Diagnosis and Treatment of Subclinical Hypercortisolism

In the paper

“Moreover, after excluding MSeC, all combinations of the remaining parameters did not show enough reliability for predicting hypocortisolism after surgery, and conversely, the normality of all parameters of HPA axis activity before surgery could not rule out with 100% probability the appearance of postsurgical adrenal insufficiency.”

What the sources say

• Not checked yetcites [58] Eller-Vainicher, 2010, Post-surgical hypocortisolism after removal of an adrenal incidentaloma: is it predictable by an accurate endocrinological work-up before surgery?, Eur J Endocrinol source

In the paper

“Also in this study, lowering the cutoff of 1-mg DST was demonstrated to lead to a reduction in specificity (from 85.7 to 23.8%) and an increase in sensitivity (from 33.3 to 79.5%).”

What the sources say

• Not checked yetcites [58] Eller-Vainicher, 2010, Post-surgical hypocortisolism after removal of an adrenal incidentaloma: is it predictable by an accurate endocrinological work-up before surgery?, Eur J Endocrinol source

In the paper

“We found that the simultaneous presence of elevated UFC and MSeC levels [Ͼ5.4 g/dl (149 nmol/liter)] before surgery had a 100% specificity for predicting postsurgical hypocortisolism, but at the expense of a 30.8% sensitivity.”

What the sources say

• Not checked yetcites [58] Eller-Vainicher, 2010, Post-surgical hypocortisolism after removal of an adrenal incidentaloma: is it predictable by an accurate endocrinological work-up before surgery?, Eur J Endocrinol source

In the paper

“The DST-UFC-ACTH combination criterion was confirmed to be useful because it showed the best accuracy in predicting improvement (sensitivity, 65.2%; specificity, 68.8%) in surgically treated patients and worsening of the endpoints (sensitivity, 55.6%; specificity, 82.9%), in the conservatively treated subjects.”

What the sources say

• Not checked yetcites [60] Eller-Vainicher, 2010, Accuracy of several parameters of hypothalamic-pituitary-adrenal axis activity in predicting before surgery the metabolic effects of the removal of an adrenal incidentaloma., Eur J Endocrinol source

In the paper

“Some studies suggested that this condition is present in 1-10% of patients with diabetes or established osteoporosis.”

In the paper

“particularly in AI patients, cortisol secretion is a continuum from completely normal to clearly increased levels, and it is highly variable in the same individual (3,22).”

What the sources say

• Not checked yetcites [3] Grumbach, 2003, Management of the clinically inapparent adrenal masses (“incidentaloma”)., Ann Intern Med source
• Not checked yetcites [22] Terzolo, 2005, Midnight serum cortisol as a marker of increased cardiovascular risk in patients with a clinically inapparent adrenal adenoma., Eur J Endocrinol source

In the paper

“The National Institutes of Health State-of-the-Science Conference (64) and the American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons Medical Guidelines for the Management of AI (65) recommend the cutoff of 5 g/dl (138 nmol/liter) as the normal level of cortisol suppression in patients with suspected SH.”

What the sources say

• Not checked yetcites [64] 2002, NIH State-of-the-science statement on management of the clinically inapparent adrenal mass (“incidentaloma”)., 2002 NIH Consensus and State-of-the-Science Statements
• Not checked yetcites [65] Zeiger, 2009, American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons medical guidelines for the management of adrenal incidentalomas., Endocr Pract source

In the paper

“Even if midnight serum cortisol (MSeC) has been shown to be a promising tool for diagnosing SH (22), its use is limited by the need of the hospital admission for the cumbersome procedure, and it could be used as a confirmative test in selected patients (60).”

What the sources say

• Not checked yetcites [22] Terzolo, 2005, Midnight serum cortisol as a marker of increased cardiovascular risk in patients with a clinically inapparent adrenal adenoma., Eur J Endocrinol source
• Not checked yetcites [60] Eller-Vainicher, 2010, Accuracy of several parameters of hypothalamic-pituitary-adrenal axis activity in predicting before surgery the metabolic effects of the removal of an adrenal incidentaloma., Eur J Endocrinol source

In the paper

“Several studies (19,21,32,34,38,39,44,46,49,53,60,61,67) and recently the French Society for Endocrinology (68), however, have proposed a lower cutoff to increase sensitivity.”

