. All patients underwent complete examinations, 24-h ambulatory blood pressure monitoring, biohumoral parameters and vascular damage markers, such as c-IMT and ankle brachial index. After long-term follow-up, we registered newly onset of CVEs such as myocardial infarction (MI), percutaneous stenting and surgical bypass (PTA/CABG), stroke, overall/cardiovascular mortality. Moreover, SH patients underwent to surgical (SSH) or pharmacological treatment (MSH). RESULTS:SH patients showed higher prevalence of metabolic syndrome, diabetes mellitus, and previous CVEs respect NFA at baseline. After follow-up MSH group showed higher recurrence of major CV events compared with NFA and SSH (RR 2.27 MSH vs NFA for MI; RR 2.30 MSH vs NFA for PTA/CABG; RR 2.41 MSH vs NFA for stroke). In SSH there was a significant reduction of the number of antihypertensive medications needed to reach target blood pressure levels (2.3 ± 1.0 to 1.5 ± 0.4 drugs). None differences were found in SH patients, distinguished in relation to cortisol plasma levels after dexamethasone suppression test (1.8-5 µg/dL, above 5 µg/dL). CONCLUSIONS:SH is linked to relevant cardiovascular and metabolic alterations, leading to worsen clinical outcomes. In eligible patients, adrenalectomy is valid and safe option to treat SH, reducing cardiometabolic abnormalities. 10.1007/s12020-020-02297-2
    Subclinical Cushing's syndrome in adrenal incidentaloma. Terzolo M,Osella G,Alì A,Borretta G,Cesario F,Paccotti P,Angeli A Clinical endocrinology OBJECTIVE:Some patients with incidentally discovered adrenal adenomas display autonomous cortisol secretion not fully restrained by pituitary feedback, a condition that may be defined as subclinical Cushing's syndrome. We have evaluated the presence of subclinical Cushing's syndrome and its natural history in a cohort of patients with incidentally discovered adrenal adenomas. PATIENTS:Fifty-three consecutive patients (30 women and 23 men; median age 58 years, range 18-81 years) were studied. Diagnostic procedures were initiated for extra-adrenal complaints. Patients with known extra-adrenal malignancies or patients with hypertension of possible endocrine origin were excluded. MEASUREMENTS:All patients underwent the following endocrine evaluation: (1) measurement of DHEA-S at 0800 h, (2) measurement of serum cortisol at 0800 and 2400 h, (3) measurement of the 24-h excretion of urinary free cortisol (UFC), (4) overnight low-dose dexamethasone suppression test, (5) measurement of plasma ACTH at 0800 h (mean of at least two samples on different days), (6) oCRH stimulation test. Different groups of healthy subjects recruited from the hospital medical staff and their relatives served as controls for the various tests. The same endocrine work-up was repeated after 12 months in 25 patients. All patients were followed up at regular intervals for at least 12 months with clinical examination and abdominal computed tomography. Subclinical hypercortisolism was arbitrarily defined as definitive, probable or possible, according to the degree of endocrine abnormalities. RESULTS:UFC was significantly higher in patients with incidentaloma than in controls (262, 25-690 nmol/24 h versus 165, 25-772 nmol/24 h; P = 0.012). The percentage of subjects who did not suppress on dexamethasone was greater among patients than among healthy subjects (9/53 (17%) versus 5/103 (5%), P = 0.026). Plasma ACTH concentrations were lower in patients with adrenal incidentaloma than in controls (3, 1-9 pmol/l versus 5, 1-14 pmol/l; P = 0.014). These findings consistently point toward a functional autonomy of the adrenal adenomas even if the degree of cortisol excess is mild. Three patients fulfilled the criteria for definitive subclinical hypercortisolism, five for probable and two possible, but none of them experienced clinical and/or biochemical progression to overt hypercortisolism after 12 months. During follow-up, no signs of extra-adrenal malignancy became manifest and the size of the mass did not increase significantly in any patient. CONCLUSIONS:This study provides a clear demonstration of the current opinion that some patients with incidentally discovered adrenal adenomas may be exposed to a subtle, silent hypercortisolism. In some patients, in whom the clustering of more abnormalities in the hypothalamo-pituitary-adrenal axis occurs, subclinical Cushing's syndrome could be assumed. This term should be preferred to that of pre-clinical Cushing's syndrome since the biochemical abnormalities do not become clinically manifest, at least in the short term.
    Subclinical Cushing's syndrome in patients with adrenal incidentaloma: clinical and biochemical features. Rossi R,Tauchmanova L,Luciano A,Di Martino M,Battista C,Del Viscovo L,Nuzzo V,Lombardi G The Journal of clinical endocrinology and metabolism Incidentally discovered adrenal masses are mostly benign, asymptomatic lesions, often arbitrarily considered as nonfunctioning tumors. Recent studies, however, have reported increasing evidence that subtle cortisol production and abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis are more frequent than previously thought. The purpose of this study was to investigate the clinical and hormonal features of patients with incidentally discovered adrenal adenomas, in relation to their clinical outcome. Fifty consecutive patients with incidentally detected adrenal adenomas, selected from a total of 65 cases of adrenal incidentalomas, were prospectively evaluated. All of them underwent abdominal computed tomography scan and hormonal assays of the HPA axis function: circadian rhythm of plasma cortisol and ACTH, urinary cortisol excretion, 17-hydroxyprogesterone, androgens, corticotropin stimulation test and low-dose (2 mg) dexamethasone test. The patients were reevaluated at regular intervals (6, 12, and 24 months) for a median period of 38 months. Subtle hypercortisolism, defined as abnormal response to at least 2 standard tests of the HPA axis function in the absence of clinical signs of Cushing's syndrome (CS), was defined as subclinical CS. Mild-to-severe hypertension was found in 24 of 50 (48%) patients, type-2 diabetes in 12 of 50 (24%), and glucose intolerance in 6 of 50 (12%) patients. Moreover, 18 of 50 patients (36%) were diffusely obese (body mass index, determined as weight/height2, > 25), and 14 patients (28%) had serum lipid concentration abnormalities (cholesterol > or = 6.21 mmol/L, low-density lipoprotein cholesterol > or = 4.14 mmol/L and/or triglycerides > or = 1.8 mmol/L). Compared with a healthy population, bone mineral density Z-score, determined by the DEXA technique, tended to be slightly (but not significantly) lower in patients with adrenal adenoma (-0.41 SD). Endocrine data were compared with 107 sex- and age-matched controls, and patients with adenomas were found to have heterogeneous hormonal abnormalities. In particular, significantly higher serum cortisol values (P < 0.001), lower ACTH concentration (P < 0.05), and impaired cortisol suppression by dexamethasone (P < 0.001) were observed. Moreover, in patients with adenomas, cortisol, 17-OH progesterone, and androstenedione responses to corticotropin were significantly increased (P < 0.001, all), whereas dehydroepiandrosterone sulfate levels were significantly lower at baseline, with blunted response to corticotropin (P < 0.001, both). However, the criteria for subclinical CS were met by 12 of 50 (24%) patients. Of these, 6 (50%) were diffusely obese, 11 (91.6%) had mild-to-severe hypertension, 5 (41.6%) had type-2 diabetes mellitus, and 6 (50%) had abnormal serum lipids. The clinical and hormonal features improved in all patients treated by adrenalectomy, but seemed unchanged in all those who did not undergo surgery (follow-up, 9 to 73 months), except for one, who was previously found as having nonfunctioning adenoma and then revealed to have subclinical CS. In conclusion, an unexpectedly high prevalence of subtle autonomous cortisol secretion, associated with high occurrence of hypertension, diabetes mellitus, elevated lipids, and diffuse obesity, was found in incidentally discovered adrenal adenomas. Although the pathological entity of a subclinical hypercortisolism state remained mostly stable in time during follow-up, hypertension, metabolic disorders, and hormonal abnormalities improved in all patients treated by adrenalectomy. These findings support the hypothesis that clinically silent hypercortisolism is probably not completely asymptomatic. 10.1210/jcem.85.4.6515
    Adrenal incidentalomas and subclinical Cushing's syndrome: is there evidence for glucocorticoid-induced osteoporosis? Angeli A,Osella G,Reimondo G,Terzolo M Frontiers of hormone research 10.1159/000061074
    Subclinical Hypercortisolism: How to Deal with It? Chiodini Iacopo,Morelli Valentina Frontiers of hormone research Subclinical hypercortisolism (SH) is a condition of mild cortisol excess, found in the 5-30% of patients with adrenal incidentalomas, defined as silent adrenal masses diagnosed throughout radiological examinations performed for unrelated diseases. Generally, the diagnosis of SH is supported by the presence of high cortisol levels after a 1-mg dexamethasone suppression test, low adrenocorticotropic hormone levels, altered cortisol circadian rhythm and 24-hour urinary free cortisol levels higher than the upper reference value. Less frequently, diagnosis is made by other tests. Unfortunately, up to now a consensus on SH diagnostic criteria is lacking. Although SH is characterized by the absence of the classical features of Cushing's syndrome by definition, it has been associated with the presence of different metabolic complications (mainly type 2 diabetes mellitus, arterial hypertension, central obesity and dyslipidemia), cardiovascular diseases, osteoporosis and vertebral fractures, altered coagulation parameters, worsening of quality of life, and increased mortality. The management of SH, as well as the improvement of metabolic parameters and other complications after surgical treatment, is still a matter of debate. 10.1159/000443862
    Subclinical hypercortisolism in adrenal incidentaloma. Debono Miguel,Newell-Price John Current opinion in endocrinology, diabetes, and obesity PURPOSE OF REVIEW:The article aims to update the reader on current developments in the area of adrenal incidentaloma complicated by subclinical hypercortisolism. We will discuss different diagnostic strategies and complications associated with this disease, and address the conflicting opinions related to the treatment of these patients. RECENT FINDINGS:Depending on diagnostic criteria used, between 30 and 50% of patients with adrenocortical incidentaloma have biochemical hypercortisolism, but lack classical external features of Cushing's syndrome. The challenge facing the clinician is that in the sixth and seventh decade of life hypertension, diabetes, osteoporosis and obesity are common and establishing whether these are directly related to the low-grade excess cortisol secretion in a given individual is not straightforward. Nevertheless, this subclinical hypercortisolism has been found to be associated with multiple cardiovascular risk factors, an increased predisposition to cardiovascular events and a higher mortality rate. The dilemma is that it is not established whether surgical excision of the adrenal adenoma in a given individual will improve these complications, and data demonstrate that surgical studies are conflicting. SUMMARY:Subclinical hypercortisolism is associated with multiple complications and definite guidelines for diagnosis are necessary. Prospective, randomized controlled studies are needed to ascertain whether medical or surgical interventions are justified, and in which patients. 10.1097/MED.0000000000000151
    The association of cortisol and adrenal androgen with trabecular bone score in patients with adrenal incidentaloma with and without autonomous cortisol secretion. Kim B-J,Kwak M K,Ahn S H,Kim J S,Lee S H,Koh J-M Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA Despite ethnic differences in cortisol sensitivity, only one study in Caucasians has assessed trabecular bone score (TBS) in patients with subclinical hypercortisolism (SH). We showed that both subtle cortisol excess and reduced adrenal androgen may contribute to impaired bone quality in Asian women with SH. INTRODUCTION:One study in Caucasians has assessed trabecular bone score (TBS), an index of bone microstructure, in adrenal incidentaloma (AI) patients with subclinical hypercortisolism (SH). There are ethnic differences in cortisol sensitivities between Caucasian and Asian populations. We investigated the associations of cortisol and the adrenal androgen dehydroepiandrosterone-sulfate (DHEA-S) with TBS in AI patients with SH, adrenal Cushing's syndrome (CS), and nonfunctional AI (NFAI). METHODS:We measured TBS, cortisol levels after the overnight 1 mg dexamethasone suppression test (1 mg DST), and cortisol/DHEA-S in 61 patients with SH (30 men; 31 women), 19 with adrenal CS (4 men; 15 women), and 355 with NFAI (213 men; 142 women). RESULTS:After adjusting for confounders, the serum cortisol level after 1 mg DST was inversely correlated with TBS in men (β = -0.133, P = 0.045) and women (β = - 0.140, P = 0.048). Higher cortisol/DHEA-S ratio was associated with lower TBS in women (β = - 0.252, P < 0.001), but not men. This inverse association of cortisol/DHEA-S ratio in women remained statistically significant after adjusting for the serum cortisol level after 1 mg DST (β = - 0.221, P = 0.008). Compared with women with NFAI, women with SH had 2.2% lower TBS (P = 0.040). Deteriorated bone microstructure (TBS < 1.230) was associated with the serum cortisol level after 1 mg DST (odds ratio [OR], 2.18; 95% confidence interval [CI], 1.04-4.53) and cortisol/DHEA-S ratio (OR, 2.05; 95% CI, 1.03-4.08). CONCLUSIONS:Subtle cortisol excess in both genders and reduced DHEA-S, especially in women, may contribute to impaired bone quality in Asian patients with SH. 10.1007/s00198-018-4608-4
    Progressively increased patterns of subclinical cortisol hypersecretion in adrenal incidentalomas differently predict major metabolic and cardiovascular outcomes: a large cross-sectional study. Di Dalmazi Guido,Vicennati Valentina,Rinaldi Eleonora,Morselli-Labate Antonio Maria,Giampalma Emanuela,Mosconi Cristina,Pagotto Uberto,Pasquali Renato European journal of endocrinology BACKGROUND:Subclinical Cushing's syndrome (SCS) is defined as alterations in hypothalamic-pituitary-adrenal axis without classic signs/symptoms of glucocorticoid excess. Whether SCS leads to metabolic and cardiovascular diseases is still controversial. AIM:To evaluate the prevalence of hypertension, type 2 diabetes (T2D), coronary heart disease (CHD), ischemic stroke, osteoporosis, and fractures, and their relationship to increasing patterns of subclinical hypercortisolism, in patients with nonsecreting adrenal adenomas (NSA) and SCS. METHODS:Using the 1 mg dexamethasone suppression test (DST), 348 patients were classified as follows: 203 were defined as NSA and 19 SCS, using the most stringent cutoff values (<50 and >138 nmol/l respectively). Patients with cortisol post-DST (50-138 nmol/l) were considered as intermediate phenotypes and classified as minor (n=71) and major (n=55) using plasma ACTH and/or urinary free cortisol as additional diagnostic tools. RESULTS:SCS patients showed higher prevalence of T2D, CHD, osteoporosis, and fractures with respect to NSA. Intermediate phenotypes also showed higher prevalence of CHD and T2D with respect to NSA. The prevalence of all clinical outcomes was not different between intermediate phenotype patients, which were therefore considered as a single group (IP) for multivariate logistic regression analysis: both IP and SCS-secreting patterns showed a significant association with CHD (odds ratio (OR), 4.09; 95% confidence interval (CI), 1.47-11.38 and OR, 6.10; 95% CI, 1.41-26.49 respectively), independently of other potential risk factors. SCS was also independently associated with osteoporosis (OR, 5.94; 95% CI, 1.79-19.68). CONCLUSIONS:Patterns of increasing subclinical hypercortisolism in adrenal adenomas are associated with increased prevalence of adverse metabolic and cardiovascular outcomes, independently of other potential risk factors. 10.1530/EJE-11-1039
    Activity of selected coagulation factors in overt and subclinical hypercortisolism. Świątkowska-Stodulska Renata,Skibowska-Bielińska Anna,Wiśniewski Piotr,Sworczak Krzysztof Endocrine journal It is universally acknowledged that glucocorticoids are hormones that exert a significant effect on hemostasis. The aim of this study was to analyze the activities of coagulation factors VIII, von Willebrand (vW), IX, X, and XI, in patients with overt and subclinical hypercortisolism, as well as to examine possible associations between activities of these factors and the degree of hypercortisolism. Thirty endogenous hypercortisolemic patients were included in the study. Twelve of them were diagnosed with overt Cushing's syndrome (OCS), and eighteen with subclinical Cushing's syndrome (SCS). Healthy, age- and sex-matched volunteers comprised the control group. Activities of coagulation factors VIII, IX, X, and XI were examined using a coagulometric method, and von Willebrand factor (vWF) using an immunoturbidimetric method. Mean activities of examined coagulation factors were significantly higher in OCS patients in comparison to healthy controls. SCS patients had significantly higher mean vWF activities versus controls; and a clear trend toward higher mean activities of other factors in SCS patients versus controls was recorded (but no significant differences). Furthermore, statistically significant positive correlations were found between activities of factor IX and: morning serum cortisol concentrations, 24-hour urinary cortisol excretion values, cortisol concentrations in the overnight suppression test with 1 mg of dexamethasone. Activities of factors X and XI positively correlated with cortisol levels in the overnight suppression test. In endogenous hypercortisolemic patients the coagulation pathway is hyperactivated as indicated by increased activities of coagulation factors. These disorders are evident among patients with overt hypercortisolism. 10.1507/endocrj.EJ14-0539
    Recent Advances on Subclinical Hypercortisolism. Zavatta Guido,Di Dalmazi Guido Endocrinology and metabolism clinics of North America During the last 20 years, a significant body of literature has accumulated regarding subclinical hypercortisolism in patients with adrenal incidentalomas. Retrospective studies have indicated these patients have an increase in cardiovascular events and mortality. Current recommendations for patients with adrenal incidentalomas include an overnight low-dose dexamethasone suppression test and a thorough evaluation of cardiovascular and metabolic risk factors. Further hormonal testing and close monitoring are necessary in patients with incomplete suppression. Unilateral adrenalectomy may be beneficial in cases with abnormal suppression and comorbidities related to hypercortisolemia. Prospective studies are need for a better risk stratification and tailored therapy. 10.1016/j.ecl.2018.01.003
    The frequency of type 2 diabetic patients who meet the endocrinological screening criteria of subclinical Cushing's disease. Murakami Hiroshi,Nigawara Takeshi,Sakihara Satoru,Kageyama Kazunori,Yamashita Maki,Matsuki Kota,Tanabe Jutaro,Matsui Jun,Tamasawa Naoki,Suda Toshihiro Endocrine journal Cushing's syndrome, including its mild form/state of adrenal-dependent subset (subclinical Cushing's syndrome; subCS), is known to enhance glucose intolerance, hypertension and obesity. Recently, subclinical Cushing's disease (subCD) has been identified, but its prevalence and the extent of consequent metabolic derangement are unclear. We screened 90 type 2 diabetic patients hospitalized in our department for subCD, according to the diagnostic guideline proposed by the working group of Japanese Ministry of Health, Welfare and Labor in 2006. Plasma ACTH and cortisol levels in the morning and at midnight were determined, and overnight 0.5 mg dexamethasone suppression test (DST) was performed. Those who showed poor cortisol suppression in DST underwent the desmopressin (DDAVP) test. Fifty-seven patients (63.3%) demonstrated abnormally high midnight cortisol levels (>or=2.5 microg/dL), while only nine of them failed to suppress plasma cortisol levels to <3 microg/dL after DST. Although none of the eight patients who underwent the DDAVP test demonstrated the anticipated paradoxical rise in plasma ACTH, these eight patients (8.9%) endocrinologically met the screening criteria of subCD. Since a considerable percentage of pituitary adenomas causing overt Cushing's disease are not identifiable in magnetic resonance imaging, many of those causing subCD may also be unidentifiable. Further follow-up studies including confirmatory testing and pituitary imaging are necessary.
