Subclinical Cushing's Syndrome Patients Research Articles

Epigenetic alterations of 11beta-hydroxysteroid dehydrogenase 1 gene in the adipose tissue of patients with primary aldosteronism.

11Beta-hydroxysteroid dehydrogenase 1 (11β-HSD1) is a key enzyme involved in metabolic syndrome. Transcript-specific epigenetic regulation of the gene encoding 11β-HSD1 (HSD11B1) has been reported. We examined the mRNA level and methylation status of the HSD11B1 promoter region in the adipose tissue of patients with primary aldosteronism (PA). We compared 10 tissue specimens from patients with PA caused by aldosterone-producing adenoma (APA) with 8 adipose tissue specimens from patients with subclinical Cushing's syndrome (SCS) caused by cortisol-producing adenomas, 4 tissue specimens from patients with Cushing's adenoma (Cu), or 7 tissue specimens from patients with non-functioning adrenal adenoma (NFA). PA, SCS, and Cu were diagnosed according to the guideline of the Japan Endocrine Society. The mRNA level of HSD11B1 was quantified using real-time PCR. Isolated DNA was treated with bisulfite and amplified using primers specific to the human HSD11B1 promoter region. The glycohemoglobin level was significantly higher in patients with APA, SCS, or Cu than in those with NFA (p < 0.05). Blood pressure was significantly higher in patients with APA than in those with SCS, Cu, or NFA (p < 0.01). The HSD11B1 mRNA level was significantly increased in the adipose tissues of APA or SCS patients compared with Cu or NFA patients (p < 0.05). The methylation ratio was significantly lower in SCS patients than in APA, Cu, or NFA patients (p < 0.05). HSD11B1 expression is partly controlled by an epigenetic mechanism in human tissues. The pathophysiological role of epigenetic regulation of HSD11B1 expression in adipose tissue requires further study.

Clinical features and outcomes of surgical versus conservative management in patients with subclinical Cushing's syndrome

Objective: 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. Methods: 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. Results: 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 P<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 P<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 (r=0.335, 0.562 and 0.463, respectively, all P<0.05). In the surgical group, body weight, body mass index (BMI) and blood pressure decreased significantly after surgery (all P<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. Conclusions: 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.

When to Intervene for Subclinical Cushing's Syndrome.

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.

Expression of adiponectin and leptin receptors in adrenal incidentaloma patients with subclinical hormone secretion.

The role of adopokines in adrenal tumors' hormonal activity remains unclear. Obesity may induce arterial hypertension, disorders of carbohydrate metabolism, and is a risk factor of cardiovascular disease. In patients with subclinical hormone secretion by the adrenal cortex or medulla the risk of metabolic disease is increased. Authors of this retrospective study selected 78 patients with subclinical hormone secretion out of all adrenal incidentaloma patients hospitalized in the Department of Endocrinology and Internal Medicine between 1995 and 2014. The analyzed group comprised of 38 subclinical Cushing's syndrome (SCS), 40 incidentally discovered pheochromocytoma (PHEO) and 42 patients operated due to an adrenal tumor without pathological hormonal activity. Expression of adiponectin (AdipoR1, AdipoR2) and leptin (Ob-R) receptors in adrenal tumors was assessed in relation to body mass index (BMI) and hormonal activity. We found statistically significant negative correlations between BMI and expression of all examined receptors in SCS patients (AdipoR1: p= 0.032; AdipoR2: p< 0.001; leptin Ob-R: p= 0.001). In PHEOs, BMI correlated negatively only with AdipoR2 (p= 0.014). Data obtained show that the most significant factor associated with the expression of AdipoR1, AdipoR2 and leptin Ob-R receptors in the adrenal tumor tissue is BMI, not their hormonal activity.

Contralateral adrenal width predicts the duration of prolonged post-surgical steroid replacement for subclinical Cushing syndrome.