What the sources say

• Not checked yetcites [19] Chiodini, 2004, Spinal volumetric bone mineral density and vertebral fractures in female patients with adrenal incidentalomas: the effect of subclinical hypercortisolism and gonadal status., J Clin Endocrinol Metab source
• Not checked yetcites [21] Chiodini, 2009, Bone mineral density, prevalence of vertebral fractures and bone quality in patients with adrenal incidentalomas with and without subclinical hypercortisolism: an Italian Multicenter Study., J Clin Endocrinol Metab source
• Not checked yetcites [32] Masserini, 2009, The limited role of midnight salivary cortisol in the diagnosis of subclinical hypercortisolism in patients with adrenal incidentalomas., Eur J Endocrinol source
• Not checked yetcites [34] Reincke, 1992, Preclinical Cushing's syndrome in adrenal incidentalomas: comparison with adrenal Cushing's syndrome., J Clin Endocrinol Metab
• Not checked yetcites [38] Bardet, 1996, 131I-6-b-Iodomethylnorcholesterol scintigraphy: an assessment of its role in the investigation of adrenocortical incidentalomas., Clin Endocrinol (Oxf) source
• Not checked yetcites [39] Bondanelli, 1997, Evaluation of hormonal function in a series of incidentally discovered adrenal masses., Metabolism source
• Not checked yetcites [44] Tanabe, 2001, Autonomy of cortisol secretion in clinically silent adrenal incidentaloma., Horm Metab Res source
• Not checked yetcites [46] Midorikawa, 2001, The improvement of insulin resistance in patients with adrenal incidentalomas by surgical resection., Clin Endocrinol (Oxf) source
• Not checked yetcites [49] Chiodini, 2001, Bone loss rate in adrenal incidentalomas: a longitudinal study., J Clin Endocrinol Metab source
• Not checked yetcites [53] Chiodini, 2002, Bone involvement in eugonadal male patients with adrenal incidentaloma and subclinical hypercortisolism., J Clin Endocrinol Metab source

In the paper

“Therefore, UFC should not be considered an adequate screening test for SH and should be used in combination with other tests or in specific populations (1,14).”

What the sources say

• Not checked yetcites [1] Terzolo, 2005, Subclinical Cushing's syndrome in adrenal incidentalomas., Endocrinol Metab Clin North Am source
• Not checked yetcites [14] Nieman, 2008, The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline., J Clin Endocrinol Metab source

In the paper

“Thus, reducing the cutoff of 1-mg DST leads to a decrease in specificity and, therefore, to more false diagnosis of SH (65).”

What the sources say

• Not checked yetcites [65] Zeiger, 2009, American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons medical guidelines for the management of adrenal incidentalomas., Endocr Pract source

In the paper

“The reason to screen for SH with a higher cutoff than that recommended for overt cortisol excess [1.8 g/dl (50 nmol/liter)] (66) is that in patients without signs or symptoms suggestive of hypercortisolism, the a priori possibility of having SH is estimated to be lower than that of a false-positive result (1).”

What the sources say

• Not checked yetcites [1] Terzolo, 2005, Subclinical Cushing's syndrome in adrenal incidentalomas., Endocrinol Metab Clin North Am source

In the paper

“Thus, this test should not be used for diagnosing SH until further studies and a standardization of the laboratory methods are available.”

In the paper

“Some authors found a low sensitivity of MSaC in identifying SH (31,32), whereas others showed that subjects with either consistent or frequent elevations of this parameter may actually have SH (69).”

What the sources say

• Not checked yetcites [31] Nunes, 2009, Late-night salivary cortisol for diagnosis of overt and subclinical Cushing's syndrome in hospitalized and ambulatory patients., J Clin Endocrinol Metab source
• Not checked yetcites [32] Masserini, 2009, The limited role of midnight salivary cortisol in the diagnosis of subclinical hypercortisolism in patients with adrenal incidentalomas., Eur J Endocrinol source
• Not checked yetcites [69] Kidambi, 2007, Limitations of nocturnal salivary cortisol and urine free cortisol in the diagnosis of mild Cushing's syndrome., Eur J Endocrinol source

In the paper

“Similarly, LDDST has been used to diagnose SH (18,40,41,55) without advantages, with the exception of patients affected with alcoholism, psychiatric disorders, and diabetes in whom this test may be more accurate (1,14,66).”