    Subclinical Cushing's Syndrome and Metabolic Disorder. Bae Ji Cheol Endocrinology and metabolism (Seoul, Korea) 10.3803/EnM.2014.29.4.441
    Nondiabetic patients with either subclinical Cushing's or nonfunctional adrenal incidentalomas have lower insulin sensitivity than healthy controls: clinical implications. Ivović Miomira,Marina Ljiljana V,Vujović Svetlana,Tančić-Gajić Milina,Stojanović Miloš,Radonjić Nevena V,Gajić Milan,Soldatović Ivan,Micić Dragan Metabolism: clinical and experimental OBJECTIVE:The aim of this study was to estimate insulin sensitivity (IS) in nondiabetic patients with adrenal incidentalomas (AI): nonfunctional adrenal incidentalomas (NAI) and patients with AI and subclinical Cushing's syndrome (SCS). METHODS:Based on the inclusion criteria (normal fasting glucose levels, no previous history of impaired fasting glucose and/or diabetes, and no medications or concomitant relevant diseases) and the exclusion criteria (pheochromocytoma, overt hypercortisolism, hyperaldosteronism, adrenal carcinoma, metastasis of extra-adrenal tumors, extra-adrenal malignancies), 142 subjects were drawn from a series of patients with AI. The subjects were age-, sex- and body mass index (BMI)-matched: 70 with NAI (50 women and 20 men), 37 with AI and SCS (31 women and 6 men) and 35 healthy control (HC) subjects (30 women and 5 men). The oral glucose tolerance test (OGTT) and several indices of insulin sensitivity (IS) were used: homeostasis model assessment (HOMA), quantitative insulin sensitivity check index (QUICKI), triglycerides and glucose index (TyG), index of whole-body insulin sensitivity (ISI-composite) and glucose to insulin ratio (G/I). RESULTS:There was a significant difference in IS between subjects with NAI and HC (HOMA, p=0.049; QUICKI, p=0.036; TyG, p=0.002; ISI-composite, p=0.024) and subjects with SCS and HC (AUC insulin, p=0.01; HOMA, p=0.003; QUICKI, p=0.042; TyG, p=0.008; ISI-composite, p=0.002). There was no difference in the tested indices of IS between subjects with NAI and SCS (p>0.05). However, subjects with SCS had a significantly higher prevalence of impaired glucose tolerance and higher area under the curve for glucose than subjects with NAI (p=0.0174). The linear regression analysis showed that 1 mg-DST cannot be used as a predictor of HOMA (R(2)=0.004, F=0.407, p=0.525). Significant relationship was found between 1 mg-DST and ISI-composite (R(2)=0.042, F=4.981, p=0.028) but this relationship was weak and standard error of estimate was high. The linear regression model also showed that ACTH cannot be used as a predictor of HOMA (R(2)=0.001, F=0.005, p=0.943) or ISI-composite (R(2)=0.015, F=1.819, p=0.187). CONCLUSIONS:Insulin resistance is a major cardiovascular risk factor; therefore, the assessment of IS in patients with AI, even nonfunctional, has a valuable place in the endocrine workup of these patients. 10.1016/j.metabol.2012.12.006
    Evaluation of the cardiovascular risk in patients with subclinical Cushing syndrome before and after surgery. Erbil Yeşim,Ademoğlu Evin,Ozbey Neşe,Barbaros Umut,Yanik Burcu Tulumoğlu,Salmaslioğlu Artur,Bozbora Alp,Ozarmağan Selçuk World journal of surgery BACKGROUND:The widespread use of ultrasound, computerized tomography, and magnetic resonance imaging has led to an increase in the number of incidental adrenal masses identified. Asymptomatic incidentally discovered adrenal masses may indicate that subclinical Cushing syndrome (SCS) is not uncommon. We aimed to evaluate the cardiovascular risk of patients with SCS before and after surgery. METHODS:An autonomous cortisol-producing tumor was detected in 11 of 94 patients with adrenal incidentaloma between 1995 and 2005. Twenty-eight patients suffering from classical Cushing syndrome (CS) associated with unilateral adrenocortical adenoma, who were treated at our department in the same period, served as a control group. Cardiovascular risk factors such as blood pressure, body mass index, and lipid profile were evaluated before and 1 year after surgery. RESULTS:The frequency of hypertension (61% versus 63%), obesity (46% versus 55%), diabetes mellitus (50% versus 36%), hypercholesterolemia (39% versus 36%), and low HDL cholesterol (28% versus 36%) were not significantly different between CS and SCS patients, respectively. Adverse cardiovascular risk profile improved 1 year after adrenalectomy in both groups, although the changes were not significant with respect to body mass index, frequency of diabetes, and hyperlipidemia in SCS patients. But frequency of systolic/diastolic hypertension decreased significantly in this group. CONCLUSIONS:These findings indicate that the increased incidence of cardiovascular risk factors commonly observed in classical CS, is also present in SCS. Unilateral adrenalectomy does not always lead to significant improvements in cardiovascular risk profile in SCS. 10.1007/s00268-005-0681-x
    New diagnostic criteria for subclinical hypercortisolism using postsurgical hypocortisolism: the Co-work of Adrenal Research study. Lee Seung Hun,Song Kee-Ho,Kim Jinju,Park Sooyoun,Ahn Seong Hee,Kim Hyeonmok,Cho Yoon Young,Suh Sunghwan,Kim Beom-Jun,Kim Jae Hyeon,Koh Jung-Min Clinical endocrinology OBJECTIVE:There is no consensus on the biochemical diagnostic criteria for subclinical hypercortisolism (SH). Using parameters related to the hypothalamic-pituitary-adrenal axis, we aimed to develop a diagnostic model of SH for predicting postsurgical hypocortisolism and metabolic complications. DESIGN:Prospective and cross-sectional, observational, multicentre study in Korea. METHODS:After exclusion of overt Cushing's syndrome, adrenal incidentaloma (AI) patients who underwent unilateral adrenalectomy (n = 99) and AI patients (n = 843) were included. Primary outcome was defined as the presence of postsurgical hypocortisolism; secondary outcome was the presence of ≥4 complications (components of the metabolic syndrome and low bone mass). Postsurgical hypocortisolism was determined on the fifth postsurgery day using the ACTH stimulation test. RESULTS:Thirty-three of the 99 patients developed postsurgical hypocortisolism. Analysis of the presurgery overnight 1-mg dexamethasone suppression test (1-mg DST) showed that all patients with cortisol levels of >138 nmol/l experienced postsurgical hypocortisolism, whereas those with levels of ≤61 nmol/l did not. The models of (i) 1-mg DST >138 nmol/l or (ii) >61 nmol/l with the presence of one among low levels of ACTH and dehydroepiandrosterone-sulphate had the highest accuracy (89·9%, P < 0·001) and odds ratio [OR 111·62, 95% confidence interval (CI) 21·98-566·74, P < 0·001] for predicting postsurgical hypocortisolism. Finally, patients with the same criteria in the 843 AI patients showed the highest risk for having ≥4 complications (OR 3·51, 95% CI 1·84-6·69, P < 0·001), regardless of gender, age, body mass index and bilaterality. CONCLUSIONS:Our proposed model is able to accurately predict subtle cortisol excess and its chronic manifestations in AI patients. 10.1111/cen.13145
    Prevalence of subclinical Cushing's syndrome in 70 patients with adrenal incidentaloma: clinical, biochemical and surgical outcomes. Emral Rifat,Uysal Ali Riza,Asik Mehmet,Gullu Sevim,Corapcioglu Demet,Tonyukuk Vedia,Erdogan Gurbuz Endocrine journal Subclinical Cushing's syndrome (SCS) is being detected with increased frequency in patients with adrenal incidentaloma. In the current study, we evaluated the prevalence of SCS in 70 patients with adrenal incidentaloma and compared the main findings on them with other patients with nonfunctional adrenal incidentaloma (NFA). Overnight 3 mg dexamethasone (DXM) suppression test to exclude cortisol hypersecretion, and high dose DXM suppression test to find out patients with SCS, were applied to all subjects. Afterwards, biochemical and clinical findings of patients with SCS were compared with the other patients with NFA. Four of the 70 patients with adrenal incidentaloma were found to have SCS, with a prevalence of 5.7%. Basal ACTH and DHEA-S levels were significantly lower (p < 0.05 and p < 0.01, respectively), and midnight cortisol and 24-hour urinary free cortisol levels were significantly higher in patients with SCS (p < 0.001 and p < 0.05, respectively). Biochemical and metabolic bone parameters were similar in patients with SCS and in patients with NFA. Hypertension, diabetes mellitus, and obesity were more common in patients with SCS. One of the patients with SCS developed adrenocortical insufficiency following unilateral adrenalectomy which lasted for about 6 months. Suppressed ACTH and DHEA-S levels, and high midnight cortisol levels may be some clues for SCS in patients with adrenal incidentaloma. Since patients with SCS frequently have risk factors for atherosclerosis such as hypertension, diabetes, and obesity, and the surgical management of SCS with adrenalectomy may offer an advantage. Patients undergoing adrenalectomy should be followed for the development of adrenal insufficiency.
    Subclinical Cushing's syndrome. Reincke M Endocrinology and metabolism clinics of North America Classic Cushing's syndrome is a rare disease with an estimated incidence of 1 case per 100,000 persons. With routine use of imaging techniques such as ultrasound and CT, adrenal masses are being detected with increased frequency. A substantial percentage of these incidentalomas are hormonally active, with 5% to 20% of the tumors producing glucocorticoids. Autonomous glucocorticoid production without specific signs and symptoms of Cushing's syndrome is termed subclinical Cushing's syndrome. With an estimated prevalence of 79 cases per 100,000 persons, subclinical Cushing's syndrome is much more common than classic Cushing's syndrome. Depending on the amounts of glucocorticoids secreted by the tumor, the clinical spectrum ranges from slightly attenuated diurnal cortisol rhythm to complete atrophy of the contralateral adrenal gland with lasting adrenal insufficiency after unilateral adrenalectomy. Patients with subclinical Cushing's syndrome lack the classical stigmata of hypercortisolism but have a high prevalence of obesity, hypertension, and type 2 diabetes. All patients with incidentally detected adrenal masses scheduled for surgery must undergo testing for subclinical Cushing's syndrome to avoid postoperative adrenal crisis. The best screening test to uncover autonomous cortisol secretion is the short dexamethasone suppression test. Because the adrenal origin of a pathologic cortisol secretion is anticipated, the author prefers a higher dexamethasone dose (3 mg instead of 1 mg) to reduce false-positive results. A suppressed serum cortisol level of less than 3 micrograms/dL (80 nmol/L) after dexamethasone excludes significant cortisol secretion by the tumor. A serum cortisol level greater than 3 micrograms/dL requires further investigation, including confirmation by high-dose dexamethasone (8 mg) suppression testing, a CRH test, and analysis of diurnal rhythm. Determination of urinary free cortisol is less useful because increased values are a late finding usually associated with emerging clinical signs of Cushing's syndrome. Patients with suppressed plasma ACTH in response to CRH generally have adrenal insufficiency after surgery and require adequate perioperative and postoperative substitution therapy. Whether patients with subclinical Cushing's syndrome should undergo adrenalectomy is a matter of debate. The author performs surgery in young patients (< 50 years), in patients with suppressed plasma ACTH, and in patients with a recent history of weight gain, substantial obesity, arterial hypertension, diabetes mellitus, and osteopenia. In completely asymptomatic patients with normal plasma ACTH concentrations and in patients older than 75 years, the author recommends a nonsurgical approach. A large prospective randomized study is necessary to evaluate the benefits of surgery versus conservative treatment in patients with subclinical Cushing's syndrome. 10.1016/s0889-8529(05)70115-8
    Cardiovascular mortality in patients with subclinical Cushing. Morelli Valentina,Arosio Maura,Chiodini Iacopo Annales d'endocrinologie Patients with adrenal incidentaloma (AI) and subclinical hypercortisolism (SH) show a high prevalence of cardiovascular risk factors and an increased prevalence and incidence of cardiovascular events. Furthermore, some recent data suggest that in these patients, the cardiovascular mortality is also increased. Unfortunately, to date, the diagnosis of SH is still a matter of debate, and, therefore, it is still not possible to address the treatment of choice (i.e. surgical or conservative approach) in many AI patients. Overall, the available data show that in AI patients with established SH the surgical removal of the adrenal mass causing SH can lead to the improvement of hypertension and diabetes, but in many patients with possible SH the effect of surgery is still largely unknown. Finally, no data are available on the effect of the recovery from SH on the cardiovascular events. Therefore, randomized studies are needed to investigate the possibility of predicting the usefulness of surgery by using the available indexes of cortisol secretion in the individual AI patient. Finally, the development of safe and well-tolerated drugs aimed to control cortisol secretion will be among the goals of the future research. 10.1016/j.ando.2018.03.005
    Surgical versus conservative management for subclinical Cushing syndrome in adrenal incidentalomas: a prospective randomized study. Toniato Antonio,Merante-Boschin Isabella,Opocher Giuseppe,Pelizzo Maria R,Schiavi Francesca,Ballotta Enzo Annals of surgery OBJECTIVE:To compare the clinical outcome of patients with subclinical Cushing syndrome (SCS) due to an adrenal incidentaloma (the autonomous hypersecretion of a small amount of cortisol, which is not enough to cause clinically-evident disease) who underwent surgery or were managed conservatively. SUMMARY BACKGROUND DATA:The most appropriate management of SCS patients is controversial, either adrenalectomy or close follow-up being recommended for their treatment. METHODS:Over a 15-year period, 45 SCS patients were randomly selected to undergo surgery (n = 23) or conservative management (n = 22). All surgical procedures were laparoscopic adrenalectomies performed by the same surgeon. All patients were followed up (mean, 7.7 years; range, 2-17 years) clinically by 2 experienced endocrinologists 6 and 12 months after surgery and then yearly, or yearly after joining the trial, particularly monitoring diabetes mellitus (DM), arterial hypertension, hyperlipidemia, obesity, and osteoporosis. The study end point was the clinical outcome of SCS patients who underwent adrenalectomy versus those managed conservatively. RESULTS:All 23 patients in the surgical arm had elective surgery. Another 3 patients randomly assigned to conservative management crossed over to the surgical group due to an increasing adrenal mass >3.5 cm. In the surgical group, DM normalized or improved in 62.5% of patients (5 of 8), hypertension in 67% (12 of 18), hyperlipidemia in 37.5% (3 of 8), and obesity in 50% (3 of 6). No changes in bone parameters were seen after surgery in SCS patients with osteoporosis. On the other hand, some worsening of DM, hypertension, and hyperlipidemia was noted in conservatively-managed patients. CONCLUSIONS:Based on the results of this study, laparoscopic adrenalectomy performed by skilled surgeons appears more beneficial than conservative management for SCS patients complying with our selection criteria. This trial is registered with Australian Clinical Trials Registry number, ANZCTR12608000567325. 10.1097/SLA.0b013e31819a47d2
    Subclinical Cushing's syndrome in adrenal incidentalomas. Sippel Rebecca S,Chen Herbert The Surgical clinics of North America Up to 20% of patients with adrenal incidentalomas have abnormal cortisol production, and can be classified as having subclinical Cushing's syndrome. Although these tumors do not secrete enough cortisol to lead to the development of overt Cushing's syndrome, they are likely playing a contributory role in the development of hypertension, diabetes, osteoporosis, and obesity. Studies suggest that many of these problems can be reversed with surgical treatment. Additionally, if this diagnosis is not sought out before pursuing an adrenalectomy for an incidentaloma, the patient can develop profound postoperative adrenal insufficiency. 10.1016/j.suc.2004.01.001
    Subclinical Cushing's syndrome in adrenal incidentalomas. Terzolo Massimo,Bovio Silvia,Reimondo Giuseppe,Pia Anna,Osella Giangiacomo,Borretta Giorgio,Angeli Alberto Endocrinology and metabolism clinics of North America This article reviews the available evidence on subclinical Cushing's syndrome in patients who have adrenal incidentalomas. The authors' aim is to present up-to-date information on the most relevant issues of subclinical Cushing's syndrome by addressing the many uncertainties and controversies surrounding this ill-defined endocrine condition. 10.1016/j.ecl.2005.01.008
    Saliva versus serum cortisol to identify subclinical hypercortisolism in adrenal incidentalomas: simplicity versus accuracy. Vieira-Correa M,Giorgi R B,Oliveira K C,Hayashi L F,Costa-Barbosa F A,Kater C E Journal of endocrinological investigation PURPOSE:Subclinical hypercortisolism (SCH) leads to metabolic derangements and increased cardiovascular risk. Cortisol autonomy is defined by the overnight 1 mg dexamethasone suppression test (DST). Saliva cortisol is an easier, stress-free, and cost-effective alternative to serum cortisol. We compared 23 h and post-1 mg DST saliva with serum cortisol to identify SCH in adrenal incidentalomas (AI). METHODS:We analyzed 359 DST obtained retrospectively from 226 AI subjects (173F/53 M; 19-83 years) for saliva and serum cortisol. We used three post-DST serum cortisol cutoffs to uncover SCH: 1.8, 2.5, and 5.0 μg/dL. We determined post-DST and 23 h saliva cortisol cutoffs by ROC curve analysis and calculated their sensitivities (S) and specificities (E). RESULTS:The sensitive 1.8 μg/dL cutoff defined 137 SCH and 180 non-functioning adenomas (NFA): post-DST and 23 h saliva cortisol S/E were: 75.2%/74.4% and 59.5%/65.9%, respectively. Using the specific 5.0 μg/dL cortisol cutoff (22 SCH/295 NFA), post-DST and 23 h saliva cortisol S/E were 86.4%/83.4% and 66.7%/80.4%, respectively. Using the intermediate 2.5 μg/dL cutoff (89 SCH/228 NFA), post-DST and 23 h saliva cortisol S/E were 80.9%/68.9% and 65.5%/62.8%, respectively. CONCLUSION:Saliva cortisol showed acceptable performance only with the 5.0 μg/dL cortisol cutoff, as in overt Cushing's syndrome. Lower cutoffs (1.8 and 2.5 μg/dL) that identify larger samples of patients with poor metabolic outcomes are less accurate for screening. These results may be attributed to pre-analytical factors and inherent patient conditions. Thus, saliva cortisol cannot replace serum cortisol to identify SCH among patients with AI for screening DST. 10.1007/s40618-019-01104-8
    Nonfunctioning and Subclinical Cortisol Secreting Adrenal Incidentalomas and their Association with Metabolic Syndrome: A Systematic Review. Indian journal of endocrinology and metabolism BACKGROUND:A growing body of evidence suggests that nonfunctioning and subclinical cortisol secreting adrenal incidentalomas (AIs) are associated with several components of metabolic syndrome resulting in increased cardiometabolic risk. The long-term metabolic outcome of these AIs is largely unknown and their most appropriate management remains controversial. OBJECTIVES:To undertake a systematic review of the prevalence of cardiometabolic abnormalities in nonfunctioning and subclinical cortisol secreting AIs and long-term outcome of conservative treatment and adrenalectomy. METHODS:MEDLINE, Cochrane Controlled Trials Register, and EMBASE were searched for relevant studies and systematic review was performed. National Institutes of Health (NIH) quality assessment tool for observational cohort and cross-sectional studies was used to assess the risk of bias in the studies. RESULTS:Of the 65 studies screened, 18 (10 retrospective, 5 prospective, 2 cross-sectional studies, and 1 randomized controlled trial) were included in the systematic review. Prevalence of hypertension (HTN), impaired glucose metabolism, dyslipidaemia, and raised body mass index (BMI) was higher in subclinical cortisol secreting AIs as compared with nonfunctioning AIs. Surgical intervention had a beneficial effect on blood pressure, glucometabolic control, and obesity in patients with subclinical Cushing's syndrome. The results for lipid metabolism were equivocal. There was no significant improvement in cardiometabolic risk factors after adrenalectomy in nonfunctioning AIs. The quality of evidence was found to be low to moderate. CONCLUSIONS:The systematic review demonstrated increased prevalence of components of metabolic syndrome in patients with subclinical cortisol secreting and nonfunctioning AIs. A beneficial role of adrenalectomy on HTN, glucometabolic control, and BMI was observed in patients with subclinical cortisol secreting AIs. 10.4103/ijem.IJEM_52_19
    Subclinical Cushing's syndrome. Terzolo Massimo,Reimondo Giuseppe,Bovio Silvia,Angeli Alberto Pituitary Clinically inapparent adrenal masses, or adrenal incidentalomas, are discovered inadvertently in the course of workup or treatment of unrelated disorders. Cortical adenoma is the most frequent type of adrenal incidentaloma accounting for approximately 50% of cases in surgical series and even greater shares in medical series. Incidentally discovered adrenal adenomas may secrete cortisol in an autonomous manner, that is not fully restrained by pituitary feed-back, in 5 to 20% of cases depending on study protocols and diagnostic criteria. A number of different alterations in the endocrine tests aimed to assess the function of the hypothalamic-pituitary-adrenal axis has been demonstrated in such patients. This heterogeneous condition has been termed as subclinical Cushing's syndrome, a definition that is more accurate than preclinical Cushing's syndrome since the evolution towards clinically overt hypercortisolism does occur rarely, if ever. The criteria for qualifying subclinical cortisol excess are controversial and we presently do not have sufficient evidence to define a gold standard for the diagnosis of subclinical Cushing's syndrome. An increased frequency of hypertension, central obesity, impaired glucose tolerance, diabetes and hyperlipoproteinemia has been described in patients with subclinical Cushing's syndrome; however, there is not evidence-based demonstration of its long-term complications and, consequently, the management of this condition is largely empirical. Either adrenalectomy or careful observation associated with treatment of metabolic syndrome has been suggested as treatment options because data are insufficient to indicate the superiority of a surgical or nonsurgical approach to manage patients with subclinical hyperfunctioning adrenal cortical adenomas. 10.1007/s11102-005-4024-6
    Clinical outcomes of surgical treatment and longitudinal non-surgical observation of patients with subclinical Cushing's syndrome and nonfunctioning adrenocortical adenoma. Maehana Takeshi,Tanaka Toshiaki,Itoh Naoki,Masumori Naoya,Tsukamoto Taiji Indian journal of urology : IJU : journal of the Urological Society of India AIMS:To investigate the outcomes of the surgical management and longitudinal assessment of patients with subclinical Cushing's syndrome (SCS) and nonfunctioning adrenocortical adenoma (NFA). MATERIALS AND METHODS:Between the years 1995 and 2008, 73 patients with asymptomatic adrenocortical adenoma were enrolled. They were informed of the risks and benefits of adrenalectomy and conservative management, and then chose the treatment. RESULTS:SCS was observed in 13 patients (17.8%) and NFA in 60 patients (82.2%). Tumor size in SCS was significantly larger than that in NFA (34.6 ± 9.7 mm vs. 24.5 ± 8.0 mm in diameter, P=0.001). Of the SCS patients, 7 also suffered from hypertension (HT), 2 from diabetes mellitus (DM) and 3 from hyperlipidemia (HL). After adrenalectomy, the insulin dose could be reduced in 2 (100%) patients with DM, in 5 (71.4%) of those with HT and in 2 (66.7%) of those with HL. In the NFA surveillance group, 1 (2.6%) case developed into SCS 3 years after the initial presentation and an increase in size of the tumor was observed in 1 (2.6%), with a mean follow-up of 51.2 months. CONCLUSIONS:Surgical resection may be beneficial for the control of SCS and is likely to provide improvement of concomitant HT, DM and HL. Although NFA can be managed conservatively, its size and hormonal activities may change longitudinally. Thus, long-term follow-up is necessary for NFA. 10.4103/0970-1591.98461
    Subclinical Cushing's syndrome: definition and management. Terzolo M,Pia A,Reimondo G Clinical endocrinology Subclinical Cushing's syndrome is an ill-defined endocrine disorder that may be observed in patients bearing an incidentally found adrenal adenoma. The concept of subclinical Cushing's syndrome stands on the presence of ACTH-independent cortisol secretion by an adrenal adenoma, that is not fully restrained by pituitary feed-back. A hypercortisolemic state of usually minimal intensity may ensue and eventually cause harm to the patients in terms of metabolic and vascular diseases, and bone fractures. However, the natural history of subclinical Cushing's syndrome remains largely unknown. The present review illustrates the currently used methods to ascertain the presence of subclinical Cushing's syndrome and the surrounding controversy. The management of subclinical Cushing's syndrome, that remains a highly debated issue, is also addressed and discussed. Most of the recommendations made in this chapter reflects the view and the clinical experience of the Authors and are not based on solid evidence. 10.1111/j.1365-2265.2011.04253.x
    Increased diagnostic probability of subclinical Cushing's syndrome in a population sample of overweight adult patients with type 2 diabetes mellitus. Caetano Maria Silvia S,Silva Regina do Carmo,Kater Claudio E Arquivos brasileiros de endocrinologia e metabologia Endogenous Cushing's Syndrome (CS) is unusual. Patients with subclinical CS (SCS) present altered cortisol dynamics without obvious manifestations. CS occurs in 2-3% of obese poorly controlled diabetics. We studied 103 overweight adult outpatients with type 2 diabetes to examine for cortisol abnormalities and SCS. All collected salivary cortisol at 23:00 h and salivary and serum cortisol after a 1 mg dexamethasone suppression test (DST). Patients whose results were in the upper quintile for each test (253 ng/dL, 47 ng/dL, and 1.8 microg/dL, respectively for the 23:00 h and post-DST saliva and serum cortisol) were re-investigated. Average values from the upper quintile group were 2.5-fold higher than in the remaining patients. After a confirmatory 2 mg x 2 day DST the investigation for CS was ended for 61 patients with all normal tests and 33 with only one (false) positive test. All 8 patients who had two abnormal tests had subsequent normal 24h-urinary cortisol, and 3 of them were likely to have SCS (abnormal cortisol tests and positive imaging). However, a final diagnosis could not to be confirmed by surgery or pathology. Although not confirmatory, the results of this study suggest that the prevalence of SCS is considerably higher in populations at risk than in the general population.