To identify pre-treatment factors affecting the duration of post-surgical steroid replacement in patients undergoing adrenalectomy for subclinical Cushing syndrome. The present retrospective analysis included 64 patients who underwent unilateral laparoscopic adrenalectomy for subclinical Cushing syndrome. Adrenal tumor and contralateral adrenal sizes together with various clinical factors were studied in association with the duration of post-surgical steroid replacement. Adrenal tumor and contralateral adrenal size were measured at the level of the maximum transverse plane of the adrenal glands using computed tomography scan or magnetic resonance imaging. Cox's proportional hazards model was used for the statistical analysis. All 64 patients were treated with post-surgical steroid replacement after adrenalectomy. The median duration of the steroid treatment was 6 months. When assessing the duration of post-surgical steroid replacement, contralateral adrenal volume <0.745 cm3 , contralateral adrenal width <6.15 mm and serum cortisol after a 1-mg dexamethasone suppression test >2.65 μg/dL were significant predictors of prolonged post-surgical steroid treatment on univariate analysis. On multivariate analysis, contralateral adrenal width <6.15 mm was the only independent predictive factor for the prolonged post-surgical steroid replacement. Contralateral adrenal width seems to represent a significant predictive factor for the duration of post-surgical steroid replacement in subclinical Cushing syndrome patients. Pre-surgical assessment of image findings might help clinicians determine the total duration of steroid therapy after adrenalectomy.

Diagnostic value of urinary free cortisol in the subclinical Cushing's syndrome in patients with adrenal incidentaloma

Objective: To evaluate the efficacy of 24 h urinary free cortisol (24 h UFC) in the diagnosis of subclinical Cushing's syndrome (SCS), and explore the best diagnostic cut-off value. Methods: The clinical data of patients with adrenal incidentaloma in Chinese PLA General Hospital between January 2008 and December 2016 was retrospectively reviewed and analyzed. All SCS patients were diagnosed based on the current Cushing's syndrome (CS) guidelines and confirmed by histopathology and then treated as study group, and additional patients with non-functional adrenal adenoma (NFA) were enrolled as control group. ROC curve was used to evaluate efficacy of 24 h UFC and 24 h UFC to creatinine ratio (UFCCR), and explore their best cut-off values. Results: There were 161 patients with NFA, of which contained 84 males and 77 females, with a mean age of (51.02±10.49) years old. There were 88 patients with SCS, of which contained 26 males and 62 females, with a mean age of (51.74±10.29) years old. The 24 h UFC and UFCCR levels were significant higher in SCS group than those in NFA group[510 (363, 698) nmol vs 335 (209, 467) nmol for 24 h UFC, and 7.82(4.79, 12.13) ml vs 4.82(2.41, 6.57)ml for UFCCR, both P<0.05]. ROC analysis showed that the optimal cut-off for 24 h UFC was 480 nmol (AUC 0.716, 95% CI: 0.648-0.784, with a sensitivity of 58.0% and a specificity of 79.4%) and the optimal cut-off for UFCCR was 6.84 ml (AUC 0.729, 95% CI: 0.662-0.796, with a sensitivity of 59.1% and a specificity of 78.7%). Conclusions: The recommended cut-off points of 24 h UFC and UFCCR for diagnosing SCS in AI patients were 480 nmol and 6.84 ml, respectively.

Assessment of platelet function in endogenous hypercortisolism.

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. 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. 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. In hypercortisolaemic patients no primary haemostasis disorders are present, as reflected by platelet adhesion and ADP- and collagen-induced aggregation measurements.

Activity of selected coagulation factors in overt and subclinical hypercortisolism

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.

Bilateral adrenal incidentalomas differ from unilateral adrenal incidentalomas in subclinical cortisol hypersecretion but not in potential clinical implications

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. Prospective observational study. 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. 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). 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.

Long-term study of subclinical Cushing's syndrome shows high prevalence of extra-adrenal malignancy in patients with functioning bilateral adrenal tumors.

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.

A Case of Incidentally Discovered Subclinical Cushing Syndrome in a Patient with Chronic Fatigue and Anxiety

Subclinical Cushing syndrome (SCS) is a hypothalamic-pituitary-adrenal axis abnormality characterized by autonomous cortisol secretion in patients with no typical signs or symptoms of Cushing syndrome. SCS patients may have adverse metabolic and cardiovascular effects due to slight, but continuous glucocorticoid secretion. Glucocorticoids also affect behavior, mood, neural activity, and a number of specific biochemical processes in the central nervous system. Here, we report a case of SCS due to an adrenal incidentaloma in a hypertensive diabetic patient who presented with chronic fatigue and anxiety that disappeared after the removal of the adrenal adenoma.