What the sources say

• Not checked yetcites [18] Rossi, 2000, Subclinical Cushing's syndrome in patients with adrenal incidentaloma: clinical and biochemical features., J Clin Endocrinol Metab
• Not checked yetcites [40] Kasperlik-Zeluska, 1997, Incidentally discovered adrenal mass (incidentaloma): investigation and management of 208 patients., Clin Endocrinol (Oxf) source
• Not checked yetcites [41] Tsagarakis, 1998, Elevated post-dexamethasone suppression cortisol concentrations correlate with hormonal alterations of the hypothalamo-pituitary adrenal axis in patients with adrenal incidentalomas., Clin Endocrinol (Oxf) source
• Not checked yetcites [55] Hadjidakis, 2003, Does subclinical hypercortisolism adversely affect the bone mineral density of patients with adrenal incidentalomas?, Clin Endocrinol (Oxf) source
• Not checked yetcites [1] Terzolo, 2005, Subclinical Cushing's syndrome in adrenal incidentalomas., Endocrinol Metab Clin North Am source
• Not checked yetcites [14] Nieman, 2008, The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline., J Clin Endocrinol Metab source
• Not checked yetcites [66] Arnaldi, 2003, Diagnosis and complications of Cushing's syndrome: a consensus statement., J Clin Endocrinol Metab source

In the paper

“Because the increase in sensitivity is accompanied by the decrease in specificity with the lowering of the 1-mg DST cutoff and vice versa, the combination of different parameters of HPA axis activity has been proposed to increase specificity without affecting sensitivity.”

In the paper

“The main criticism to this approach for diagnosing SH is that postsurgical hypocortisolism reflects only the pituitary sensi- tivity to cortisol excess and not that at the peripheral tissues (25)(26)(27)(28)(29)(30).”

What the sources say

• Not checked yetcites (25)(26)(27)(28)(29)(30)

In the paper

“In particular, ACTH levels above 20 pg/ml (4.4 pmol/liter) or below 10 pg/ml (2.2 pmol/liter) suggest an ACTH-dependent or -independent cause of SH, respectively (66).”

What the sources say

• Not checked yetcites [66] Arnaldi, 2003, Diagnosis and complications of Cushing's syndrome: a consensus statement., J Clin Endocrinol Metab source

In the paper

“However, if the lowest cutoffs were used [1.8 and 2.2 g/dl (50 and 60.6 nmol/liter), respectively], specificity decreased to 67-72%, whereas sensitivity increased to 75-100% (48 -62, 64 -67).”

What the sources say

• Not checked yetcites [48] Valli, 2001, Biochemical screening for subclinical cortisol-secreting adenomas amongst adrenal incidentalomas., Eur J Endocrinol source
• Not checked yetcites [49] Chiodini, 2001, Bone loss rate in adrenal incidentalomas: a longitudinal study., J Clin Endocrinol Metab source
• Not checked yetcites [50] Barzon, 2002, Development of overt Cushing's syndrome in patients with adrenal incidentalomas., Eur J Endocrinol source
• Not checked yetcites [51] Bülow, 2002, Adrenal incidentaloma—experience of a standardized diagnostic programme in the Swedish prospective study., J Intern Med source
• Not checked yetcites [52] Libè, 2002, Long-term follow-up study of patients with adrenal incidentalomas., Eur J Endocrinol source
• Not checked yetcites [53] Chiodini, 2002, Bone involvement in eugonadal male patients with adrenal incidentaloma and subclinical hypercortisolism., J Clin Endocrinol Metab source
• Not checked yetcites [54] Emral, 2003, Prevalence of subclinical Cushing's syndrome in 70 patients with adrenal incidentalomas: clinical, biochemical and surgical outcomes., Endocr J source
• Not checked yetcites [55] Hadjidakis, 2003, Does subclinical hypercortisolism adversely affect the bone mineral density of patients with adrenal incidentalomas?, Clin Endocrinol (Oxf) source
• Not checked yetcites [56] Katabami, 2005, Discrepancies in results of low- and high-dose dexamethasone suppression tests for diagnosing preclinical Cushing's syndrome., Endocr J source
• Not checked yetcites [57] Toniato, 2009, Surgical versus conservative management for subclinical Cushing syndrome in adrenal incidentalomas: a prospective randomized study., Ann Surg source

In the paper

“Moreover, the use of the DST-UFC-ACTH combination criterion is limited to the diagnosis of SH of adrenal origin because ACTH levels are useless in patients with suspected ACTH-dependent SH.”

In the paper

“The occurrence of hypocortisolism after the removal of an adrenal adenoma has been proposed as the gold standard for diagnosing SH (58).”