    Subclinical Cushing's syndrome. Terzolo Massimo,Bovio Silvia,Pia Anna,Osella Giangiacomo,Borretta Giorgio,Angeli Alberto,Reimondo Giuseppe Arquivos brasileiros de endocrinologia e metabologia Subclinical Cushing's syndrome (CS) is attracting increasing interest since the serendipitous discovery of an adrenal mass has become a rather frequent event owing to the routine use of sophisticated radiologic techniques. Cortical adenoma is the most frequent type of adrenal incidentaloma accounting for approximately 50% of cases in surgical series and even greater shares in medical series. Incidentally discovered adrenal adenomas may secrete cortisol in an autonomous manner that is not fully restrained by pituitary feedback, in 5 to 20% of cases depending on study protocols and diagnostic criteria. The criteria for qualifying subclinical cortisol excess are controversial and presently there is no consensus on a gold standard for the diagnosis of this condition. An increased frequency of hypertension, central obesity, impaired glucose tolerance, diabetes and hyperlipemia has been described in patients with subclinical CS; however, there is still no clear demonstration of the long-term complications of this condition whose management remains largely empirical. Either adrenalectomy or careful observation associated with treatment of the metabolic syndrome have been suggested as treatment options.
    [Subclinical Cushing's syndrome in populations at risk]. Caetano Maria Silvia S,Vilar Lucio,Kater Claudio E Arquivos brasileiros de endocrinologia e metabologia Based on autopsy studies, adrenal masses are among the most common tumors in humans. Endogenous Cushing's syndrome (CS) is unusual and adrenal adenomas account for 10% of all cases of CS. Patients with subclinical CS (SCS) present abnormal cortisol dynamics without obvious manifestations. The prevalence of hypercortisolism in clinically inapparent adrenal masses has been reported as 9%. Data from several small series of patients indicate that fewer than 20% develop hormone overproduction when followed for up to 10 years. Follow-up of patients with subclinical CS suggests that rarely masses increase in size or progress to overt CS. Adrenal incidentalomas and subclinical CS are related to metabolic disorders, in special to type-2 diabetes. The scarce available data suggest that treatment of hypercortisolism correct the metabolic abnormalities and blood pressure. Some studies evaluating the prevalence of subclinical CS in overweight type-2 diabetes patients suggest that it is considerably higher in populations at risk than in the general population.
    Posterior retroperitoneoscopic adrenalectomy for clinical and subclinical Cushing's syndrome. Agarwal Sudhi,Chand Gyan,Agarwal Amit World journal of surgery 10.1007/s00268-010-0679-x
    Supper-selective ACTH-stimulated adrenal vein sampling is necessary for detecting precisely functional state of various lesions in unilateral and bilateral adrenal disorders, inducing primary aldosteronism with subclinical Cushing's syndrome. Omura Masao,Saito Jun,Matsuzawa Yoko,Nishikawa Tetsuo Endocrine journal
    Subclinical Cushing's syndrome in adrenal incidentaloma: a common problem or an artefact of current diagnostic testing? Gagliardi Lucia,Torpy David J Clinical endocrinology 10.1111/j.1365-2265.2009.03616.x
    Subclinical Cushing's syndrome associated with an adrenocortical oncocytoma. Lee S S,Baek K H,Lee Y S,Lee J M,Kang M I,Cha B Y,Lee K W,Son H Y,Kang S K Journal of endocrinological investigation Oncocytoma is a neoplasm that can arise in several organs, and it has been more commonly described in the kidney, salivary gland and thyroid. Oncocytoma arising in the adrenal gland is a rare finding. Moreover, functioning adrenocortical oncocytoma is exceptionally rare. A 47-yr-old man was incidentally discovered to have a right adrenal mass. The patient had no clinical features suggestive of increased adrenal function. However, hormonal evaluation showed a disturbed cortisol circadian rhythm, supranormal urinary cortisol excretion, a low level of ACTH, and a lack of suppressibility of cortisol secretion after dexamethasone. Right adrenalectomy was performed, and this revealed a well-circumscribed dark-brown tumor that measured 2.4x2.2 cm. The tumor consisted almost exclusively of large eosinophilic and epitheloid cells whose cytoplasm was packed with eosinophilic granulations, which corresponded to the numerous mitochondria confirmed on electron microscopy. This is a rare case of subclinical Cushing's syndrome that was caused by adrenocortical oncocytoma. 10.1007/BF03345624
    Pros and cons of dexamethasone suppression test for screening of subclinical Cushing's syndrome in patients with adrenal incidentalomas. Reimondo G,Allasino B,Bovio S,Saba L,Ardito A,Angeli A,Terzolo M Journal of endocrinological investigation The results of dexamethasone suppression tests (DST) in the screening of subclinical hypercortisolism are not readily comparable. Aim of the present study was to review the effectiveness of overnight 1-mg DST and 8-mg DST to look for functional autonomy of clinically inapparent adrenal adenomas. Sixty-eight consecutive patients with clinically inapparent adrenal adenomas were enrolled. All patients underwent 1-mg DST. The 8-mg DST was performed in the 11 patients who had post 1-mg DST cortisol >138 nmol/l and in 11 patients who had post 1-mg DST cortisol between 50 and 138 nmol/l. The a priori probability to have autonomous cortisol secretion was defined by the presence of at least two alterations of the hypothalamic-pituitary-adrenal axis among reduced ACTH concentrations, elevated urinary free cortisol (UFC) or elevated midnight serum cortisol. Cortisol levels >138 nmol/l after the 1-mg DST increases the post-test probability of adrenal functional autonomy to 55%, whereas cortisol levels <50 nmol/l reduce the post-test probability to 8%. Cortisol levels recorded after the 8-mg DST were nonsignificantly lower than after the 1-mg DST and all the patients with cortisol >138 nmol/l after the 1-mg DST maintained cortisol above this cut-point. The 1-mg DST should be considered as the more effective test to detect autonomous cortisol secretion by a clinically inapparent adrenal adenoma when cortisol levels are >138 nmol/l, while cortisol levels <50 nmol/l reduce remarkably the post-test probability of this event. The 8-mg DST seems to replicate by large the results of the 1-mg DST. 10.3275/7167
    Assessment of vertebral microarchitecture in overt and mild Cushing's syndrome using trabecular bone score. Vinolas Helene,Grouthier Virginie,Mehsen-Cetre Nadia,Boisson Amandine,Winzenrieth Renaud,Schaeverbeke Thierry,Mesguich Charles,Bordenave Laurence,Tabarin Antoine Clinical endocrinology OBJECTIVE:Osteoporotic fractures associated with Cushing's syndrome (CS) may occur despite normal bone mineral density (BMD). Few studies have described alterations in vertebral microarchitecture in glucocorticoid-treated patients and during CS. Trabecular bone score (TBS) estimates trabecular microarchitecture from dual-energy X-ray absorptiometry acquisitions. Our aim was to compare vertebral BMD and TBS in patients with overt CS and mild autonomous cortisol secretion (MACE), and following cure of overt CS. SETTING:University Hospital. DESIGN:Monocentric retrospective cross-sectional and longitudinal studies of consecutive patients. PATIENTS:A total of 110 patients were studied: 53 patients had CS (35, 11 and 7 patients with Cushing's disease, bilateral macronodular adrenal hyperplasia and ectopic ACTH secretion respectively); 39 patients had MACE (10 patients with a late post-operative recurrence of Cushing's disease and 29 patients with adrenal incidentalomas); 18 patients with non-secreting adrenal incidentalomas. 14 patients with overt CS were followed for up to 2 years after cure. RESULTS:Vertebral osteoporosis at BMD and degraded microarchitecture at TBS were found in 24% and 43% of patients with CS, respectively (P < .03). As compared to patients with nonsecreting incidentalomas, patients with MACE had significantly decreased TBS (P < .04) but not BMD. Overt fragility fractures tended to be associated with low TBS (P = .07) but not with low BMD. TBS, but not BMD values, decreased with the intensity of hypercortisolism independently of its aetiology (P < .01). Following remission of CS, TBS improved more markedly and rapidly than BMD (10% vs 3%, respectively; P < .02). CONCLUSION:Trabecular bone score may be a promising, noninvasive, widely available and inexpensive complementary tool for the routine assessment of the impact of CS and MACE on bone in clinical practice. 10.1111/cen.13743
    Editorial comment from Dr Fang to increased expression of CYP17 and CYP11B1 in subclinical Cushing's syndrome due to adrenal adenomas. Fang Yujiang International journal of urology : official journal of the Japanese Urological Association 10.1111/j.1442-2042.2011.02843.x
    Adrenal incidentalomas and subclinical Cushing's syndrome. Abdelmannan Dima,Aron David C Reviews in endocrine & metabolic disorders The issue of cortisol secretion by adrenal masses discovered incidentally in the course of evaluation for an unrelated reason (Subclinical Cushing's Syndrome) is among the most controversial and contentious issues in clinical endocrine practice. This derives from our relatively poor ability to accurately determine clinically those at increased risk among the majority who are not, the significant limitations of available diagnostic tests, the lack of a gold standard for diagnosis or even universally agreed criteria for diagnosis. A consensus for diagnostic criteria would be a good first step on which to base the kinds of studies needed to address our uncertainties. In the meantime, we must be careful to recognize the limitations of the current evidence avoid the pitfalls of overestimation of disease prevalence and of the benefits of therapy resulting from advances in diagnostic imaging and sophisticated laboratory testing. There remains an essential role for clinical judgment. 10.1007/s11154-010-9141-5
    Editorial comment from Dr Ishidoya to increased expression of CYP17 and CYP11B1 in subclinical Cushing's syndrome due to adrenal adenomas. Ishidoya Shigeto International journal of urology : official journal of the Japanese Urological Association 10.1111/j.1442-2042.2011.02840.x
    Aberrant cortisol regulations in bilateral macronodular adrenal hyperplasia: a frequent finding in a prospective study of 32 patients with overt or subclinical Cushing's syndrome. Libé Rossella,Coste Joël,Guignat Laurence,Tissier Frédérique,Lefebvre Hervé,Barrande Gaëlle,Ajzenberg Christiane,Tauveron Igor,Clauser Eric,Dousset Bertrand,Bertagna Xavier,Bertherat Jérôme,Groussin Lionel European journal of endocrinology CONTEXT:ACTH-independent macronodular adrenal hyperplasia (AIMAH) is a rare and heterogeneous condition characterized by abnormal steroid production. Cortisol secretion can be regulated by aberrant hormone receptors. OBJECTIVE:A large series of patients with AIMAH were evaluated to provide information on the prevalence and profile of aberrant regulations, in relation with the functional status. DESIGN AND PATIENTS:Thirty-two consecutive patients with AIMAH were prospectively studied: 10 had a Cushing's syndrome (CS), and 22 had a subclinical CS (SCS). METHODS:A baseline endocrine evaluation was followed by an in vivo protocol in search of aberrant cortisol responses (seven provocative tests). An acute inhibition test with the somatostatin analog octreotide was also performed. RESULTS:At least one aberrant cortisol response was identified in 28 of 32 (87%) patients. The overall prevalence of aberrant responses was independent of the functional status. Responses to the upright posture and to metoclopramide were frequently observed (67 and 56% respectively). A glucagon response was frequently observed in the SCS group (58%). A cortisol inhibition by octreotide was specifically found in the three CS patients who positively responded to the mixed meal, and was observed also in 12 of 13 (92%) patients with SCS. CONCLUSIONS:Cortisol responses indicative of aberrant receptor expression were highly prevalent in AIMAH. Thorough phenotyping of AIMAH may help uncover the underlying pathophysiology. 10.1530/EJE-10-0195
    [Arterial hypertension and subclinical Cushing's syndrome]. Fassnacht Martin,Beuschlein Felix,Quinkler Marcus,Petersenn Stephan MMW Fortschritte der Medizin
    [ACTH-independent macronodular adrenal hyperplasia and subclinical Cushing's syndrome]. Cortés-Berdonces María,Avilés-Pérez María Dolores,García-Martín Antonia,Muñoz-Torres Manuel Medicina clinica 10.1016/j.medcli.2011.05.003
    "Subclinical Cushing's syndrome" is not subclinical: improvement after adrenalectomy in 9 patients. Mitchell Ian C,Auchus Richard J,Juneja Kavita,Chang Alice Y,Holt Shelby A,Snyder William H,Nwariaku Fiemu E Surgery BACKGROUND:A subgroup of patients with adrenal cortisol hypersecretion fails to meet the biochemical criteria for Cushing's syndrome. Appropriate therapy for this entity, subclinical Cushing's syndrome (subclinical CS), is unclear. We examined outcomes for patients who underwent unilateral adrenalectomy for subclinical CS. METHODS:Between 2003 and 2006, all patients who underwent adrenalectomy for cortisol hypersecretion caused by an adrenal mass were examined. We analyzed biochemical, metabolic, and clinical outcomes. RESULTS:Overall, 24 patients underwent adrenalectomy for adrenal cortisol hypersecretion, of which 9 were found to have subclinical CS. Median serum cortisol was 2.0 microg/dL (range, 1.1-6.1) after 1-mg overnight dexamethasone suppression testing. Suspicious clinical findings on preoperative examination included skin bruising, unexplained weight gain, proximal muscle weakness, abnormal fat pads, skin thinning, fatigue, and facial plethora. During a median follow-up period of 5 months (range, 1-30 months), all 8 patients with easy bruising noted resolution postoperatively. Fatigue improved in 4 of 5 patients, muscle weakness in 6 of 8 patients, and weight in 7 of 9 patients, with a median body mass index change of -2.0 kg/m(2) (range, -7.1 to +0.5 kg/m(2)). CONCLUSION:Adrenalectomy improves clinical and metabolic parameters for many patients with subclinical CS. 10.1016/j.surg.2007.10.001
    Improvement of hypercortisolism by β-blocker therapy in subclinical Cushing's syndrome associated with ACTH-independent macronodular adrenocortical hyperplasia. Oki Kenji,Yamane Kiminori,Nakanishi Shuhei,Nakashima Reiko,Jitsuiki Kuniaki,Kohno Nobuoki Endocrine A 61-year-old man with hypertension and diabetes was referred for the evaluation of multiple bilateral adrenal tumors. While Cushingoid features were not apparent, an elevated cortisol level in response to a low-dose dexamethasone suppression test (187.7 nmol/l), an elevated urinary cortisol level (170.9 nmol/day), and a weak response to a cosyntropin-releasing hormone (CRH) provocation test were observed. Furthermore, the serum cortisol level increased in response to a posture test or isoproterenol infusion. Accordingly, the patient was diagnosed as having ACTH-independent macronodular adrenal hyperplasia (AIMAH) with subclinical Cushing's syndrome associated with the aberrant expression of β-adrenergic receptors. After 2 months of propranolol therapy, the serum cortisol responses to a posture test and isoproterenol infusion, the cortisol level in response to a low-dose dexamethasone suppression test (102.1 nmol/l), and the urinary cortisol level (165.9 nmol/day) all normalized. While the suppression of cortisol secretion was sustained for 24 months, glucose metabolism and adrenal size were unaffected. To our knowledge, this is the first report of AIMAH accompanied by subclinical Cushing's syndrome associated with the aberrant expression of β-adrenergic receptors. Furthermore, propranolol inhibited cortisol hypersecretion in the present case. Additional cases or controlled studies are needed to determine the potential effect of propranolol on metabolic disorders and adrenal size in patients with AIMAH. 10.1007/s12020-009-9246-3
    Do the diagnostic criteria for subclinical hypercortisolism exist? Tabarin Antoine Annales d'endocrinologie "Subclinical hypercortisolism" (SH) refers to a condition associated with a mild chronic increase in cortisol secretion. By definition, patients with SH do not exhibit specific symptoms of overt Cushing's syndrome (such as purple striae, easy bruising, proximal muscle weakness), SH has been preferred to "subclinical Cushing's syndrome", a semantic ambiguity since Cushing's syndrome is, by definition, a set of symptoms; and to the term "preclinical Cushing syndrome" because the progression toward overt clinical hypercortisolism is very rare. However, SH still is misnomer as a number of studies suggest that this condition may induce long-term non-specific adverse conditions related to the mild cortisol excess (i.e. diabetes, hypertension, obesity, and osteoporosis). Various attempts have been made to define SH that remains a matter of controversies and uncertainties. 10.1016/j.ando.2018.03.013
    [Subclinical Cushing's syndrome in adrenal incidentalomas]. Bovio Silvia,Reimondo Giuseppe,Daffara Fulvia,Allasino Barbara,Angeli Alberto,Terzolo Massimo Recenti progressi in medicina In the heyday of high-tech medicine, the incidental discovery of an adrenal mass is a frequent event owing to the routine use of sophisticated radiological techniques. The potential harm to health associated with incidentally discovered cortical adenoma, the most frequent tumor among adrenal incidentalomas, is unclear at present. Incidentally discovered adrenal adenoma may secrete cortisol autonomously, in a way that is no longer under close control by pituitary feedback, in 5 to 20% of cases. At present, data are insufficient to estimate the outcome of patients with subclinical Cushing's syndrome. However, evidence is gathering that subclinical Cushing's syndrome may contribute to develop the phenotype of insulin resistance thus portending to atherosclerosis and relevant cardiovascular complications. It is tempting to speculate that subclinical Cushing's syndrome represents a very mild variant of endogenous glucocorticoid excess syndrome. Even if progression to overt glucocorticoid excess is rare, subclinical Cushing's syndrome has the potential to carry an adverse prognosis. At present, data are insufficient to indicate the superiority of a surgical or nonsurgical approach to manage patients with subclinical hyperfunctioning adrenal cortical adenoma. It is of the utmost importance to establish collaborative prospective studies with clearly defined entry criteria and standardized evaluation protocols and treatment modalities to appraise the natural history and long-term morbidity of clinically inapparent adrenal adenoma and subclinical Cushing's syndrome.