Acute administration of alprazolam, a benzodiazepine activating GABA receptors, inhibits cortisol secretion in patients with subclinical but not overt Cushing’s syndrome

The purpose of this study is to verify whether acute pre-treatment with alprazolam (ALP), a benzodiazepine that inhibits HPA secretion in normal subjects, could better characterize patients with subclinical Cushing's syndrome (SCS) than the 1-mg dexamethasone test (DST). In 22 patients with SCS, 10 with overt Cushing's syndrome (CS), 11 with non-functioning adrenal incidentalomas (NF) and 14 normal subjects (NS) we studied the effect of ALP (1 mg, p.o. at 2300 hours) on cortisol levels after 1-mg DST. Cortisol levels (mean ± SEM) after DST were lower (P = 0.012) in SCS (3.9 ± 0.3 μg/dl) than in overt CS (10.4 ± 1.9 μg/dl), while they were higher (P = 0.0005) than in NF (1.1 ± 0.1 μg/dl) and NS (1.5 ± 0.1 μg/dl). After ALP pre-treatment, cortisol levels further decreased (P = 0.004) in SCS (3.0 ± 0.3 μg/dl), but neither in CS (9.3 ± 1.3 μg/dl) nor in NF (1.3 ± 0.1 μg/dl) and in NS (1.3 ± 0.1 μg/dl). In SCS, cortisol levels after ALP + 1-mg DST persisted lower (P = 0.0005) than those in CS, but higher (P = 0.0005) than those in NF and NS. Considering individual cases, ALP pre-treatment reduced cortisol levels < 3 and < 1.8 μg/dl in 50 and 23 % of SCS patients, respectively. ALP amplifies the cortisol inhibition exerted by 1-mg DST in patients with SCS but not in those with CS. The clinical usefulness of ALP to increase the sensitivity of 1-mg DST to identify true autonomous cortisol release in patients with adrenal incidentalomas as well as to predict different clinical outcomes remains to be clarified.

Evaluation of salivary cortisol measurements for the diagnosis of subclinical Cushing’s syndrome

Late-night salivary cortisol (NSC) has been recognized as a sensitive and easy-to-perform screening test for the diagnosis of overt Cushing's syndrome (CS). However, there have been few reports on the diagnostic utility of salivary cortisol (SC) measurement in the diagnosis of subclinical Cushing's syndrome (SCS). Therefore, the present study was designed to evaluate the usefulness of SC measurements at late-night and after overnight 1 mg dexamethasone suppression test (DST) for the diagnosis of SCS in 42 patients with adrenal incidentaloma. We evaluated 16 patients with SCS, 12 with nonfunctioning adenoma (NFA), 8 with primary aldosteronism (PA), and 6 with pheochromocytoma (Pheo). NSC levels in SCS patients (0.238 ± 0.106 µg/dL) were significantly (P < 0.05) higher than those in NFA patients (0.154 ± 0.104 µg/dL); the cutoff value (0.11 µg/dL) by ROC analysis gave high sensitivity (100%) with low specificity (50%). Post DST SC levels in SCS patients (0.238 ± 0.116 µg/dL) were significantly (P = 0.0081) higher than those in NFA patients (0.136 ± 0.110 µg/dL); the cutoff value (0.12 µg/dL) by ROC analysis gave high sensitivity (93.8%) with somewhat improved specificity (58.3%). Both NSC and post DST SC levels were comparable between NFA, PA, and Pheo patients. In conclusion, our study revealed that measurements of NSC and/or post DST SC among patients with adrenal incidentaloma prove to have high sensitivities, but low specificities for the diagnosis of SCS from NFA, suggesting its possible alternative option before the screening tests for SCS currently employed in Japan.