What the sources say

• Not checked yetcites [58] Eller-Vainicher, 2010, Post-surgical hypocortisolism after removal of an adrenal incidentaloma: is it predictable by an accurate endocrinological work-up before surgery?, Eur J Endocrinol source

In the paper

“Using the highest cutoff [5 g/dl (138 nmol/liter)], 1-mg DST was confirmed to have good specificity (83-100%) but low sensitivity (44 -58%).”

What the sources say

• Not checked yetcites [48] Valli, 2001, Biochemical screening for subclinical cortisol-secreting adenomas amongst adrenal incidentalomas., Eur J Endocrinol source
• Not checked yetcites [67] Barzon, 2001, Overnight dexamethasone suppression of cortisol is associated with radiocholesterol uptake patterns in adrenal incidentalomas., Eur J Endocrinol source

In the paper

“The limit of this approach is that these complications (i.e.osteoporosis, diabetes mellitus, and hypertension) are not specific for cortisol excess, being highly prevalent in the general population.”

In the paper

“In a seminal paper, Terzolo et al. (42) proposed the use of different combinations of several different parameters (i.e.high UFC levels, cortisol levels after 1-mg DST, high average daily serum cortisol, altered circadian cortisol rhythm, low basal ACTH levels, or blunted ACTH response to CRH) to screen for SH and the terms “definitive SH,” “probable SH,” and “possible SH”.”

What the sources say

• Not checked yetcites [42] Terzolo, 1998, Subclinical Cushing's syndrome in adrenal incidentaloma., Clin Endocrinol (Oxf) source

In the paper

“Overall, in these studies, the different parameters showed a good specificity (90 -98%, using 1-mg DST) but, generally, a poor sensitivity (41-86% using ACTH levels).”

What the sources say

• Not checked yetcites [9] Mantero, 2000, A survey on adrenal incidentaloma in Italy., J Clin Endocrinol Metab
• Not checked yetcites [31] Nunes, 2009, Late-night salivary cortisol for diagnosis of overt and subclinical Cushing's syndrome in hospitalized and ambulatory patients., J Clin Endocrinol Metab source
• Not checked yetcites [32] Masserini, 2009, The limited role of midnight salivary cortisol in the diagnosis of subclinical hypercortisolism in patients with adrenal incidentalomas., Eur J Endocrinol source
• Not checked yetcites [52] Libè, 2002, Long-term follow-up study of patients with adrenal incidentalomas., Eur J Endocrinol source

In the paper

“A few studies (summarized in Table 2) evaluated the sensitivity and specificity of the different HPA axis parameters or combination of parameters for diagnosing SH.The difficulty in performing such studies is due to the lack of a clinical, biochemical, or functional parameter that can be used as the gold standard.”

In the paper

“It is known that diabetes mellitus and osteoporosis are frequently found in patients with cortisol excess.”

In the paper

“The altered circadian rhythm, evaluated by either MSaC or MSeC, and UFC levels were not found to be sensitive enough for diagnosing SH (31,32).”

What the sources say

• Not checked yetcites [31] Nunes, 2009, Late-night salivary cortisol for diagnosis of overt and subclinical Cushing's syndrome in hospitalized and ambulatory patients., J Clin Endocrinol Metab source
• Not checked yetcites [32] Masserini, 2009, The limited role of midnight salivary cortisol in the diagnosis of subclinical hypercortisolism in patients with adrenal incidentalomas., Eur J Endocrinol source

In the paper

“This study confirmed the low sensitivity and specificity of 1-mg DST when the high or low cutoff, respectively, is used and the low accuracy of the reduced ACTH and increased UFC level, when used as single criterion (59).”

What the sources say

• Not checked yetcites [59] Morelli, 2010, Subclinical hypercortisolism: correlation between biochemical diagnostic criteria and clinical aspects., Clin Endocrinol (Oxf) source

In the paper

“However, to date, the DST-UFC-ACTH combination criterion seems the best compromise to diagnose SH because it has been validated on a clinical basis (32,59,60).”