    Subclinical Cushing syndrome: a review. Starker Lee F,Kunstman John W,Carling Tobias The Surgical clinics of North America Owing to its diagnostic challenges, subclinical Cushing syndrome (SCS) is likely to be highly underdiagnosed and undertreated, and the overall incidence may be as high as 5% to 20% in patients with adrenal incidentalomas. The diagnosis can be established by a systematic and thorough biochemical evaluation. SCS has been associated with significant morbidity, which at least partly may be reversed by surgery. Given the low rates of complications and the possibility to reverse the detrimental effects of elevated cortisol secretion, minimally invasive adrenalectomy is recommended for patients with biochemically proven or suspected SCS who are appropriate surgical candidates. 10.1016/j.suc.2014.02.008
    Subclinical Cushing's syndrome and cardiovascular disease. Anagnostis Panagiotis,Karras Spyridon N,Athyros Vasilios G,Mikhailidis Dimitri P,Karagiannis Asterios The lancet. Diabetes & endocrinology 10.1016/S2213-8587(14)70080-4
    The Recovery of Hypothalamic-Pituitary-Adrenal Axis Is Rapid in Subclinical Cushing Syndrome. Kim Hee Kyung,Yoon Jee Hee,Jeong Yun Ah,Kang Ho Cheol Endocrinology and metabolism (Seoul, Korea) BACKGROUND:In subclinical Cushing syndrome (SC), it is assumed that glucocorticoid production is insufficient to cause a clinically recognizable syndrome. Differences in hormonal levels or recovery time of the hypothalamic-pituitary-adrenocortical (HPA) axis after adrenalectomy between patients with overt Cushing syndrome (OC) and SC remain unknown. METHODS:Thirty-six patients (10 with OC and 26 with SC) with adrenal Cushing syndrome who underwent adrenalectomy from 2004 to 2014 were reviewed retrospectively. Patients were treated with glucocorticoid after adrenalectomy and were reevaluated every 1 to 6 months using a rapid adrenocorticotropic hormone (ACTH) stimulation test. RESULTS:Levels of basal 24-hour urine free cortisol (UFC), serum cortisol after an overnight dexamethasone suppression test (DST), and serum cortisol and 24-hour UFC after low-dose DST and high-dose DST were all significantly lower in patients with SC compared with OC. Basal ACTH levels showed significantly higher in patients with SC compared with OC. The probability of recovering adrenal function during follow-up differed significantly between patients with OC and SC (P=0.001), with significant correlations with the degree of preoperative cortisol excess. Patients with OC required a longer duration of glucocorticoid replacement to recover a normal ACTH stimulation test compared with patients with SC (median 17.0 months vs. 4.0 months, P<0.001). CONCLUSION:The HPA axis recovery time after adrenalectomy in patients with SC is rapid and is dependent on the degree of cortisol excess. More precise definition of SC is necessary to achieve a better management of patients and to avoid the risk of under- or over-treatment of SC patients. 10.3803/EnM.2016.31.4.592
    Increased expression of CYP17 and CYP11B1 in subclinical Cushing's syndrome due to adrenal adenomas. Cao Caixia,Yang Xuecheng,Li Li,Sun Ruixia,Xian Yuxin,Lv Wenshan,Wang Jing,Xu Yijun,Gao Yanyan International journal of urology : official journal of the Japanese Urological Association OBJECTIVES:To determine whether steroidogenic enzyme expression is associated with the steroid secretory pattern of subclinical Cushing's syndrome (SCS) by investigating the mRNA and protein expression of CYP17 and CYP11B1 in SCS adenomas, normal adrenal cortices (NA), non-functional adrenal adenomas (NFA) and cortisol-producing adenomas (CPA). METHODS:Total RNA and protein were extracted from 20 CPA, six SCS, 15 NFA, and eight NA. Real-time quantitative polymerase chain reaction (PCR) and western blotting analysis were performed to determine the mRNA and protein expression of CYP17 and CYP11B1 in different tissues. The expression of CYP17 and CYP11B1 in the adrenocortical tumors was compared expression in NA. RESULTS:Expression of both CYP11B1 and CYP17 mRNA and protein was detected in all samples tested. The expression of CYP11B1 mRNA and protein was significantly higher in the CPA group than in the other groups and was slightly higher in SCS samples compared with NA and NFA samples (all P < 0.05). There was no significant difference in CYP11B1 mRNA and protein expression between NA and NFA samples (P > 0.05). The expression of CYP17 mRNA and protein in different tissues was similar to that of CYP11B1. Neither CYP11B1 nor CYP17 mRNA and protein expression was correlated with plasma cortisol or adrenocorticotrophin levels (all P > 0.05). CONCLUSIONS:In conclusion, CYP11B1 and CYP17 are overexpressed in subclinical CPA and their overexpression accounts for the increased production of cortisol that is characteristic of CPA. 10.1111/j.1442-2042.2011.02836.x
    Cardiovascular risks and their long-term clinical outcome in patients with subclinical Cushing's syndrome. Tsuiki Mika,Tanabe Akiyo,Takagi Sachiko,Naruse Mitsuhide,Takano Kazue Endocrine journal Although subclinical Cushing's syndrome has been commonly experienced, details of the clinical outcome and its indication for adrenalectomy have yet to be established. In the present study, we investigated the prevalence of cardiovascular risks, their clinical outcome during long-term follow up before and after adrenalectomy in 20 patients with subclinical Cushing's syndrome. We also correlated the hypercortisolism and age with the cardiovascular risks and the clinical outcome. The prevalence of hypertension, impaired glucose metabolism, dyslipidemia, and obesity was 45%, 65%, 65%, and 25%, respectively. In the non-operated group (n = 12), six patients (50%) showed deterioration of at least one of the cardiovascular risks. Four patients showed an increase of at least one risk, while none of the patients showed a decrease in the number of risks. One patient developed overt Cushing's syndrome. In the operated group (n = 10) including two operated patients of the non-operated group, eight patients (80%) showed an improvement of at least one of the cardiovascular risks after surgery and five patients (50%) showed a decrease of at least one risk. The prognosis in terms of the changes of the cardiovascular risks was significantly better in the operated group than in the non-operated group (p<0.001). Neither the hypercortisolism nor age correlated to the presence and the clinical outcome of the cardiovascular risks. The present study clearly demonstrated probability of deterioration during the clinical course and improvement after adrenal surgery in patients with subclinical Cushing's syndrome. Careful follow-up of the cardiovascular risks is therefore warranted. Adrenalectomy could be a treatment of choice despite the hypercortisolism and age of the patients, especially when the cardiovascular risks show signs of deterioration.
    Laparoscopic adrenalectomy in patients with subclinical Cushing syndrome. Perysinakis Iraklis,Marakaki Chrisanthi,Avlonitis Spyridon,Katseli Anastasia,Vassilatou Evangeline,Papanastasiou Lambrini,Piaditis George,Zografos George N Surgical endoscopy BACKGROUND:Subclinical Cushing syndrome in patients with adrenal incidentalomas has been associated with an increased prevalence of the metabolic syndrome and cardiovascular risk. The management of these patients, be it conservative or surgical, is still debated, but there is accumulating evidence that surgery is best and that laparoscopic adrenalectomy, when possible, is the most preferred procedure. Here we present the short- and long-term results of laparoscopic adrenalectomy for subclinical Cushing syndrome and determine the effect of this procedure on components of the metabolic syndrome. METHODS:Twenty-nine patients, 8 men and 21 women with adrenal incidentalomas and subclinical Cushing syndrome who underwent laparoscopic adrenalectomy, were studied retrospectively. They had undergone postoperative follow-up for improvement or worsening of their arterial blood pressure, body weight, and fasting glucose level for a mean period of 77 months. RESULTS:Preoperatively, 17 patients (58.6 %) had arterial hypertension, 14 (48.3 %) had a body mass index exceeding 27 kg/m(2), and 12 (41.4 %) had diabetes mellitus. Postoperatively, a decrease in mean arterial pressure was found in 12 patients (70.6 %), a decrease in body mass index in 6 patients (42.9 %), and an improvement in glycemic control in 5 patients (41.7 %). CONCLUSIONS:Laparoscopic adrenalectomy is beneficial in many patients with subclinical Cushing syndrome because it reduces arterial blood pressure, body weight, and fasting glucose levels. Prospective randomized studies are needed to compare laparoscopic adrenalectomy with a conservative approach and to confirm these results. 10.1007/s00464-012-2730-5
    Clinical outcome of subclinical Cushing's syndrome after surgical and conservative treatment. Akaza Itaru,Yoshimoto Takanobu,Iwashima Fumiko,Nakayama Chisato,Doi Masaru,Izumiyama Hajime,Hirata Yukio Hypertension research : official journal of the Japanese Society of Hypertension Subclinical Cushing's syndrome (SCS), a subtle cortisol hypersecretion from an adrenal tumor, may be a common adrenal disease. However, the cardiovascular prognosis and the optimal surgical and conservative treatment in SCS remain elusive. The present study was undertaken to evaluate the prevalence of cardiovascular risk factors in 16 SCS cases, their relationships to cortisol secretory activities, and the clinical outcome after surgical and medical treatment. The prevalence of hypertension, impaired glucose tolerance (IGT), diabetes mellitus (DM), dyslipidemia and obesity in our SCS cases were 56%, 50%, 50%, and 19%, respectively, and 75% of cases were associated with two or more cardiovascular risk factors. In our series, 24-h urinary free-cortisol excretion showed a significant positive correlation with HbA1c and a negative correlation with high-density lipoprotein-cholesterol, but no correlation with age, body mass index, blood pressure or glycemic and lipid profile was found. Eight cases underwent unilateral adrenalectomy (operated (OP) group); the remaining eight cases were a conservative-treatment group (non-OP group). The number of cardiovascular risk factors decreased significantly in the OP group, but not in the non-OP group. In terms of differential changes in risk factors between the groups, more significant improvements of hypertension, dyslipidemia and IGT/DM were observed in the OP group than in the non-OP group. In conclusion, the present study showed the increased prevalence of cardiovascular risk factors in SCS patients with mild hypercortisolism related to impaired glucose/lipid metabolism. Adrenalectomy decreased accumulated cardiovascular risk factors in certain SCS patients, suggesting the possible involvement of mild hypercortisolism in the development of cardiovascular risk factors in SCS. 10.1038/hr.2011.90
    Lower extremity insufficiency fractures: an underappreciated manifestation of endogenous Cushing's syndrome. Poonuru S,Findling J W,Shaker J L Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA This report describes the presence of lower extremity insufficiency fractures in 10 women prior to the clinical and biochemical diagnosis of endogenous Cushing's syndrome (CS). Osteoporosis is a well-recognized complication of overt CS resulting in a high rate of vertebral and other fractures. After institutional review board (IRB) approval, we did a retrospective chart review of patients with lower extremity (LE) insufficiency fractures (IF) and CS. This chart review found 10 women in whom LE-IF preceded the diagnosis of endogenous CS. Low bone density was found in all but one patient. The CS was considered to be mild (or subclinical) in five patients. LE-IF should be considered part of the skeletal spectrum of CS. Physicians caring for patients with LE-IF should have a low threshold for the consideration of CS even in patients without overt physical evidence of cortisol excess. 10.1007/s00198-016-3712-6
    Is it worthwhile to screen patients with type 2 diabetes mellitus for subclinical Cushing's syndrome? Budyal Sweta,Jadhav Swati Sachin,Kasaliwal Rajeev,Patt Hiren,Khare Shruti,Shivane Vyankatesh,Lila Anurag R,Bandgar Tushar,Shah Nalini S Endocrine connections Variable prevalence of subclinical Cushing's syndrome (SCS) has been reported in patients with type 2 diabetes mellitus (T2DM), making the need for screening in this population uncertain. It is unknown if this variability is solely due to study-related methodological differences or a reflection of true differences in ethnic predisposition. The objective of this study is to explore the prevalence of SCS in Asian Indian patients with T2DM. In this prospective single center study conducted in a tertiary care referral center, 993 T2DM outpatients without any discriminatory clinical features (easy bruising, facial plethora, proximal muscle weakness, and/or striae) of hypercortisolism underwent an overnight 1 mg dexamethasone suppression test (ODST). ODST serum cortisol ≥1.8 μg/dl was considered positive, and those with positive results were subjected to 48 h, 2 mg/day low dose DST (LDDST). A stepwise evaluation for endogenous hypercortisolism was planned for patients with LDDST serum cortisol ≥1.8 μg/dl. Patients with positive ODST and negative LDDST were followed up clinically and re-evaluated a year later for the development of clinically evident Cushing's syndrome (CS). In this largest single center study reported to date, we found 37 out of 993 (3.72%) patients had ODST serum cortisol ≥1.8 μg/dl. None of them had LDDST cortisol ≥1.8 μg/dl, nor did they develop clinically evident CS over a follow-up period of 1 year. Specificity of ODST for screening of CS was 96.3% in our cohort. None of the T2DM outpatients in our cohort had SCS, hence cautioning against routine biochemical screening for SCS in this cohort. We suggest screening be based on clinical suspicion only. 10.1530/EC-15-0078
    Subclinical Cushing's syndrome. Tsinberg Michael,Liu Chienying,Duh Quan-Yang Journal of surgical oncology Subclinical Cushing's syndrome (SCS) refers to subtle autonomous cortisol hypersecretion that is insufficient to generate the typical, clinically recognizable overt syndrome. Diagnosis of SCS is challenging. The combination of 1 mg overnight dexamethasone suppression test, serum ACTH level, and urinary cortisol level are used to diagnose SCS. Laparoscopic adrenalectomy is the treatment of choice for SCS. Patients with adrenal incidentalomas and SCS should be treated with perioperative steroids to prevent post-operative hypocortisolism. 10.1002/jso.23143
    Clinical Usefulness of Corticotropin Releasing Hormone Testing in Subclinical Cushing's Syndrome for Predicting Cortisol Replacement after Adrenalectomy. Inoue Masahiro,Ide Hisamitsu,Kurihara Koji,Koseki Tatsuro,Yu Jingsong,China Toshiyuki,Saito Keisuke,Isotani Shuji,Muto Satoru,Horie Shigeo Korean journal of urology PURPOSE:The purpose of this study was to investigate the clinical and hormonal features of patients with incidentally discovered adrenal adenomas in relation to corticotropin releasing hormone (CRH) testing and the clinical outcome of adrenalectomy. MATERIALS AND METHODS:Twenty-three consecutive patients with incidentally detected adrenal adenomas were included in this retrospective study. All the patients underwent abdominal computed tomography scans and hormonal assays, including assessment of circadian rhythms of plasma cortisol and corticotropin (adrenocorticotropic hormone, ACTH), a corticotropin stimulation test, and low-dose and high-dose dexamethasone tests. The patients were reevaluated at regular intervals (6, 12, and 24 months) for a median period of 24 months. Subclinical Cushing's syndrome (SCS) was diagnosed in patients with subtle hypercortisolism who did not present clinical signs of Cushing's syndrome. RESULTS:We calculated the responsive index (peak value of ACTH in CRH test/baseline value of ACTH in CRH test). Of 23 patients, 6 had Cushing's syndrome, 8 had SCS, and 9 had a non-functioning tumor. All patients underwent laparoscopic adrenalectomy. Several patients (5 of 6 with Cushing's syndrome and 2 of 8 with SCS) required cortisol replacement therapy after surgery. The remaining patients required no hormonal replacement after surgery. Those who required hormone replacement had a responsive index of less than 1.2. Those who did not need hormone replacement therapy had a responsive index of more than 2.0. CONCLUSIONS:In our limited experience, the responsive index of the CRH test might be a valuable tool for predicting the need for cortisol replacement after surgery in patients with SCS. 10.4111/kju.2012.53.6.414
    Is Prophylactic Steroid Treatment Mandatory for Subclinical Cushing Syndrome After Unilateral Laparoscopic Adrenalectomy? Wang Dong,Li Han-Zhong,Zhang Yu-Shi,Wang Liang,Ji Zhi-Gang Surgical laparoscopy, endoscopy & percutaneous techniques OBJECTIVE:This study aimed to provide rational guidelines for patients with subclinical Cushing syndrome (SCS), who are undergoing laparoscopic adrenalectomy, in order to avoid the risk of overtreatment. METHODS:A total of 59 patients diagnosed with SCS caused by unilateral adrenal adenoma, who underwent laparoscopic adrenalectomy from 2010 to 2017, were included into the study. These patients did not receive prophylactic steroid treatment. After discharge, patients with adrenal insufficiency (AI) were treated with glucocorticoid. Then, cortisol levels were reevaluated at three months after surgery by morning serum cortisol. RESULTS:No severe perioperative complications occurred. After unilateral laparoscopic adrenalectomy, no patient developed AI and was readmitted. In the first week after surgery, 10 patients (16.9%) received steroid therapy at the clinic because of mild symptoms of AI. The probability of developing AI was greater in patients with 1-mg dexamethasone midnight suppression test (1 mg-DST) >5 μg/dL than patients with mg-DST ranging within 1.8 to 5.0 μg/dL (P=0.042). The initial dose of hydrocortisone was 20.00±6.67 mg/d (range, 10 to 30), and the duration of treatment was 6.90±3.51 weeks (range, 3 to 12 wk). At three months after surgery, morning cortisol was >5 μg/dL in all patients. CONCLUSIONS:After laparoscopic adrenalectomy, the probability of AI is small in patients with adrenal SCS, and the symptoms of AI were mild. Meanwhile, the HPA axis rapidly recovered. Therefore, prophylactic steroid treatment is not mandatory. Given that AI is more frequent in patients with higher cut-offs of 1 mg-DST, a more precise definition of SCS is necessary to better manage these patients. 10.1097/SLE.0000000000000585
    Clinical Characteristics and Metabolic Features of Patients with Adrenal Incidentalomas with or without Subclinical Cushing's Syndrome. Kim Bo Yeon,Chun A Reum,Kim Kyu Jin,Jung Chan Hee,Kang Sung Koo,Mok Ji Oh,Kim Chul Hee Endocrinology and metabolism (Seoul, Korea) BACKGROUND:The aim of this study was to examine the clinical characteristics of adrenal incidentalomas discovered by computed tomography (CT) and to investigate metabolic features of subclinical Cushing's syndrome (SCS) in patients with adrenal incidentalomas in a tertiary hospital in Korea. METHODS:This retrospective study examined the clinical aspects of 268 patients with adrenal incidentalomas discovered by CT at Soonchunhyang University Bucheon Hospital. Clinical data and endocrine function of the patients as well as histological findings were obtained from medical records, while anatomic characteristics were analyzed by reviewing imaging studies. Hormonal tests for pheochromocytoma, Cushing's syndrome, and aldosterone-secreting adenoma were performed. RESULTS:Most (n=218, 81.3%) cases were nonfunctioning tumors. Of the 50 patients with functioning tumors (18.7%), 19 (7.1%) were diagnosed with SCS, nine (3.4%) with overt Cushing's syndrome, 12 (4.5%) with primary aldosteronism, and 10 (3.7%) with pheochromocytoma. Malignant tumors (both primary and metastatic) were rare (n=2, 0.7%). Body mass index, fasting glucose, hemoglobin A1c, and total cholesterol were significantly higher in patients with SCS in comparison with those with nonfunctioning tumors. The prevalence of type 2 diabetes mellitus and hypertension were significantly higher in patients with SCS compared with those with nonfunctioning tumors. CONCLUSION:Functioning tumors, especially those with subclinical cortisol excess, are commonly found in patients with adrenal incidentalomas, although malignancy is rare. In addition, patients with SCS in adrenal incidentalomas have adverse metabolic and cardiovascular profiles. 10.3803/EnM.2014.29.4.457
    The estimation of selected endogenous anticoagulation system parameters in patients with subclinical Cushing's syndrome. Swiatkowska-Stodulska Renata,Kaniuka-Jakubowska Sonia,Wisniewski Piotr,Skibowska-Bielinska Anna,Sworczak Krzysztof European journal of endocrinology OBJECTIVE:An increased tendency towards thromboembolic events is observed in patients with Cushing's syndrome. There are much fewer publications available about thromboembolic complications in patients with subclinical Cushing's syndrome (SCS). Therefore, a question arises whether hemostatic disturbances appear in this particular disease phase. AIM OF STUDY:Estimation of protein C (PC), free protein S (FPS), antithrombin (AT) activity, thrombomodulin (TM) concentration and activated PC resistance (APCR) in patients with SCS. MATERIALS AND METHODS:We studied 35 patients with SCS. The control group consisted of 33 healthy volunteers. The activity of PC, AT, FPS, APCR and the concentration of TM was estimated in all representatives. RESULTS:The comparison of the examined coagulation parameters between the patients with SCS and the healthy individuals revealed significantly higher mean PC activity and mean FPS activity in the SCS group. Mean TM concentration was significantly lower in patients with SCS compared with the control group. The differences in APCR and AT activity were not significant. We did not prove any statistically significant correlations between the examined coagulation parameters and hormonal parameters. We did not find any correlation between the concentration of cortisol and basic coagulation parameters such as international normalized ratio, activated partial thromboplastin time or fibrinogen in the group with SCS either. CONCLUSIONS:The patients with SCS present disturbances in endogenous anticoagulation system defined as PC, FPS activity and TM concentration. This finding suggests an impact of mild autonomic cortisol overproduction on coagulation system. 10.1530/EJE-11-0535
    Adrenal incidentalomas and subclinical Cushing's syndrome: diagnosis and treatment. Mazzuco Tânia Longo,Bourdeau Isabelle,Lacroix André Current opinion in endocrinology, diabetes, and obesity PURPOSE OF REVIEW:Adrenal incidentaloma has become a frequent clinical dilemma. Even in the absence of specific clinical features of Cushing's syndrome, adrenocortical incidentalomas may display steroid secretory activity at different degrees. The recognition of endocrine and metabolic dysfunctions associated with subclinical hypercortisolism leads to current awareness about its potential consequences. RECENT FINDINGS:Different protocols and threshold values to define normal cortisol secretion and diagnosis of subclinical Cushing's syndrome have been proposed, including recent practice guidelines for the diagnosis of overt Cushing's syndrome. Follow-up studies have provided additional data about the natural course of the disease and related cardiovascular and metabolic consequences. The study of bilateral adrenocorticotropin-independent macronodular adrenocortical hyperplasia in some familial cases offers a new approach to understanding the spectrum of subclinical cortisol hypersecretion. SUMMARY:The prevalence of subclinical hypercortisolism may be higher than previously reported as more sensitive diagnostic criteria are now recommended. The absence of a single gold standard test, the diversity of diagnostic criteria and the requirement of subsequent meticulous biochemical evaluations before a decision for treatment represent a challenge for the clinical management of this condition. 10.1097/MED.0b013e32832b7043
    Challenges in the diagnostic work-up and management of patients with subclinical Cushing's syndrome and bilateral adrenal masses. Maghrabi Adam,Yaqub Abid,Denning Krista L,Benhamed Nesreen,Faiz Saba,Saleem Tipu Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists OBJECTIVE:To review the challenges encountered in the diagnostic work-up and management of patients with subclinical Cushing's syndrome (SCS) and bilateral adrenal masses to aid in the case description of a patient with SCS and adrenocorticotropic hormone (ACTH)-independent macronodular adrenal hyperplasia (AIMAH). METHODS:We describe our experience managing a patient with AIMAH and SCS. This case report is followed by an extensive review of the literature regarding differential diagnoses, work-up including adrenal venous sampling (AVS), and treatment of SCS with bilateral adrenal masses. RESULTS:A 51-year-old female who was diagnosed with recent onset hypertension and diabetes mellitus type 2 was evaluated for adrenal masses discovered incidentally on computed tomography (CT). She did not have any Cushingoid features. Magnetic resonance imaging (MRI) of abdomen was performed for further evaluation. Hormonal evaluation came back consistent with SCS. The AVS results were consistent with bilateral autonomous cortisol hypersecretion without lateralization. Collectively, the findings favored the diagnosis of bilateral AIMAH. A left adrenalectomy was performed, and the patient's clinical response was favorable with improvement in blood pressure (BP) accompanied by significant weight loss. Follow-up hormonal testing for autonomous cortisol hypersecretion was within the target range. CONCLUSIONS:AIMAH is a rare cause of SCS. AVS is a useful diagnostic tool that helps localize the source of autonomous cortisol hypersecretion in ACTH-independent SCS with bilateral adrenal masses, especially if radiological features are inconclusive. Patients undergoing unilateral adrenalectomy should be followed for monitoring of clinical response, as well as progression of AIMAH in the contralateral adrenal gland. 10.4158/EP12277.RA
    Subclinical Cushing's syndrome in adrenal incidentalomas--possible metabolic consequences. Bohdanowicz-Pawlak Anna,Szymczak Jadwiga,Waszczuk Ewa,Bolanowski Marek,Bednarek-Tupikowska Grażyna Endokrynologia Polska INTRODUCTION:The presence of subclinical Cushing's syndrome (SCS) and some features of the metabolic syndrome were evaluated in adrenal incidentaloma patients. MATERIAL AND METHODS:165 patients were studied. Plasma cortisol, ACTH, DHEA-S, 17-OH-P, aldosterone, renin activity and 24-h urinary methoxycatecholamines were measured. Fasting concentrations of glucose, insulin, triglycerides, T-chol., HDL-chol. and LDL-chol. were determined and the FIRI and QUICKI indices were calculated. Blood pressure, WHR and BMI were determined in all patients. Forty healthy volunteers were the controls. RESULTS:133 patients had unchanged endocrine function, 32 demonstrated hormonal disturbances without clinical symptoms (in 26 nonclinical hypercortisolism). The WHR and blood pressure in the SCS group were significantly higher than in the patients with nonfunctioning adenoma (NA). T-chol and LDL-chol were significantly higher, but HDL-chol was significantly lower, in the SCS than in the NA patients. Fasting insulin level was significantly higher in the SCS than in the NA patients and controls, while fasting glucose level was comparable. QUICKI was significantly lower in the SCS and NA patients than in the controls, while FIRI was significantly higher in the SCS group. CONCLUSIONS:In incidentaloma patients, hormonal function of the adrenal gland should be estimated because some of them present subclinical hyperfunction. These patients frequently display features of metabolic syndrome such as insulin resistance, hypertension, high triglycerides, T-chol and LDL-chol levels. Subtle autonomous cortisol secretion may be the cause of these features.