Clinical outcomes of surgical treatment and longitudinal non-surgical observation of patients with subclinical Cushing′s syndrome and nonfunctioning adrenocortical adenoma

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.

Clinical outcome of subclinical Cushing's syndrome after surgical and conservative treatment

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.

Long-term morphological, hormonal, and clinical follow-up in a single unit on 118 patients with adrenal incidentalomas

To evaluate long-term morphological, functional, and clinical outcome in adrenal incidentalomas. A total of 118 patients (77 F and 47 M; age 62.3+/-1.0 years) with adrenal incidentalomas were evaluated at baseline and followed-up for median 3 years (range 1-10 years) by clinical, biochemical, hormonal, and morphological evaluation. Among them, six patients with diagnosis of subclinical Cushing's syndrome (SCS) underwent surgery. At entry, 86% (n=102) of tumors were nonfunctioning (NF) and 14% (n=16) showed SCS. Comparing NF with SCS patients, a significantly higher percentage of dyslipidemia was found in the group of SCS patients (50 vs 23%, P=0.033). During follow-up, adrenal function remained normal in all NF patients, none of them developed subclinical or overt endocrine disease. The cumulative risk of mass enlargement was globally low (25%), but progressive up to 8 years. SCS was confirmed in all patients, and none of them shifted to overt Cushing's syndrome. The cumulative risk of developing metabolic-cardiovascular abnormalities was globally low (22%), but progressive up to 8 years and new diseases were recorded in the group of NF patients only (three patients with dyslipidemia, four with impaired fasting glucose/impaired glucose tolerance, and three with diabetes mellitus). SCS patients who underwent surgery did not show any significant clinical improvement. The risk of mass enlargement, hormonal, and metabolic impairment over time is globally low. Conservative management seems to be appropriate, but further prospective studies are needed to establish the long-term outcome of such patients, especially for metabolic status, cardiovascular risk profile and their relationship with endocrine function.

Surgical Versus Conservative Management for Subclinical Cushing Syndrome in Adrenal Incidentalomas: A Prospective Randomized Study

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. The most appropriate management of SCS patients is controversial, either adrenalectomy or close follow-up being recommended for their treatment. 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. 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. 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.

Evaluation of the Cardiovascular Risk in Patients with Subclinical Cushing Syndrome Before and After Surgery

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. 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. 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. 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.

Patients with subclinical Cushing's syndrome due to adrenal adenoma have increased cardiovascular risk.

Subclinical Cushing's syndrome (SCS) is increasingly being reported in incidentally discovered adrenal adenomas; its hallmark is mild autonomous cortisol hyperproduction without specific clinical signs of cortisol excess. Increased prevalence of hypertension, obesity, and impaired glucose tolerance have been described in SCS, but there is no specific study of the risk factors for cardiovascular diseases. In this cross-sectional study we assessed the cardiovascular profile in 28 consecutive SCS patients (19 women and 9 men; aged 56 +/- 10.6 yr) compared with 100 controls matched for age, gender, and body mass index. Systolic (P < 0.001) and diastolic (P < 0.005) blood pressures were higher in patients, as were fasting glucose, insulin, total cholesterol, triglycerides (all P < 0.001), and fibrinogen (P < 0.05). Moreover, the insulin resistance index was increased in patients as was the waist to hip ratio and mean carotid artery intima-media thickness (all P < 0.001). Of the patients, 60.7% had arterial hypertension, 71.4% had lipid abnormalities, 28.6% had impaired glucose tolerance, 35.7% type 2 diabetes mellitus, and 53.6% had abnormalities in hemostatic parameters. Atherosclerotic plaques were more frequent in patients (P < 0.0001). Only 4 (14.3%) patients did not have multiple risk factors for cardiovascular events. Six (21.3%) had clinical evidence of cardiovascular disease; another 11 (39.3%) had cardiovascular abnormalities as revealed by ultrasound scanning of carotid arteries and/or electrocardiogram records. These results strongly suggest that an increased cardiovascular risk profile, similar to that described in overt Cushing's syndrome, is present in SCS subjects. This finding supports the concept that chronic mild endogenous cortisol excess may have important systemic effects on the human body.