    Towards a universally accepted definition of subclinical Cushing's syndrome - subclinical autonomous hypercortisolism. Inder Warrick J Clinical endocrinology 10.1111/cen.13244
    [Subclinical Cushing's syndrome in patients with incidental adrenal tumor]. Zhonghua nei ke za zhi 10.3760/cma.j.issn.0578-1426.2017.07.012
    Nonconformity in the clinical practice guidelines for subclinical Cushing's syndrome: which guidelines are trustworthy? Shen Jing,Sun Mingfang,Zhou Bo,Yan Juping European journal of endocrinology OBJECTIVE:This study aimed to systematically evaluate the quality of clinical practice guidelines (CPGs) and to compare their recommendations for managing subclinical Cushing's syndrome (SCS) to assist practitioners in making rapid clinical decisions. DESIGN AND METHODS:SCS management guidelines were retrieved from electronic databases. The Appraisal of Guidelines Research and Evaluation II (AGREE-II) tool and the Institute of Medicine (IOM) criteria were used to evaluate the quality of the selected guidelines. In addition, we further compared recommendations, cited references and levels of evidence between the SCS management guidelines. RESULTS:We included five guidelines that were obtained through the literature selection process. On the basis of the AGREE-II and IOM criteria, none of the selected guidelines were satisfactory in all aspects. However, the Italian Association of Clinical Endocrinologists (IACE) guidelines demonstrated slightly higher scores than did the other guidelines, so this guideline was recommended (with certain modifications for several domains). Regarding the content of the CPGs, we found considerable differences in the recommendations for managing SCS. These differences were derived from citation selection bias, evidence interpretation bias, differences in the composition of the guidelines' workgroups and the omission of guidelines for updating and externally reviewing the recommendations. CONCLUSIONS:There is generally poor guideline quality among different organisations, and remarkable differences exist in the recommendations for the same clinical subject. Therefore, future guideline development should be performed in strict accordance with the AGREE-II and IOM criteria. 10.1530/EJE-14-0345
    Subclinical Cushing's syndrome. De Leo Monica,Cozzolino Alessia,Colao Annamaria,Pivonello Rosario Best practice & research. Clinical endocrinology & metabolism The routine use of abdominal procedure has significantly increased the incidental finding of adrenal masses. The prevalence of these tumors, commonly defined as adrenal incidentalomas, ranges between 2-3% in autopsy and 4% in radiological series, reaching 5-8% in oncological studies and increasing with patients age. Although clinically silent, in 5-20% of cases, adrenal incidentalomas are responsible for a subtle cortisol overproduction, commonly defined as "subclinical Cushing's syndrome" (SCS). This term is used to describe autonomous cortisol secretion in patients who don't have the typical signs and symptoms of hypercortisolism. The optimal strategy for identification and management of SCS is unknown; the standard biochemical tests used to screen for overt Cushing's syndrome are generally ill-suited to the assessment of patients who have no, or only very mild signs of cortisol excess, then many tests aimed to study the hypothalamus-pituitary-adrenal axis (HPA) axis do not have sufficient sensitivity to recognize very mild degree of cortisol excess. An increased frequency of hypertension, central obesity, impaired glucose tolerance or diabetes, hyperlipemia and osteoporosis has been described in patients with SCS since patients are exposed to a chronic albeit slight, cortisol excess; however, there is not evidence-based demonstration of long term complications and, consequently, the management of this condition is largely empirical. Adrenalectomy or medical management of associated disease has been indicated as therapeutic options due to lack of data demonstrating the superiority of a surgical or non-surgical treatment. 10.1016/j.beem.2012.02.001
    Posterior retroperitoneoscopic adrenalectomy for clinical and subclinical Cushing's syndrome. Alesina Pier F,Hommeltenberg Silvia,Meier Beate,Petersenn Stephan,Lahner Harald,Schmid Kurt W,Mann Klaus,Walz Martin K World journal of surgery BACKGROUND:Because of co-morbidity, adrenalectomy for adrenal Cushing's syndrome may be associated with an increased complication rate and long operating times. In the present study we report our experience with the posterior retroperitoneoscopic adrenalectomy in a large group of patients with clinical or subclinical Cushing's syndrome. PATIENTS AND METHODS:Between July 1994 and June 2009, 170 patients (17 males, 153 females age 50 +/- 13 years; range: 12-78 years) affected by Cushing's syndrome underwent operation via posterior retroperitoneoscopic access. Patients were divided into two groups, those with manifest Cushing's syndrome (mCS) [99 patients: 6 male, 93 female; age 45 +/- 13 years] and those with subclinical Cushing's syndrome (sCS) [71 patients: 11 male, 60 female; age: 56 +/- 11 years]. The sCS classification was assumed in cases without typical clinical symptoms but with a pathological dexamethasone suppression test. Partial adrenalectomy was performed in 35 cases (24 in the mCS-group and 11 in the sCS-group). RESULTS:Mortality was zero; major complications did not occur. The incidence of postoperative minor complications was 5.3%. Mean operating time was 58 +/- 36 min (range: 20-230 min) and did not differ between mCS and sCS patients (58 versus 59 min; p = ns). Postoperative oral steroids supplementation (POSS) was administered in 136 patients (99 mCS, 37 sCS). If POSS was started, mean duration of therapy was 12.3 months (mCS) and 10.3 months (sCS) [p = 0.08], respectively. After a mean follow-up of 70.9 +/- 46.5 months the cure rate was 99.4%. CONCLUSIONS:The posterior retroperitoneoscopic approach is fast and safe even in patients with Cushing's syndrome. Partial adrenalectomy represents a new option in the treatment of cortisol-producing adenomas. 10.1007/s00268-010-0453-0
    [Subclinical Cushing's syndrome:analysis of diagnosis and surgical effect]. Feng Chao,Li Han-Zhong,Xiao He,Yan Wei-Gang,Li Yong-Qiang,Xu Wei-Feng Zhonghua wai ke za zhi [Chinese journal of surgery] OBJECTIVE:To improve the diagnostic and therapeutic ability on subclinical Cushing's syndrome. METHODS:Retrospective analysis for the clinical data of 24 cases of subclinical Cushing's syndrome, the clinical and biological characters pre and post operation were compared. RESULTS:None of the 24 cases of subclinical Cushing's syndrome had the classic symptoms and signs of Cushing's syndrome. The common symptoms of these patients were hypertension in 17 cases, diabetes mellitus in 11 cases, hyperlipidemia in 9 cases, high plasma cortisol value in 13 cases and high 24 h UFC value in 9 cases. None of patients did respond to low dose dexamethasone suppression test, but 16 cases of them did not respond to high dose dexamethasone suppression test. All the cases were found adrenal tumors by CT scan, 10 cases in left adrenal and 14 cases in right adrenal. All the patients underwent retroperitoneal laparoscopic operation and were pathologic diagnosed to adrenal adenomas. During follow-up, the symptoms of 20 cases (83.3%) were cured after surgery, and hormone supplement was required in 8 cases. CONCLUSIONS:Subclinical Cushing's syndrome may be incidentally detected on clinical manifestations, laboratory findings and imaging examinations. CT scan, assays of plasma cortisol, urinary free cortisol and dexamethasone suppression test are most useful in the diagnosis. The potential benefit of surgery should be considered in those who have a definite diagnosis of subclinical Cushing's syndrome. Hormone supplement is required in some patients. It is safe and practical to perform retroperitoneal laparoscopic surgery on the patients with subclinical Cushing's syndrome.
    Long-term study of subclinical Cushing's syndrome shows high prevalence of extra-adrenal malignancy in patients with functioning bilateral adrenal tumors. Kawate Hisaya,Kohno Michiko,Matsuda Yayoi,Akehi Yuko,Tanabe Makito,Horiuchi Toshihiro,Ohnaka Keizo,Nomura Masatoshi,Yanase Toshihiko,Takayanagi Ryoichi Endocrine journal Subclinical Cushing's syndrome (SCS) is characterized by subtle autonomous cortisol secretion from adrenal tumors without specific signs and symptoms of hypercortisolism. Patients with SCS have a high prevalence of "lifestyle-related diseases," such as hypertension, diabetes mellitus, dyslipidemia, and osteoporosis. Long-term follow-up of SCS patients is reportedly indispensable for establishing indications for surgical treatment of SCS. We performed a follow-up survey of 27 patients with SCS (median: 5.3 years) and compared those who had undergone surgical treatment (n=15) with those who had not (n=12). The mean diameter of tumors was 31 mm; 16 (59%) patients had unilateral lesions and 11 (41%) carried bilateral ones. In 67% and 60% of the treatment group, respectively, hypertension and diabetes mellitus improved. We also noticed that eight of 11 (73%) SCS patients with bilateral adrenal tumors had extra-adrenal malignancies in various tissues. Interestingly, among nine SCS patients who had malignancies, eight showed bilateral adrenal uptake in ¹³¹I-aldosterol scintigraphy. The results imply that surgical treatment can reduce cardiovascular risks in SCS patients. Screening for malignancy may be necessary in patients with bilateral adrenal tumors suspected of autonomous hypersecretion of cortisol from both sides. 10.1507/endocrj.EJ14-0155
    Proposed diagnostic criteria for subclinical Cushing's syndrome associated with adrenal incidentaloma. Akehi Yuko,Kawate Hisaya,Murase Kunitaka,Nagaishi Ryoko,Nomiyama Takashi,Nomura Masatoshi,Takayanagi Ryoichi,Yanase Toshihiko Endocrine journal Subclinical Cushing's syndrome (SCS) associated with adrenal incidentaloma is usually characterized by autonomous cortisol secretion without overt symptoms of Cushing's syndrome (CS). Although the diagnostic criteria for SCS differ among countries, the 1 mg dexamethasone suppression test (DST) is essential to confirm the presence and the extent of cortisol overproduction. Since 1995, SCS has been diagnosed in Japan based on serum cortisol levels ≥3 μg/dL (measured by radioimmunoassay [RIA]) after a 1 mg DST. However, the increasing use of enzyme immunoassays (EIA) instead of RIA has hindered the diagnosis of SCS because of the differing sensitivities of commercially available assays, particularly for serum cortisol levels of around 3 μg/dL. One way to overcome this problem is to lower the cortisol threshold level after a 1 mg DST. In the present study, we examined the clinical applicability of lowering the cortisol threshold to 1.8 μg/dL, similar to the American Endocrine Society's guidelines for CS, by reanalyzing 119 patients with adrenal incidentaloma. Our findings indicate that serum cortisol levels ≥1.8 μg/dL after 1 mg DST are useful to confirm the diagnosis of SCS if both of the following criteria are met: (1) basal ACTH level <10 pg/mL (or poor plasma ACTH response to corticotrophin-releasing hormone) and (2) serum cortisol ≥5 μg/dL at 21:00 to 23:00 h. If only one of (1) and (2) are met, we recommend that other clinical features are considered in the diagnosis of SCS, including serum dehydroepiandrosterone sulfate levels, urine free cortisol levels, adrenal scintigraphy, and clinical manifestation.
    Plasma Steroid Profiles in Subclinical Compared With Overt Adrenal Cushing Syndrome. Masjkur Jimmy,Gruber Matthias,Peitzsch Mirko,Kaden Denise,Di Dalmazi Guido,Bidlingmaier Martin,Zopp Stephanie,Langton Katharina,Fazel Julia,Beuschlein Felix,Bornstein Stefan Richard,Reincke Martin,Eisenhofer Graeme The Journal of clinical endocrinology and metabolism CONTEXT:Diagnosis of subclinical adrenal hypercortisolism is based on several tests of the hypothalamic-pituitary-adrenal axis to establish mild alterations of cortisol secretion and dysregulated cortisol physiology. OBJECTIVE:We assessed whether plasma steroid profiles might assist diagnosis of subclinical Cushing syndrome (SC). DESIGN:Retrospective cross-sectional study. SETTING:Two tertiary medical centers. PATIENTS:Of 208 patients tested for hypercortisolism, disease was excluded in 152 and confirmed in 21 with overt adrenal Cushing syndrome (AC) compared to 35 with SC. Another 277 age- and sex-matched hypertensive and normotensive volunteers were included for reference. MAIN OUTCOME MEASURES:A panel of 15 plasma steroids was measured by mass spectrometry, with classification by discriminant analysis. RESULTS:Patients with SC had lower plasma concentrations of dehydroepiandrosterone and dehydroepiandrosterone-sulfate than subjects without SC (P < 0.05). The largest increases (P < 0.001) in plasma steroids among patients with SC were observed for 11-deoxycortisol and 11-deoxycorticosterone. Nevertheless, concentrations of 11-deoxycorticosterone, 11-deoxycortisol, and pregnenolone in patients with AC were higher (P < 0.05) than in those with SC. Patients with SC or AC could be distinguished from subjects without disease using this combination of steroids as precisely as with use of measurements of serum cortisol after administration of dexamethasone. The steroid combination provided superior diagnostic performance compared with each of the other routine biochemical tests. CONCLUSION:Distinct plasma steroid profiles in patients with SC may provide a simple and reliable screening method for establishing the diagnosis. 10.1210/jc.2018-02349
    Systematic review of surgical treatment of subclinical Cushing's syndrome. Iacobone M,Citton M,Scarpa M,Viel G,Boscaro M,Nitti D The British journal of surgery BACKGROUND:Subclinical Cushing's syndrome (SCS) is a condition of biochemical cortisol excess without the classical clinical features of overt hypercortisolism; it may be associated with some consequences of metabolic syndrome. The most appropriate treatment remains controversial. This study aimed to assess the outcomes of adrenalectomy for SCS. METHODS:A systematic review was performed. MEDLINE, Embase and Cochrane Databases (1980-2013) were searched for studies reporting the outcomes of unilateral adrenalectomy with respect to hypertension, diabetes, dyslipidaemia, obesity and osteoporosis in patients with SCS. Studies with a questionable diagnosis of SCS, bilateral adrenal involvement and insufficient data were excluded. RESULTS:Of the 105 papers screened, seven were selected; there were six retrospective studies and one randomized clinical trial, including 230 patients. Data analysis was limited by heterogeneity in definition of SCS and endpoints. Hypercortisolism was cured in all operated patients. Laparoscopy was the preferred approach, with a morbidity rate of 0·8 per cent. A beneficial effect of surgery on blood pressure, glucometabolic control and obesity was evident in all studies, with cure or improvement in 72, 46 and 39 per cent of patients respectively, compared with conservative management. The results for lipid metabolism were equivocal, because of a decrease in triglyceridaemia but discordant effects on cholesterol metabolism among the different studies. No beneficial effects on osteoporosis were found. CONCLUSION:Laparoscopic adrenalectomy seems to be beneficial in reversing several metabolic effects of hypercortisolism, with a low morbidity rate. However, the heterogeneity and low quality of the available studies preclude definitive recommendations. 10.1002/bjs.9742
    Adrenal function after adrenalectomy for subclinical hypercortisolism and Cushing's syndrome: a systematic review of the literature. Di Dalmazi Guido,Berr Christina M,Fassnacht Martin,Beuschlein Felix,Reincke Martin The Journal of clinical endocrinology and metabolism CONTEXT:The postoperative course of patients with subclinical hypercortisolism (SH) is yet to be clarified. The aims are to review the prevalence and predictive factors of postoperative adrenal insufficiency and the time to recover a normal adrenocortical function in patients with SH and Cushing's syndrome (CS). EVIDENCE ACQUISITION:Using the PubMed database, we conducted a systematic review of the literature, selecting studies published from 1980 to 2013. EVIDENCE SYNTHESIS:Of the 1522 papers screened, 28 were selected (13 retrospective, 14 prospective, and one randomized controlled trial). The prevalence of postoperative adrenal insufficiency was 65.3% in 248 SH subjects and 99.7% in 377 CS patients. Patients with SH were reclassified according to the following diagnostic criteria: subjects defined by pathological dexamethasone test only (DEX), and those defined by the dexamethasone test with one (DEX+1) or two additional criteria (DEX+2); and they were compared with CS patients. The prevalence of adrenal insufficiency was 51.4, 60.6, 91.3, and 99.7%, respectively, with no significant difference between the two latter groups. The test with the best compromise between sensitivity (64%) and specificity (81%) in predicting adrenal insufficiency was the midnight serum cortisol. The time to achieve eucortisolism was lower in SH patients than in CS patients (6.5 vs 11.2 mo; P < .001). CONCLUSIONS:Adrenal insufficiency occurs in about half of the patients with SH if defined only by the pathological dexamethasone test. However, prevalence of adrenal insufficiency and time to recovery are tightly related to the degree of hypercortisolism and diagnostic criteria to define SH, which might help to better define SH for future studies. 10.1210/jc.2014-1401
    Adrenalectomy may improve cardiovascular and metabolic impairment and ameliorate quality of life in patients with adrenal incidentalomas and subclinical Cushing's syndrome. Iacobone Maurizio,Citton Marilisa,Viel Giovanni,Boetto Riccardo,Bonadio Italo,Mondi Isabella,Tropea Saveria,Nitti Donato,Favia Gennaro Surgery BACKGROUND:Adrenalectomy represents the definitive treatment in clinically evident Cushing's syndrome; however, the most appropriate treatment for patients with subclinical Cushing's syndrome (SCS) with an adrenal incidentaloma remains controversial. This study was aimed to assess whether adrenalectomy may improve cardiovascular and metabolic impairment and quality of life compared with conservative management. METHODS:Twenty patients with adrenal incidentaloma underwent laparoscopic adrenalectomy for SCS, whereas 15 were managed conservatively. Hormonal laboratory parameters of corticosteroid secretion, arterial blood pressure (BP), glycometabolic profile, and quality of life (by the SF-36 questionnaire) were compared at baseline and the end of follow-up. RESULTS:The 2 groups were equivalent concerning all the examined parameters at baseline. In the operative group, laboratory corticosteroid parameters normalized in all patients but not in the conservative-management group (P < .001). In operated patients, a decrease in BP occurred in 53% of patients, glycometabolic control improved in 50%, and body mass index decreased; in contrast, no improvement or some worsening occurred in the conservative-management group (P < .01). SF-36 evaluation improved in the operative group (P < .05). CONCLUSION:Adrenalectomy can be more beneficial than conservative management in SCS and may achieve remission of laboratory hormonal abnormalities and improve BP, glycemic control, body mass index, and quality of life. 10.1016/j.surg.2012.08.054
    Glucose metabolism in patients with subclinical Cushing's syndrome. Giordano Roberta,Guaraldi Federica,Berardelli Rita,Karamouzis Ioannis,D'Angelo Valentina,Marinazzo Elisa,Picu Andreea,Ghigo Ezio,Arvat Emanuela Endocrine This clinical review will summarize the available data regarding the effect of either physiological or increased glucocorticoid concentrations on glucose metabolism and insulin-sensitivity, in order to clarify the role, if any, of subclinical Cushing's syndrome (SCS), a status of altered hypothalamic-pituitary-adrenal axis secretion in the absence of the classical signs or symptoms of overt cortisol excess, in patients with adrenal incidentalomas (AI) and diabetes mellitus type 2. Focusing on patients with SCS associated to AI, while there is convincing evidence in the literature that even a mild hyper cortisolemia is associated with alterations of glucose metabolism, evidence is insufficient to conclude that the simple correction of chronic, even mild, hypercortisolism can completely revert metabolic, mainly glycemic alterations. At the same time, considering the variability of the prevalence of Cushing's syndrome in patients with diabetes mellitus type 2 reported in the literature, no agreement does exist whether screening for CS can be useful and recommended in those patients. 10.1007/s12020-012-9628-9
    A rare presentation of subclinical Cushing's syndrome as a pubic fracture. Arduc Ayse,Dogan Bercem Aycicek,Akbaba Gulhan,Dagdelen Iffet,Kucukler Kerim,Isik Serhat,Ozuguz Ufuk,Berker Dilek,Guler Serdar Internal medicine (Tokyo, Japan) Osteoporosis and bone fractures are commonly seen in patients with Cushing's syndrome (CS). Fractures usually occur in the vertebrae and ribs whereas pubic fractures are less common. Similar to obvious hypercortisolemia, subclinical hypercortisolemia can increase the risk of fractures. However, in subclinical cases, bone fractures are very rarely seen as the presenting symptom. We herein report the case of a 62-year-old postmenopausal woman who was presented with a pubic fracture. During the evaluation of the fracture, thoracoabdominal magnetic resonance imaging of the patient demonstrated an adrenal mass. Although the patient did not show any signs of overt hypercortisolism, an endocrinologic evaluation revealed hypercortisolism due to an adrenal tumor. Adrenalectomy was performed, which resulted in a cure of the disease. During the orthopedic follow-up, the patient's pubic area pain gradually improved, and the pubic fracture healed without any accompanying new bone fractures. One year after the surgery, a remarkable improvement was detected in the patient's bone density in spite of the lack of administration of any medications for osteoporosis. Subclinical CS can present as a pubic fracture, and awareness of this relationship can help physicians to diagnose the disease. 10.2169/internalmedicine.53.1489
    Adrenal Incidentaloma and Subclinical Cushing's Syndrome: A Longitudinal Follow-Up Study by Endoscopic Ultrasound. Collienne Maike,Timmesfeld Nina,Bergmann Simona Raluca,Goebel Joachim,Kann Peter Herbert Ultraschall in der Medizin (Stuttgart, Germany : 1980)  Adrenal incidentaloma (AI) and adrenal masses in cases of subclinical Cushing's syndrome (SCS) initially require follow-up imaging. In this study we used endoscopic ultrasound (EUS) as a method for high-resolution imaging. The aim was to evaluate the growth rate of AI and SCS by EUS.  This retrospective analysis included 93 out of 229 patients with AI or SCS who were investigated longitudinally by EUS in our university hospital between 1997 and 2013. The longitudinal follow-up required at least two investigations by EUS and evaluation of endocrine function. Plasma renin, serum aldosterone, 24 h urinary catecholamines and 2 mg dexamethasone suppression test were performed. EUS was performed at baseline and during follow-up. Each time, the maximum diameter was measured. Three groups were defined: non-functioning adenomas (NFA), non-functioning nodular hyperplasias (NFH) and SCS.  86 patients had non-functioning masses [NFM] (59 NFA, 48 NFH) and 7 patients had SCS (10 masses). At baseline the mean diameter was 19.4 (± 9.3) mm (NFM) and 19.6 (± 9.2) mm (SCS). The mean follow-up period was 31.6 ± 28.7 months. The estimated mean growth rates per year were low: They were 0.35 mm/yr [NFA], 0.02 mm/yr [NFH] and 0.53 mm/yr [SCS]. Furthermore, there was no malignant progression of any mass.  The growth rate as determined by EUS was low for all tumor entities observed in this study. There was no difference in tumor growth between the groups. 10.1055/s-0041-107996
    DHEAS for the prediction of subclinical Cushing's syndrome: perplexing or advantageous? Yener Serkan,Yilmaz Hamiyet,Demir Tevfik,Secil Mustafa,Comlekci Abdurrahman Endocrine The diagnostic accuracy of dehydroepiandrosterone sulfate (DHEAS) to predict subclinical Cushing's syndrome (sCS) has been a matter of debate. The primary objective of this study was to assess the diagnostic power of DHEAS in predicting sCS. This retrospective study was conducted in a tertiary referral center and based on subjects referred between 2004 and 2014. Data of 249 subjects with adrenal incidentalomas were evaluated. We also reviewed 604 DHEAS measurements from adults, which were performed during the same period in our laboratory (LB group). Adrenocortical function, tumor size, and clinical characteristics were assessed. We diagnosed sCS in 15.2 % of the participants in the presence of ≥2 of the following; 1 mg dexamethasone suppression test >3.0 μg/dl, urinary free cortisol >70 μg/24 h, and corticotrophin (ACTH) <10 pg/ml. DHEAS levels were significantly reduced in patients with sCS (n = 38) compared to sCS (-) (n = 141) and LB groups (n = 604) (27.95, 65.90, and 66.80 µg/dl, respectively, p < 0.001) while age was comparable. The ROC curve analysis showed that the cut-off of the DHEAS with the best diagnostic accuracy for detecting sCS was 40.0 μg/dl (SN, 68 %; SP, 75; PPV, 43 %; NPV, 90 %, AUC: 0.788, p < 0.001). Logistic regression assessed the impact of age, BMI, low DHEAS (<40 μg/dl), bilateral tumors, and tumor size on the likelihood of having sCS. The strongest predictor was low DHEAS, recording an OR of 9.41. DHEAS levels are inversely associated with the extent of cortisol excess. In subjects with intermediate laboratory findings, detection of low DHEAS could be advantageous for distinguishing sCS. 10.1007/s12020-014-0387-7
    [Evaluation of the 1 mg overnight dexamethasone suppression test in the diagnosis of the subclinical Cushing's syndrome in patients with Adrenal Incidentaloma]. Li Lele,Han Baiyu,Dou Jingtao,Yang Guoqing,Gu Weijun,Lü Zhaohui,Mu Yiming Zhonghua yi xue za zhi OBJECTIVE:To evaluate efficacy of the 1 mg overnight dexamethasone suppression test (1 mg overnight DST) in the diagnosis of subclinical Cushing's syndrome, and to explore the best diagnostic cut-off value. METHODS:The clinical data of patients with adrenal incidentaloma in Chinese PLA General Hospital from 1995 to 2013 were gathered. The data of subclinical Cushing's syndrome (SCS) and non-functional adrenal adenoma (NFA) was retrospectively analyzed. The ROC curve was used to evaluate the efficacy of the 1 mg overnight DST and to explore the best cut-off value with high sensitivity and specificity. RESULTS:There were 447 patients with NFA (224 male and 223 female), and the mean age was 53±11 years old.49 patients were with SCS (19 male and 30 female), and the mean age was 47±12 years old. The area under the ROC of serum cortisol level after 1 mg overnight DST was 0.967 (95%CI: 0.942-0.993). The best cut-off value of serum cortisol after 1 mg overnight DST was 63.65 nmol/L, with a sensitivity of 100.0% and a specificity of 88.8%. The best cut-off value of the suppression ratio of serum cortisol was 85.64%, with a sensitivity of 83.3% and a specificity of 84.6%. CONCLUSIONS:The best criterion for 1 mg overnight DST in the diagnosis of SCS was serum cortisol level , and the recommend cut-off point was 63.65 nmol/L, with both a higher sensitivity and specificity. The suppression ratio of serum cortisol after 1 mg overnight DST was also considered as a suitable criterion in the diagnosis of SCS. 10.3760/cma.j.issn.0376-2491.2015.48.008
    A case of subclinical Cushing's syndrome presenting as catatonia. Yamaguchi Hiroyuki,Chiba Yuhei,Katsuse Omi,Tamazawa Akihide,Hirayasu Yoshio Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society 10.1111/psyg.12394
    Adrenal incidentalomas and subclinical Cushing syndrome: indications to surgery and results in a series of 26 laparoscopic adrenalectomies. Pisano Giuseppe,Calò Pietro Giorgio,Erdas Enrico,Pigliaru Francesca,Piras Stefano,Sanna Sandro,Manca Alessandro,Dazzi Claudio,Nicolosi Angelo Annali italiani di chirurgia BACKGROUND:Casual detection of an adrenal mass, the so called incidentaloma (AI) requires an in-depth analysis of imaging phenotype together with hormonal investigation, in order to evaluate both its potential malignancy and the occurrence of a preclinical condition of hypercortisolism (Subclinical Cushing Syndrome, SCS). Aim of the present work is to evaluate surgical indications and results of surgery in patients harbouring an AI with inapparent hypercortisolism. METHODS:The study has been carried on in a series of 26 Laparoscopic Adrenalectomies (LA) performed from January 2009 and January 2015. Indications to surgery included AI (11 cases), Cushing's syndrome (7 cases), suspected metastases (5 cases) and Conn's disease (3 cases). Six patients with AI had a SCS associated with variable forms of a metabolic syndrome: they were evaluated in detail analysing cortisol secretion and values of Arterial Hypertension, Diabetes Mellitus and BMI before and after surgery. RESULTS:As far as SCS is concerned, LA was completed in 5 patients (one case converted). Pathology revealed 5 adenomas and one nodular hyperplasia. Four cases required oral cortisone administration at the discharge. At a mean follow- up of 33 months cortisol secretion returned to normal range in all patients; an improvement of metabolic condition was observed in 60, 25, and 50 per cent of hypertensive, diabetic and obese patients respectively. CONCLUSION:Indications to LA in case of AI and SCS is strongly supported by the presence of an associated metabolic syndrome. In spite of a limited number, our experience confirms the favourable results of surgery in such patients. KEY WORDS:Adrenal incidentaloma, Laparoscopic adrenalectomies, Subclinical Cushing syndrome.
    Approach to the Patient with Subclinical Cushing's Syndrome. Ivović Miomira,Marina Ljiljana V,Šojat Antoan S,Tančić-Gajić Milina,Arizanović Zorana,Kendereški Aleksandra,Vujović Svetlana Current pharmaceutical design A growing number of patients with adrenal incidentalomas and subclinical Cushing's syndrome (SCS) led to an increasing number of different guidelines, and diagnostic and treatment recommendations. Excess cortisol secretion in patients with SCS is associated with several comorbidities, such as hypertension, dyslipidemia, type 2 diabetes mellitus, and obesity, which in the long-term increase mortality of these patients. Subtle cortisol secretion affects bone health, quality of life and causes depression, but due to the unapparent clinical features, patients with SCS are often at risk between over and under treatment. This narrative review aimed to summarize the latest recommendations on the approach to the patient with subclinical Cushing's syndrome. 10.2174/1381612826666200813134328
    Alterations in hypothalamic-pituitary-adrenal function immediately after resection of adrenal adenomas in patients with Cushing's syndrome and others with incidentalomas and subclinical hypercortisolism. Khawandanah Dena,ElAsmar Nadine,Arafah Baha M Endocrine BACKGROUND:Patients with cortisol secreting adrenal adenomas present with Cushing's syndrome (CS), while 5-15% of subjects with adrenal incidentalomas have subclinical hypercortisolism (SH) as they have biochemical abnormalities suggesting autonomous cortisol secretion without associated clinical features of CS. GOALS:Examine HPA function immediately after resection of either of these adenomas and utilize the data to decide on initiating glucocorticoid replacement. METHODS:ACTH, cortisol, and DHEA-S levels were measured frequently for 8 h after adrenalectomy in 14 patients with CS and 19 others with incidentalomas + SH. Glucocorticoids were withheld before/during surgery and administered 6-8 h postoperatively to those who had cortisol levels of <3 ug/dL (83 nmol/L). RESULTS:Preoperatively, incidentalomas + SH patients had larger tumors, higher ACTH, and DHEA-S but lower dexamethasone-suppressed serum cortisol levels than those with CS. Postoperatively, ACTH levels increased in both groups: (90.1 ± 31.6; 24.1 ± 14.4 ng/L, respectively; P < 0.001). Postoperative ACTH levels correlated negatively with preoperative Dexamethasone-suppressed cortisol concentrations in both groups. Patients with CS had steeper decline in cortisol concentrations than those with incidentalomas + SH. All patients with CS had hypocortisolemia requiring glucocorticoid therapy for several months, while only 5/19 with incidentalomas + SH had cortisol levels <3 ug/dL;(83 nmol/L) 6-8 h after adrenalectomy and received hydrocortisone replacement therapy for ≤4 weeks. CONCLUSIONS:Surgical stress stimulates HPA function even in patients with hypercortisolemia. Patients with incidentalomas + SH have incomplete HPA suppression that allows more robust response to surgical stress than that observed in patients with CS. HPA assessment immediately after surgical resection of adrenal incidentalomas identified those requiring glucocorticoid replacement before discharge. 10.1007/s12020-018-1769-z
    Subclinical Cushing's syndrome in patients with bilateral compared to unilateral adrenal incidentalomas: a systematic review and meta-analysis. Paschou Stavroula A,Kandaraki Eleni,Dimitropoulou Fotini,Goulis Dimitrios G,Vryonidou Andromachi Endocrine The purpose of this study was to systematically review the literature for studies that have investigated possible differences in the prevalence of subclinical Cushing's syndrome (SCS) and related clinical implications between patients with unilateral (UAI) and bilateral adrenal incidentalomas (BAI) and to meta-analyze the best evidence available. Electronic databases PubMed and EMBASE were systematically searched. Main study outcome was the prevalence of SCS in patients with UAI and BAI. Secondary outcomes were the prevalence of obesity, diabetes, glucose intolerance, hypertension, dyslipidemia, and osteoporosis in patients with UAI and BAI. Risk differences (RD) or mean differences (MD) and 95 % confidence intervals (CIs) were calculated. Meta-analysis was conducted using Review Manager (RevMan 5.3). Six studies were included in the meta-analysis involving in total 1239 patients, 968 with UAI, and 271 with BAI. Patients with UAI had lower prevalence of SCS compared with those with BAI [RD (95 % CI) -0.13 (-0.22 to -0.05), I (2) = 42 %]. The mass diameter of UAI did not differ from BAI (the size of the largest lesion) [MD (95 % CI) -0.45 (-1.09 to 0.19), I (2) = 91 %]. The prevalence of obesity [MD (95 % CI) 0.42 (-0.53 to 1.37), I (2) = 4 %], diabetes [RD (95 % CI) -0.04 (-0.11 to 0.04), I (2) = 0 %], hypertension [RD (95 % CI) 0.00 (-0.18 to 0.18), I (2) = 75 %], and dyslipidemia [RD (95 % CI) -0.02 (-0.16 to 0.13), I (2) = 50 %] did not differ between UAI and BAI. The present meta-analysis provided evidence that patients with BAI present a higher prevalence of SCS compared to patients with UAI. 10.1007/s12020-015-0776-6
    THERAPY OF ENDOCRINE DISEASE: Improvement of cardiovascular risk factors after adrenalectomy in patients with adrenal tumors and subclinical Cushing's syndrome: a systematic review and meta-analysis. Bancos Irina,Alahdab Fares,Crowley Rachel K,Chortis Vasileios,Delivanis Danae A,Erickson Dana,Natt Neena,Terzolo Massimo,Arlt Wiebke,Young William F,Murad M Hassan European journal of endocrinology OBJECTIVE:Beneficial effects of adrenalectomy on cardiovascular risk factors in patients with subclinical Cushing's syndrome (SCS) are uncertain. We sought to conduct a systematic review and meta-analysis with the following objectives: (i) determine the effect of adrenalectomy compared with conservative management on cardiovascular risk factors in patients with SCS and (ii) compare the effect of adrenalectomy on cardiovascular risk factors in patients with SCS vs those with a nonfunctioning (NF) adrenal tumor. METHODS:MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE and Cochrane Central Register of Controlled Trial were searched on 17 November 2015. Reviewers extracted data and assessed methodological quality in duplicate. RESULTS:We included 26 studies reporting on 584 patients with SCS and 457 patients with NF adrenal tumors. Studies used different definitions of SCS. Patients with SCS undergoing adrenalectomy demonstrated an overall improvement in cardiovascular risk factors (61% for hypertension, 52% for diabetes mellitus, 45% for obesity and 24% for dyslipidemia). When compared with conservative management, patients with SCS undergoing adrenalectomy experienced improvement in hypertension (RR 11, 95% CI: 4.3-27.8) and diabetes mellitus (RR 3.9, 95% CI: 1.5-9.9), but not dyslipidemia (RR 2.6, 95% CI: 0.97-7.2) or obesity (RR 3.4, 95% CI: 0.95-12). Patients with NF adrenal tumors experienced improvement in hypertension (21/54 patients); however, insufficient data exist for comparison to patients with SCS. CONCLUSIONS:Available low-to-moderate-quality evidence from heterogeneous studies suggests a beneficial effect of adrenalectomy on cardiovascular risk factors in patients with SCS overall and compared with conservative management. 10.1530/EJE-16-0465
    Outcome of adrenalectomy for subclinical hypercortisolism and Cushing syndrome. Raffaelli Marco,De Crea Carmela,D'Amato Gerardo,Gallucci Pierpaolo,Lombardi Celestino P,Bellantone Rocco Surgery BACKGROUND:We compared operative and metabolic outcomes in patients with subclinical Cushing syndrome and Cushing syndrome caused by unilateral adrenal lesion, aiming to clarify the role of glucocorticoid replacement treatment in patients with subclinical Cushing syndrome after adrenalectomy. METHODS:The medical records of all the patients who underwent unilateral adrenalectomy for subclinical Cushing syndrome or Cushing syndrome were reviewed. Diagnostic criteria for subclinical Cushing syndrome were a pathologic dexamethasone suppression test plus 2 additional criteria. RESULTS:Twenty-nine patients with subclinical Cushing syndrome and 50 with Cushing syndrome were identified. No significant difference was found between patients with subclinical Cushing syndrome and Cushing syndrome regarding lesion size, operative time, and hospital stay. Two patients out of 29 with subclinical Cushing syndrome and 3 out of 50 patients with Cushing syndrome experienced Clavien-Dindo grade II complications (P = .87). All the patients required postoperative glucocorticoid replacement that was discontinued within 6 months in 28 of the 29 patients with subclinical Cushing syndrome and in 3 out of 50 Cushing syndrome patients (P < .005). At long-term follow-up, adrenalectomy significantly improved hypertension and diabetes in affected patients, with no differences between subclinical Cushing syndrome and Cushing syndrome. Hypercortisolism was resolved in all the cases. CONCLUSION:Operative and metabolic outcomes of adrenalectomy are similar in subclinical Cushing syndrome and Cushing syndrome. Postoperative glucocorticoid replacement treatment is advisable in all patients with subclinical Cushing syndrome. Prolonged adrenal insufficiency is more frequent in Cushing syndrome patients. 10.1016/j.surg.2016.07.042
    [Surgery versus conservative management for subclinical Cushing's syndrome in adrenal incidentalomas]. Li L L,Zhao L,Dou J T,Yang G Q,Gu W J,Lü Z H,Ba J M,Mu Y M,Lu J M,Pan C Y Zhonghua yi xue za zhi To determine the effect of the surgical and conservative approaches on the metabolic profiles in patients with subclinical Cushing's syndrome (SCS) in adrenal incidentalomas (AI). A hundred and thirty AI patients with SCS in Department of Endocrinology, PLA General Hospital between January 2008 and December 2016 were studied, surgery was performed in 88 patients (surgical group), and the rest received conservative approach (conservative group). The improvement/worsening of blood pressure, blood glucose, lipid profiles and body weight after a duration of >18 months follow-up were analyzed, respectively. Baseline demographics, clinical characteristics were similar between surgical and conservative groups. In the surgical group, blood pressure, blood glucose, lipid profiles and body weight improved more frequently than that in conservative group (29.69% vs 3.12%, =0.003; 10.94% vs 3.12%, =0.262; 7.81% vs 3.12%, =0.660; 39.06% vs 9.38%, =0.004, respectively). In conservative group, blood pressure, blood glucose, lipid profiles and body weight worsened more frequently than that in surgical group (28.13% vs 0, <0.001; 25.0% vs 0, <0.001; 18.75% vs 0, =0.003; 40.62% vs 20.31%, =0.051, respectively). Logistic regression analysis indicated surgical treatment was associated with improvement of blood pressure (=10.687, 95%: 1.279-89.299) and weight loss (=5.541, 95%: 1.404-21.872) independently of gender, age, duration of follow-up, serum cortisol level after 1 mg-dexamethasone suppression test and the mass size. In AI patients with SCS, surgery was beneficial in the aspect of metabolic profiles. 10.3760/cma.j.issn.0376-2491.2017.40.007
    Which type 2 diabetes mellitus patients should be screened for subclinical Cushing's syndrome? Cansu Güven Barış,Atılgan Sevgi,Balcı Mustafa Kemal,Sarı Ramazan,Özdem Sebahat,Altunbaş Hasan Ali Hormones (Athens, Greece) OBJECTIVE:Diabetes or impaired glucose tolerance are common in patients with Cushing's syndrome (CS). In this study we investigated the incidence of subclinical Cushing's syndrome (SCS) in type 2 diabetic patients with poor and good metabolic control and the relationship between blood glucose and cortisol levels. DESIGN:A total of 400 type 2 diabetes mellitus (T2DM) patients (Group A, HbA1c ≥8%, n=250; Group B, HbA1c ≤6.5%, n=150) were included in the study. Biochemical tests followed by the 1 mg dexamethasone suppression test (DST) were performed. If post-DST cortisol levels were above 1.8 μg/dl (non-suppressed group), the 2 mg DST test was performed for 2 days. Among the patients, post-DST cortisol of at least 1.8 μg/dL and midnight serum cortisol levels of at least 7.5 μg/dL confirmed the diagnosis of CS. RESULTS:While SCS was observed in 5 patients (2%) in Group A, no case was observed in group B. There was a statistically significant difference between groups for basal cortisol and post-DST cortisol results (p<0.001 and p<0.001, respectively). Microvascular complication rates were higher in the non-suppressed group (p=0.007). Post-DST cortisol levels had a positive correlation with the number of complications and HbA1c levels (respectively r=0.213, p<0.001, and r=0.191, p<0.001). Multivariate regression analysis revealed that durations of DM, HbA1c level, and post 1 mg DST cortisol levels were associated with the number of complications. CONCLUSIONS:This study shows the presence of SCS in a notable number in T2DM patients having poor metabolic control. Screening with 1 mg and 2 mg DST of T2DM patients with poor metabolic control who are also obese and hypertensive and have microvascular complications may be an appropriate method for detection of SCS. 10.14310/horm.2002.1716
    Surgical outcomes of laparoscopic adrenalectomy for patients with Cushing's and subclinical Cushing's syndrome: a single center experience. Miyazato Minoru,Ishidoya Shigeto,Satoh Fumitoshi,Morimoto Ryo,Kaiho Yasuhiro,Yamada Shigeyuki,Ito Akihiro,Nakagawa Haruo,Ito Sadayoshi,Arai Yoichi International urology and nephrology OBJECTIVE:We retrospectively examined the outcome of patients who underwent laparoscopic adrenalectomy for Cushing's/subclinical Cushing's syndrome in our single institute. PATIENTS AND METHODS:Between 1994 and 2008, a total of 114 patients (29 males and 85 females, median age 54 years) with adrenal Cushing's/subclinical Cushing's syndrome were studied. We compared the outcome of patients who underwent laparoscopic adrenalectomy between intraperitoneal and retroperitoneal approaches. Surgical complications were graded according to the Clavien grading system. We also examined the long-term results of subclinical Cushing's syndrome after laparoscopic adrenalectomy. RESULTS:Laparoscopic surgical outcome did not differ significantly between patients with Cushing's syndrome and those with subclinical Cushing's syndrome. Patients who underwent laparoscopic intraperitoneal adrenalectomy had longer operative time than those who received retroperitoneal adrenalectomy (188.2 min vs. 160.9 min). However, operative blood loss and surgical complications were similar between both approaches. There were no complications of Clavien grade III or higher in either intraperitoneal or retroperitoneal approach. We confirmed the improvement of hypertension and glucose tolerance in patients with subclinical Cushing's syndrome after laparoscopic adrenalectomy. CONCLUSIONS:Laparoscopic adrenalectomy for adrenal Cushing's/subclinical Cushing's syndrome is safe and feasible in either intraperitoneal or retroperitoneal approach. The use of the Clavien grading system for reporting complications in the laparoscopic adrenalectomy is encouraged for a valuable quality assessment. 10.1007/s11255-011-9950-9
    Update on subclinical Cushing's syndrome. Nieman Lynnette K Current opinion in endocrinology, diabetes, and obesity PURPOSE OF REVIEW:The present review summarizes recent findings in the diagnosis and treatment of subclinical Cushing's syndrome, a condition of subtle cortisol dysregulation with a spectrum of clinical and biochemical abnormalities. RECENT FINDINGS:The diagnosis of subclinical Cushing's syndrome is suggested by abnormal suppression to dexamethasone in a patient with an adrenal mass. The natural history of this disorder includes progression in a minority of cases, and increased cardiovascular disease in patients with more severe and progressive disease, much as is found in overt Cushing's syndrome. In patients with an abnormal response to dexamethasone, additional biochemical and metabolic features increase confidence in the ability of adrenalectomy to reverse clinical abnormalities. In addition, bilateral masses and larger masses are more likely to be associated with hypercortisolism. SUMMARY:We review the recent literature on subclinical cortisol secretion and suggest that additional studies are needed to define optimal diagnostic and therapeutic approaches. 10.1097/MED.0000000000000159
    In the overnight dexamethasone suppression test, 1.0 mg loading is superior to 0.5 mg loading for diagnosing subclinical adrenal Cushing's syndrome based on plasma dexamethasone levels determined using liquid chromatography-tandem mass spectrometry. Sasaki Yosuke,Katabami Takuyuki,Asai Shiko,Fukuda Hisashi,Tanaka Yasushi Endocrine journal The low-dose dexamethasone suppression test (DST) is one of the commonly used initial tests for endogenous Cushing's syndrome (CS). However, there are two loading dose regimens (0.5-mg and 1-mg), which may cause some confusion in daily practice in Japan; furthermore, there are no reports regarding whether 0.5-mg DST is a better loading dose for detecting adrenal subclinical CS (SCS) based on the plasma dexamethasone (DEX) levels. Therefore, the aims of this study were (a) to develop a novel assay to measure DEX by using liquid chromatography tandem-mass spectrometry (LC-MS/MS) and (b) to compare between the 0.5-mg and 1-mg DST for SCS diagnosis based on the DEX levels. The study retrospectively analyzed 52 consecutive subjects hospitalized for diagnosis of adrenal incidentaloma but who did not exhibit an overt CS phenotype; eight (15.4%) patients were affected with adrenal SCS. Inter-individual variability of DEX levels after the DST was high, but intra-individual variability was low. DEX levels after 1-mg loading in each patient was around two times higher than those after 0.5-mg loading (ρ = 0.853 and p < 0.001). There were 45 (86.5%) and 17 (32.7%) subjects with DEX levels ≤2.2 ng/mL after the 0.5-mg and 1-mg DST, respectively (p < 0.001). Twenty-eight (93.3%) of 30 subjects and four (21.1%) of 19 subjects with detectable ACTH levels after the 0.5-mg and 1.0-mg DST, respectively, did not exhibit DEX levels >2.2 ng/mL. These results clearly indicate that the 1-mg DST is superior to 0.5-mg loading for the diagnosis of adrenal SCS. 10.1507/endocrj.EJ17-0083
    Posterior retroperitoneoscopic adrenal surgery for clinical and subclinical Cushing's syndrome in patients with bilateral adrenal disease. Lowery Aoife J,Seeliger Barbara,Alesina Pier F,Walz Martin K Langenbeck's archives of surgery BACKGROUND:The treatment of hypercortisolism for patients with bilateral adrenal disease (BAD) is controversial. Bilateral total adrenalectomy results in permanent hypocortisolaemia requiring lifelong steroid replacement. A more conservative surgical approach, with less than bilateral total adrenalectomy (leaving functional adrenal tissue either unilaterally or bilaterally), represents an alternative option; however, long-term outcome or recurrence data are limited. We report our experience with the surgical management of hypercortisolism caused by BAD. METHODS:Between 2004 and 2016, 42 patients (12 male, 30 female; mean age 58 ± 10 years) with clinical or subclinical Cushing's syndrome (CS/sCS) caused by BAD underwent adrenal surgery via the posterior retroperitoneoscopic approach. Adrenal surgery was defined as "adrenalectomy" when total gland excision was performed or "resection" when a partial or subtotal adrenal resection was performed. Clinical, radiological and biochemical parameters were evaluated preoperatively and postoperatively. RESULTS:Seventy adrenal operations performed in total included unilateral resection (n = 3), unilateral adrenalectomy (n = 15), bilateral resection (n = 9), adrenalectomy and contralateral resection (n = 14) and bilateral total adrenalectomy (n = 3). Median operating time was 47.5 min (30-150) with no difference between unilateral and bilateral (synchronous included) procedures (p = 0.15). Mortality was zero. Clavien-Dindo grade of postoperative complications was I (n = 5) and IV (n = 3). All but one patient with CS and 17/31 patients with sCS received postoperative steroid supplementation for a median duration of 20 (1.5-129) months. After median follow-up of 40 months (3-129), the remission rate was 92%; 11 patients required ongoing steroid supplementation. There were three biochemical recurrences (two underwent contralateral resection); two patients with new/progressive radiological nodularity are biochemically eucortisolaemic. A significant reduction in BMI (p = 0.01) and antihypertensive requirements (p = 0.04) was observed postoperatively. CONCLUSION:A surgical approach which facilitates the conservation of functional adrenal tissue represents a suitable strategy for hypercortisolism caused by BAD. This approach avoids the necessity for lifelong steroid replacement in the majority of cases with low rates of adrenal insufficiency and recurrence. 10.1007/s00423-017-1569-6
    New diagnostic criteria of adrenal subclinical Cushing's syndrome: opinion from the Japan Endocrine Society. Yanase Toshihiko,Oki Yutaka,Katabami Takuyuki,Otsuki Michio,Kageyama Kazunori,Tanaka Tomoaki,Kawate Hisaya,Tanabe Makito,Doi Masaru,Akehi Yuko,Ichijo Takamasa Endocrine journal New diagnostic criteria and the treatment policy for adrenal subclinical Cushing's syndrome (SCS) are proposed on behalf of the Japan Endocrine Society. The Japanese version has been published, and the essential contents are presented in this English-language version. The current diagnostic criteria for SCS have elicited two main problems: (i) the relatively low reliability of a low range of serum cortisol essential for the diagnosis by an overnight 1-mg dexamethasone suppression test (DST); (ii) different cutoff values for serum cortisol after a 1-mg DST compared with those of other countries. Thus, new criteria are needed. In the new criteria, three hierarchical cortisol cutoff values, 5.0, 3.0 and 1.8 μg/dL, after a 1-mg DST are presented. Serum cortisol ≥5 μg/dL after a 1-mg DST alone is considered sufficient to judge autonomous cortisol secretion for the diagnosis of SCS, and the current criterion based on serum cortisol ≥3 μg/dL after a 1-mg DST can continue to be used. Clinical evidence suggests that serum cortisol ≥1.8-2.9 μg/dL after a 1-mg DST is not always normal, so cases who meet the cutoff value as well as a basal adrenocorticotropic hormone (ACTH) level <10 pg/mL (or poor ACTH response to corticotropin-releasing hormone (CRH)) and nocturnal serum cortisol ≥5 μg/dL are proposed to have SCS. We suggest surgery if cases show serum cortisol ≥5 μg/dL after a 1-mg DST (or are disheartened by treatment-resistant problems) or suspicious cases of adrenal cancer according to tumor imaging. 10.1507/endocrj.EJ17-0456
    Adipokine and cytokine levels in patients with adrenocortical cancer, subclinical Cushing's syndrome and healthy controls. Babinska Anna,Kaszubowski Mariusz,Kmieć Piotr,Sworczak Krzysztof Steroids INTRODUCTION:In recent years researchers have focused at hormonal activity in Cushing's syndrome (CS) in connection with metabolic disorders and the role of adipokines and cytokines secreted by the adipose tissue. The aim of the study was to investigate levels of adipokines and cytokines in patients with: subclinical CS (SCS) - in relation to hormonal parameters of hypercortisolemia, and, adrenocortical cancer (ACC). MATERIALS AND METHODS:The study included 20 SCS as well as 7 ACC patients, and 18 healthy participants. Hormonal activity and serum concentrations of adiponectin, leptin, resistin, tumor necrosis factor alpha (TNFα), interleukin 6 (IL6), and monocyte chemoattractant protein 1 (MCP1), were analyzed. RESULTS:In SCS patients compared to healthy volunteers a trend toward higher concentrations of all pro-inflammatory cytokines was noted, however, statistically significant differences were only found for TNFα and IL6 (p = 0.047 and p = 0.028, respectively). Adiponectin concentrations were significantly lower in the SCS group (p = 0.006). Serum adipokine and cytokine levels were independent of the presence of diabetes mellitus (DM) and hypertension (HT) in the SCS group. A significant correlation was found between subclinical glucocorticoid secretion and IL6 concentration (Pearson's r = 0.517, p = 0.02). Acquired results were independent of BMI. In ACC patients compared to controls higher IL6, TNFα and MCP1 levels were recorded. CONCLUSION:It is possible that higher adipokine and pro-inflammatory cytokine concentrations as well as lower anti-inflammatory adiponectin concentrations comprise an additional risk factor of metabolic and cardiovascular diseases in SCS patients. It seems that at least among patients with SCS adipokine and cytokine secretion is independent of hormonal activity (except for IL6). 10.1016/j.steroids.2018.08.011
    Adrenalectomy was recommended for patients with subclinical Cushing's syndrome due to adrenal incidentaloma. Wang Dong,Ji Zhi-Gang,Li Han-Zhong,Zhang Yu-Shi Cancer biomarkers : section A of Disease markers OBJECTIVE:To assess whether adrenalectomy may improve biochemical and metabolic impairment for patients with subclinical Cushing syndrome (SCS) due to adrenal incidentaloma (AI) compared with conservative management. METHODS:A total of 87 patients with SCS due to AI in Peking Union Medical College Hospital between September 2011 and January 2016 have been treated. Forty-eight patients underwent laparoscopic adrenalectomy (operative group), whereas 39 were managed conservatively (control group). RESULTS:The duration of follow-up was 32.5 ± 10.6 months in operative group, and 30.1 ± 13.1 months in control group, respectively. In the operative group, laboratory corticosteroid parameters normalized in all patients but not in the control group. In the operative group, BP of hypertensive patients improved or normalized (22 of 48); to the contrary, in the control group, cure or improvement was never achieved among the patients with hypertension, whereas a worsening was observed in 5 patients (P= 0.004). No significant difference was found in glycemic control and blood lipid change between the two groups. However, a decrease in triglyceridaemia and HBA1c was found in operative group compared with the control group (P= 0.011 and P= 0.017, respectively). Substitutive corticosteroid treatment was administered in 3 patients due to postoperative adrenal insufficiency during hospital stay, and the duration of treatment was 9 weeks, 10 weeks and 12 weeks, respectively. CONCLUSIONS:Laparoscopic adrenalectomy should be performed for patients with SCS due to AI. 10.3233/CBM-170531
    Cardiovascular events and mortality in patients with adrenal incidentalomas that are either non-secreting or associated with intermediate phenotype or subclinical Cushing's syndrome: a 15-year retrospective study. Di Dalmazi Guido,Vicennati Valentina,Garelli Silvia,Casadio Elena,Rinaldi Eleonora,Giampalma Emanuela,Mosconi Cristina,Golfieri Rita,Paccapelo Alexandro,Pagotto Uberto,Pasquali Renato The lancet. Diabetes & endocrinology BACKGROUND:Incidental discovery of adrenal masses has increased over the past few years. Mild alterations in cortisol secretion without clinical signs of overt hypercortisolism (subclinical Cushing's syndrome) are a common finding in patients with these tumours. Although metabolic alterations and increased cardiovascular risk have been noted in patients with subclinical Cushing's syndrome, incidence of cardiovascular events and mortality in the long term have not been assessed. We aimed to ascertain the frequency of new cardiovascular events and mortality in patients with non-secreting adrenal incidentalomas, tumours of intermediate phenotype, or those causing subclinical Cushing's syndrome. METHODS:From January, 1995, to September, 2010, consecutive outpatients with adrenal incidentalomas who were referred to the endocrinology unit of S Orsola-Malpighi Hospital, Bologna, Italy, were enrolled into our study. Individuals were assessed every 18-30 months for the first 5 years (mean follow-up 7·5 [SD 3·2] years, range 26 months to 15 years). Cortisol concentrations after the 1 mg dexamethasone suppression test (DST) were used to define non-secreting (+50 nmol/L) and intermediate phenotype (50-138 nmol/L) adrenal incidentalomas and subclinical Cushing's syndrome (+138 nmol/L). At the end of follow-up, patients were reclassified as having either unchanged or worsened secreting patterns from baseline. FINDINGS:198 outpatients were assessed; at the end of follow-up, 114 patients had stable non-secreting adrenal incidentalomas, 61 had either a stable intermediate phenotype or subclinical Cushing's syndrome, and 23 had a pattern of secretion that had worsened. By comparison with patients with stable non-secreting adrenal incidentalomas, the incidence of cardiovascular events was higher in individuals with a stable intermediate phenotype or subclinical Cushing's syndrome (6·7% vs 16·7%; p=0·04) and in those with worsened secreting patterns (6·7% vs 28·4%; p=0·02). Cardiovascular events were associated independently with a change (from baseline to the end of follow-up) in cortisol concentrations post DST (hazard ratio 1·13, 95% CI 1·05-1·21; p=0·001). Survival rates for all-cause mortality were lower in patients with either stable intermediate phenotype adrenal incidentalomas or subclinical Cushing's syndrome compared with those with stable non-secreting masses (57·0% vs 91·2%; p=0·005). Factors associated with mortality were age (hazard ratio 1·06, 95% CI 1·01-1·12; p=0·03) and mean concentrations of cortisol post DST (1·10, 1·01-1·19; p=0·04). Compared with patients with stable non-secreting adrenal incidentalomas, unadjusted survival for cardiovascular-specific mortality was lower in patients with either a stable intermediate phenotype or subclinical Cushing's syndrome (97·5% vs 78·4%; p=0·02) and in those with worsened secreting patterns (97·5% vs 60·0%; p=0·01). Cancer mortality did not differ between groups. INTERPRETATION:Even when clinical signs of overt hypercortisolism are not present, patients with adrenal incidentalomas and mild hypercortisolism have an increased risk of cardiovascular events and mortality. FUNDING:None. 10.1016/S2213-8587(13)70211-0
    Subclinical Cushing's syndrome: current concepts and trends. Zografos George N,Perysinakis Iraklis,Vassilatou Evangeline Hormones (Athens, Greece) Clinically inapparent adrenal masses which are incidentally detected have become a common problem in everyday practice. Approximately 5-20% of adrenal incidentalomas present subclinical cortisol hypersecretion which is characterized by subtle alterations of the hypothalamic-pituitary-adrenal axis due to adrenal autonomy. This disorder has been described as subclinical Cushing's syndrome, since there is no typical clinical phenotype. The diagnosis of subclinical Cushing's syndrome is based on biochemical evaluation; however, there is still no consensus for the biochemical diagnostic criteria. An abnormal 1mg dexamethasone suppression test (DST) as initial screening test in combination with at least one other abnormal test of the hypothalamic-pituitary-adrenal axis has been advocated by most experts for the diagnosis of subclinical Cushing's syndrome. DST is the main method of establishing the diagnosis, while there is inhomogeneity of the information that other tests provide. Arterial hypertension, diabetes mellitus type 2 or impaired glucose tolerance, central obesity, osteoporosis/vertebral fractures and dyslipidemia are considered as detrimental effects of chronic subtle cortisol excess, although there is no proven causal relationship between subclinical cortisol hypersecretion and these morbidities. Therapeutic strategies include careful observation along with medical treatment of morbidities potentially related to subtle cortisol hypersecretion versus laparoscopic adrenalectomy. The optimal management of patients with subclinical Cushing's syndrome is not yet defined. The conservative approach is appropriate for the majority of these patients; however, the duration of follow-up and the frequency of periodical evaluation still remain open issues. Surgical resection may be beneficial for patients with hypertension, diabetes mellitus type 2 or abnormal glucose tolerance and obesity. 10.14310/horm.2002.1506
    Effectiveness of unilateral laparoscopic adrenalectomy in ACTH-independent hypercortisolaemia and subclinical Cushing's syndrome - a retrospective study on a large cohort. Pogorzelski Ryszard,Toutounchi Sadegh,Ambroziak Urszula,Krajewska Ewa,Wołoszko Tomasz,Szostek Małgorzata,Jakuczun Wawrzyniec,Celejewski Krzysztof,Legocka Małgorzata,Kwasiborski Przemysław,Gałązka Zbigniew,Biskup Ewelina Endokrynologia Polska INTRODUCTION:To assess the effectiveness of early unilateral laparoscopic adrenalectomy in ACTH-independent and subclinical hypercor-tisolaemia. MATERIAL AND METHODS:We conducted a unicentric, retrospective study. Between 2010 and 2015, 356 laparoscopic adrenalectomies were performed in the Department of General and Endocrine Surgery of the MUW. Hypercortisolaemia was found in 50 (14%) patients, while overt hypercortisolaemia was found in 31 patients. In the hypercortisolaemia group, ACTH-dependent hypercortisolaemia was diagnosed in five (10%) and ACTH-independent hypercortisolaemia in 25 patients (50%). One patient with overt hypercortisolaemia had cancer of the adrenal cortex. The remaining 19 (38%) patients had subclinical Cushing's syndrome. For our study, we compared patients with ACTH-independent hypercortisolaemia (n = 25) with those with Cushing's syndrome (n = 19). Patients with ACTH-dependent hyper-cortisolaemia (n = 5) and the patient with cancer of the adrenal cortex (n = 1) were excluded. RESULTS:Patients from both groups (n = 44) underwent a unilateral transperitoneal adrenalectomy. Good early outcomes were observed in 42 patients (93.3%). In one patient, an additional laparoscopic surgery was necessary on postoperative day 0 due to bleeding. In another patient, on day 22 post-surgery, we found an abscess in the site of the excised adrenal gland, which was drained under laparoscopic guid-ance. In three patients (6.8%) with substantial obesity, temporary respiratory insufficiency of varying degrees occurred. We did not observe any thromboembolic complications. All patients with overt hypercortisolaemia and nine patients with subclinical hypercortisolaemia had secondary adrenal insufficiency postoperatively. CONCLUSIONS:Transperitoneal unilateral laparoscopic adrenalectomy is an efficient and safe treatment option in patients with ACTH- -independent hypercortisolaemia, both overt and subclinical. 10.5603/EP.a2018.0039
    When to Intervene for Subclinical Cushing's Syndrome. Hsieh Lily B,Mackinney Erin,Wang Tracy S The Surgical clinics of North America Without the overt clinical signs and symptoms associated with Cushing's syndrome, the diagnosis of subclinical Cushing's syndrome (SCS) is primarily based on biochemical evaluation. Despite being labeled as "subclinical," SCS is associated with significant morbidity that can be improved with adrenalectomy. Minimally invasive adrenalectomy is associated with low morbidity in the hands of experienced adrenal surgeons and is recommended as the treatment of choice for SCS patients with SCS-associated comorbidities. 10.1016/j.suc.2019.04.011
    [Clinical features and outcomes of surgical versus conservative management in patients with subclinical Cushing's syndrome]. Liu M S,Zhang W J,Zhu K Y,Feng W H,Huang H,Zhu D L,Li P Zhonghua yi xue za zhi To examine the clinical characteristics and metabolic features of subclinical Cushing's syndrome (SCS), and determine the effects of surgical or conservative approaches on the hormone levels and metabolic comorbidities in patients with SCS, thereby providing the evidence for decision-making in SCS management. A total of 56 consecutive SCS patients were selected in Drum Tower Hospital Affiliated to Nanjing University Medical School between 2010 and 2018, with 41 patients undergoing surgical treatment and 15 patients receiving conservative therapy. Meanwhile, 56 and 68 cases of sex-and age-matched patients diagnosed as nonfunctional adrenal adenoma (NFA) and adrenal Cushing's syndrome (CS) were included respectively. Clinical characteristics of patients in different groups were compared. Hormone levels and metabolic comorbidities were also observed during follow-up. There were 56 SCS patients, including 15 males and 41 females, with an age of (52.0±12.6) years. The circadian rhythms of adrenocorticotropic hormone (ACTH) and cortisol disappeared in CS and SCS groups. Compared to NFA group, patients with SCS were characterized by suppressed plasma ACTH level [2.40 (1.11, 4.33) pmol/L vs 4.23 (2.74, 6.26) pmol/L], elevated midnight cortisol level [(240±121) nmol/L vs (59±8) nmol/L] and increased cortisol level after 1 mg overnight dexamethasone suppression test [(241±130) nmol/L vs (34±12) nmol/L] (all 0.01). The derangement of ACTH-cortisol axis was more obvious in CS patients compared to SCS patients. The prevalence of hypertension, glucose intolerance, dyslipidemia and osteopenia/osteoporosis were higher in SCS patients compared to NFA patients (75.0% vs 41.1%, 33.9% vs 12.5%, 62.5% vs 28.6%, 35.7% vs 8.9%, all 0.05). The 24-hour urine free cortisol correlated positively with systolic blood pressure, glycated hemoglobin A1c (HbA1c) and fasting blood glucose in SCS patients (0.335, 0.562 and 0.463, respectively, all 0.05). In the surgical group, body weight, body mass index (BMI) and blood pressure decreased significantly after surgery (all 0.05). Glucose intolerance/diabetes mellitus improved in 6 of 9 patients, BMI of 4 of 11 overweight/obesity patients normalized, and hypertension in 54.5% of patients (12/22) showed improvement after surgery. However, no alterations of hormone levels and metabolic parameters were observed in conservatively-managed patients. Patients with SCS are characterized by mild autonomous cortisol secretion and increased risk of metabolic comorbidities. Compared with conservative management, hormone abnormalities were corrected and metabolic abnormalities were improved in some SCS patients after surgery. 10.3760/cma.j.cn112137-20200213-00274
    Six controversial issues on subclinical Cushing's syndrome. Chiodini Iacopo,Albani Adriana,Ambrogio Alberto Giacinto,Campo Michela,De Martino Maria Cristina,Marcelli Giorgia,Morelli Valentina,Zampetti Benedetta,Colao Annamaria,Pivonello Rosario, Endocrine Subclinical Cushing's syndrome is a condition of hypercortisolism in the absence of signs specific of overt cortisol excess, and it is associated with an increased risk of diabetes, hypertension, fragility fractures, cardiovascular events and mortality. The subclinical Cushing's syndrome is not rare, being estimated to be between 0.2-2 % in the adult population. Despite the huge number of studies that have been published in the recent years, several issues remain controversial for the subclinical Cushing's syndrome screening, diagnosis and treatment. The Altogether to Beat Cushing's syndrome Group was founded in 2012 for bringing together the leading Italian experts in the hypercortisolism-related diseases. This document represents the Altogether to Beat Cushing's syndrome viewpoint regarding the following controversial issues on Subclinical Cushing's syndrome (SCS): (1) Who has to be screened for subclinical Cushing's syndrome? (2) How to screen the populations at risk? (3) How to diagnose subclinical Cushing's syndrome in patients with an adrenal incidentaloma? (4) Which consequence of subclinical Cushing's syndrome has to be searched for? (5) How to address the therapy of choice in AI patients with subclinical Cushing's syndrome? (6) How to follow-up adrenal incidentaloma patients with subclinical Cushing's syndrome surgically or conservatively treated? Notwithstanding the fact that most studies that faced these points may have several biases (e.g., retrospective design, small sample size, different criteria for the subclinical Cushing's syndrome diagnosis), we believe that the literature evidence is sufficient to affirm that the subclinical Cushing's syndrome condition is not harmless and that the currently available diagnostic tools are reliable for identifying the majority of individuals with subclinical Cushing's syndrome. 10.1007/s12020-016-1017-3
    Incompatibility between fasting and postprandial plasma glucose in patients with Cushing's syndrome. Otsuki Michio,Kitamura Tetsuhiro,Tamada Daisuke,Tabuchi Yukiko,Mukai Kosuke,Morita Shinya,Kasayama Soji,Shimomura Iichiro,Koga Masafumi Endocrine journal It is shown that glucocorticoids have discordant effects on plasma glucose concentration through their effects on hepatic glycogen deposition, gluconeogenesis and peripheral insulin resistance. Cushing's syndrome caused by cortisol overproduction is frequently accompanied with diabetes mellitus, but fasting plasma glucose (FPG) and post-glucose load plasma glucose levels are not examined in patients with Cushing's syndrome. The aim of this study was to investigate FPG, HbA1c and oral glucose tolerance test (OGTT) 2-h PG and their relationship in patients with Cushing's syndrome, in comparison with control subjects. Sixteen patients with Cushing's syndrome (ACTH-dependent 31%, ACTH-independent 69% and diabetes mellitus 50%) and 64 controls (32 patients with type 2 diabetes mellitus and 32 non-diabetic subjects matched for age, sex and BMI) were enrolled in this study. HbA1c and FPG in the patients with Cushing's syndrome were not different from the controls, whereas the FPG/HbA1c ratio was significantly lower in the patients with Cushing's syndrome than the controls. OGTT 2-h PG was significantly higher in the non-diabetic patients with Cushing's syndrome than the non-diabetic controls, while HbA1c was not different between both groups and FPG was significantly lower in the patients with Cushing's syndrome than the controls. HOMA-β but not HOMA-R was significantly higher in the patients with Cushing's syndrome than the controls. In conclusion, FPG was rather lower in the patients with Cushing's syndrome than the controls. Postprandial PG or post-glucose loaded PG, but not FPG, is useful to evaluate the abnormality of glucose metabolism in patients with Cushing's syndrome. 10.1507/endocrj.EJ15-0748
    Reference intervals of salivary cortisol and cortisone and their diagnostic accuracy in Cushing's syndrome. European journal of endocrinology OBJECTIVE:The challenge of diagnosing Cushing's syndrome (CS) calls for high precision biochemical screening. This study aimed to establish robust reference intervals for, and compare the diagnostic accuracy of, salivary cortisol and cortisone in late-night samples and after a low-dose (1 mg) dexamethasone suppression test (DST). DESIGN AND METHODS:Saliva samples were collected at 08:00 and 23:00 h, and at 08:00 h, after a DST, from 22 patients with CS and from 155 adult reference subjects. We also collected samples at 20:00 and 22:00 h from 78 of the reference subjects. Salivary cortisol and cortisone were analysed with liquid chromatography-tandem mass spectrometry. The reference intervals were calculated as the 2.5th and 97.5th percentiles of the reference population measurements. Diagnostic accuracies of different tests were compared, based on areas under the receiver-operating characteristic curves. RESULTS:The upper reference limits of salivary cortisol and cortisone at 23:00 h were 3.6 nmol/L and 13.5 nmol/L, respectively. Using these reference limits, CS was detected with a sensitivity (95% CI) of 90% (70-99%) and specificity of 96% (91-98%) for cortisol, and a 100% (84-100%) sensitivity and 95% (90-98%) specificity for cortisone. After DST, cortisol and cortisone upper reference limits were 0.79 nmol/L and 3.5 nmol/L, respectively. CS was detected with 95% (75-100%) sensitivity and 96% (92-99%) specificity with cortisol, and 100% (83-100%) sensitivity and 94% (89-97%) specificity with cortisone. No differences in salivary cortisol or cortisone levels were found between samples collected at 22:00 and 23:00 h. CONCLUSION:Salivary cortisol and cortisone in late-night samples and after DST showed high accuracy for diagnosing CS, salivary cortisone being slightly, but significantly better. 10.1530/EJE-19-0872
    Sexual function in women with Cushing's Syndrome: A controlled study. Keskin Fatma Ela,Özkaya Hande Mefkure,Ortaç Mazhar,Salabaş Emre,Kadıoğlu Ateş,Kadıoğlu Pınar Turkish journal of urology OBJECTIVE:The aim of this study is to determine the severity of female sexual dysfunction (FSD), quality of life, and depression status in female patients with Cushing's syndrome (CS). MATERIAL AND METHODS:This study included 29 sexually active women with CS and 30 healthy age and body mass index matched women. The Female Sexual Function Index (FSFI) questionnaire, Beck Depression Inventory (BDI) and Short Form Health Survey (SF-36) were filled by each participant. Plasma levels of FSH, LH, PRL, cortisol, DHEA-S, 17-hydroxyprogesterone, androstenedione, free testosterone, total testosterone and estradiol were measured. RESULTS:Female sexual dysfunction was present in 88.9% of the women with CS and 24.1% of the control group. The CS group showed a lower total FSFI score [16.6 (IQR: 5-23)] compared to the healthy women [26.8 (IQR: 25.5-30.4) (p<0.001)]. The FSFI scores in the arousal, lubrication, orgasm, pain and satisfaction domains were all lower in the women with CS (p<0.001). Both summary scores of the SF-36 were reduced in women with Cushing's syndrome compared to the control group (p=0.001). The BDI scores of patients were significantly higher than those of the control subjects (p=0.007). In patients with CS, levels of LH, estradiol, and DHEA-S04 were significantly lower while cortisol (p<0.05), and 17 hydroxyprogestrone levels were higher than control subjects (p<0.05). CONCLUSION:This study showed that majority of the women with CS had FSD. This may be related to the inhibitory effect of cortisol on sex hormones. 10.5152/tud.2018.74240
    Analysis of cortisol secretion in hormonally inactive adrenocortical incidentalomas: study of in vitro steroid secretion and immunohistochemical localization of steroidogenic enzymes. Midorikawa S,Sanada H,Hashimoto S,Suzuki T,Watanabe T,Sasano H Endocrine journal Adrenal incidentalomas have recently increased in incidence, and thus it has become important to establish clinical management of these patients. It is also important to evaluate whether these tumors are different from preclinical or overt Cushing's syndrome in their steroidogenesis. In this study, we therefore examined steroidogenesis of hormonally inactive adrenal incidentalomas via short-term culture of tumor specimens, in addition to an immunohistochemical study of steroidogenic enzymes. Five patients (two men and three women) diagnosed with adrenocortical incidentaloma without any clinical signs of adrenocortical hormonal excess except for hypertension and disturbed glucose tolerance, were recruited for this study. Hormonal findings, including circadian rhythms for cortisol and ACTH secretion, the response of ACTH to CRH infusion and results of dexamethasone suppression test were all within normal limits in these patients. Immunoreactivity for all steroidogenic enzymes involved in cortisol production was detected in tumor cells in all cases examined. Results of in vitro steroidogenesis analysis using short-term culture revealed that levels of cortisol secretion varied among the cases. There were no differences in the immunolocalization of steroidogenic enzymes and/or the levels of cortisol secretion between these hormonally inactive tumors and preclinical and/or overt Cushing's syndrome. Dehydroepiandrosterone-sulfotransferase (DHEA-ST) immunoreactivity in nonneoplastic regions was suppressed in one case in which the tumor secreted cortisol similar to preclinical and/or overt Cushing's syndrome. These results demonstrate that the levels of in vitro steroid production and/or the immunolocalization of steroidogenic enzymes in hormonally inactive adrenocortical tumors vary markedly and are not overtly different from those of preclinical and/or overt Cushing's syndrome.
    Accuracy of new recommendations for adrenal incidentalomas in the evaluation of excessive cortisol secretion and follow-up. Ruiz Ana,Michalopoulou Theodora,Megia Ana,Näf Silvia,Simón-Muela Inmaculada,Solano Esther,Martínez Laia,Vendrell Joan European journal of clinical investigation OBJECTIVE:To evaluate whether the 2016 European Society of Endocrinology (ESE) recommendations for the management of adrenal incidentalomas accurately classifies those patients who do not require further follow-up. DESIGN AND METHODS:Single centre retrospective study. From 2010 to 2015, 130 patients with adrenal incidentaloma were evaluated and followed-up. Clinical, analytical and radiological data were recorded and the presence of comorbidities was assessed. Patients were grouped as nonfunctional or subclinical Cushing syndrome according to American guidelines; and nonfunctional, possible autonomous cortisol secretion and autonomous cortisol secretion, according to ESE guidelines. RESULTS:Based on American guidelines, 94% of patients had nonfunctional adrenal incidentalomas and 6% had subclinical Cushing syndrome. Based on ESE guidelines, patients were classified into nonfunctional (54%), possible autonomous cortisol secretion (40%) and autonomous cortisol secretion (6%) groups. No differences were observed in demographic characteristics and comorbidities between groups in either classification. Following ESE guidelines, no patient in the nonfunctional group was reclassified into the possible autonomous or autonomous cortisol secretion groups during follow-up, but one patient in the possible autonomous cortisol secretion group was reclassified into the autonomous cortisol secretion group. Also, 30 patients included in the groups of possible autonomous or autonomous cortisol secretion experienced progression of a comorbidity associated with cortisol excess, with diabetes mellitus as the most frequent comorbidity observed. CONCLUSION:Although adrenal incidentalomas with an excess of cortisol secretion were more frequently diagnosed with the new ESE recommendations, patients who did not require longer follow-up after first evaluation were accurately classified. 10.1111/eci.13048
    Sex Differences in Presentation but Not in Outcome for ACTH-Dependent Cushing's Syndrome. Broersen Leonie H A,van Haalen Femke M,Kienitz Tina,Biermasz Nienke R,Strasburger Cristian J,Dekkers Olaf M,Pereira Alberto M Frontiers in endocrinology Sex differences in clinical picture of ACTH-dependent Cushing's syndrome are controversial, except for the known higher prevalence in females. We compared a broad range of potential differences to enable a more accurate understanding of the clinical picture of sex-specific ACTH-dependent Cushing's syndrome. Cohort study including consecutive patients with ACTH-dependent Cushing's syndrome from Leiden and Berlin diagnosed between 2000 and 2016. We compared clinical presentation, biochemical parameters, diagnostic tests, surgical outcome, and comorbidities between men and women. We included 130 patients: 37 males and 93 females. With similar cortisol concentrations, ACTH concentrations were higher in males than females at time of diagnosis (median: 116 vs. 57 ng/L). The prevalence of osteoporosis was higher in males than in females (48.6 vs. 25.0%), persisting after surgery, with more vertebral fractures (16.2 vs. 5.4%) before surgery. Males showed more anemia (75.9 vs. 36.8%) after surgery. There were no differences in etiology, pituitary tumor size, diagnostic and therapeutic strategy, or surgical outcome between sexes. Based on this study, males and females with ACTH-dependent Cushing's syndrome present different clinical patterns. However, these differences do not justify different diagnostic strategies or treatment based on sex, considering the similar surgical outcome. Clinicians should be alert to diagnose accompanying osteoporosis (with fractures) in male patients with ACTH-dependent Cushing's syndrome. 10.3389/fendo.2019.00580
    Lipid abnormalities in patients with adrenal incidentalomas: role of subclinical hypercortisolism and impaired glucose metabolism. Masserini B,Morelli V,Palmieri S,Eller-Vainicher C,Zhukouskaya V,Cairoli E,Orsi E,Beck-Peccoz P,Spada A,Chiodini I Journal of endocrinological investigation BACKGROUND:Subclinical hypercortisolism (SH) has been associated with metabolic complications such as type 2 diabetes mellitus, obesity and dyslipidemia. Scarce data are available regarding the lipid pattern abnormalities in SH, in relation to insulin resistance and impaired glucose metabolism (IGM). We aimed to evaluate the possible influence of SH on lipid pattern in relation to the presence/absence of impaired glucose metabolism. METHODS:In 338 patients with adrenal incidentaloma, the presence of SH, hypertension, dyslipidemia and IGM was evaluated. According to the presence of SH and IGM the patients were divided into 4 groups (IGM+SH+, IGM+SH-, IGM-SH+, IGM-SH-). We recruited 98 subjects without IGM (IGM-) and 100 with IGM (IGM+) as control groups. RESULTS:The prevalence of dyslipidemia was comparable among Group IGM+SH+, Group IGM+SH- and IGM+ controls (57.9, 58.4, 56%, P = NS). No difference in dyslipidemia prevalence among IGM- patients and IGM- controls was observed. The IGM+SH+ patients had a higher prevalence of dyslipidemia (57.9%) than IGM-SH+ ones (29.1%, P < 0.01). The IGM+SH- patients showed an increased prevalence of hypertension (76.6 vs 54.8%, P < 0.01) and dyslipidemia (58.4 vs 23.8%, P < 0.0001) as compared with IGM-SH- patients. Logistic regression analysis showed that only IGM was associated to dyslipidemia (OR 4.31, 95% CI 2.61-7.12, P = 0.0001) regardless of age, SH and gender. CONCLUSIONS:In the absence of alterations of glucose metabolism the presence of a subtle cortisol excess has no effect on lipid pattern. IGM seems to influence the lipid metabolism regardless of the presence of SH. 10.1007/s40618-014-0232-0