What the sources say

• Not checked yetcites [32] Masserini, 2009, The limited role of midnight salivary cortisol in the diagnosis of subclinical hypercortisolism in patients with adrenal incidentalomas., Eur J Endocrinol source
• Not checked yetcites [59] Morelli, 2010, Subclinical hypercortisolism: correlation between biochemical diagnostic criteria and clinical aspects., Clin Endocrinol (Oxf) source
• Not checked yetcites [60] Eller-Vainicher, 2010, Accuracy of several parameters of hypothalamic-pituitary-adrenal axis activity in predicting before surgery the metabolic effects of the removal of an adrenal incidentaloma., Eur J Endocrinol source

In the paper

“Because in past years several studies have shown that SH may also be associated with a high risk of osteoporotic fractures and metabolic consequences (15)(16)(17)(18)(19)(20)(21)(22)”

What the sources say

• Not checked yetcites (15)(16)(17)(18)(19)(20)(21)(22)

In the paper

“Importantly, the criteria for defining an improvement of the possible complications of SH have been different among the different studies and were not always reported.”

In the paper

“The only available prospective randomized study found in 23 surgically treated subjects improvement of hypertension, diabetes, obesity, and dyslipidemia in 66.7, 62.5, 50, and 37.5% of cases, respectively (57).”

What the sources say

• Not checked yetcites [57] Toniato, 2009, Surgical versus conservative management for subclinical Cushing syndrome in adrenal incidentalomas: a prospective randomized study., Ann Surg source

In the paper

“Rossi et al. (18) found that blood pressure and diabetes improved in 100 and 60% of five surgically treated SH patients, respectively, whereas no changes were seen in seven conservatively treated SH subjects.”

What the sources say

• Not checked yetcites [18] Rossi, 2000, Subclinical Cushing's syndrome in patients with adrenal incidentaloma: clinical and biochemical features., J Clin Endocrinol Metab

In the paper

“In a larger study of a similar population using 1-mg DST as a screening test with a lower and, therefore, more sensitive cutoff, SH was ascertained in four (three of pituitary and one of adrenal origin) of 200 diabetic patients studied (2.0% prevalence) (82).”

What the sources say

• Not checked yetcites [82] Catargi, 2003, Occult Cushing's syndrome in type-2 diabetes., J Clin Endocrinol Metab source

In the paper

“On the contrary, in 22 conservatively treated patients, hypertension, diabetes, and dyslipidemia worsened in 80, 33.3, and 20% of cases (57).”

What the sources say

• Not checked yetcites [57] Toniato, 2009, Surgical versus conservative management for subclinical Cushing syndrome in adrenal incidentalomas: a prospective randomized study., Ann Surg source

In the paper

“A subsequent study from our group on more than 200 patients using the same screening test showed that SH was present in 4.8% of patients with osteoporosis and 10.8% of patients with osteoporosis and vertebral fractures.In this study, SH was of adrenal and pituitary origin in 4.1 and 0.7% of patients, respectively (91).”

What the sources say

• Not checked yetcites [91] Chiodini, 2007, Subclinical hypercortisolism among outpatients referred for “osteoporosis.”, Ann Intern Med source

In the paper

“These studies suggest that SH may be more frequent in patients with diabetes and osteoporosis, thus explaining the increased fracture risk.”

In the paper

“A subsequent study of 10 subjects found after recovery from SH an improvement of blood pressure, metabolic control of diabetes, and dyslipidemia in 83, 22, and 67% of cases, respectively, whereas in 12 conservatively treated subjects, hypertension, diabetes, and obesity worsened in 17, 25, and 17% of cases, respectively (96).”

What the sources say

• Not checked yetcites [96] Tsuiki, 2008, Cardiovascular risks and their long-term clinical outcome in patients with subclinical Cushing's syndrome., Endocr J source

In the paper

“These data were confirmed in a similar controlled study on 294 diabetic inpatients in whom a 10.8% prevalence of SH was found, with pituitary, adrenal, and undefined/ectopic origin accounting for 1.4, 7.2, and 2.2%, respectively (83).”

What the sources say

• Not checked yetcites [83] Chiodini, 2005, Association of subclinical hypercortisolism with type 2 diabetes mellitus: a case-control study in hospitalized patients., Eur J Endocrinol source

In the paper

“It is possible to hypothesize that some patients classified as not having SH had, in fact, a mild degree of cortisol hypersecretion, suggesting that the diagnosis of SH had not been sensitive enough.”

In the paper

“This study clearly suffers from the limits of the small sample and of its retrospective and nonrandomized design.”

In the paper

“Moreover, in reducing the cutoff of the screening test and therefore increasing its sensitivity, the adrenal cause of SH became more frequent than the pituitary cause.”

In the paper

“In a cross-sectional study on 90 obese diabetic patients with poor metabolic control, Leibowitz et al. (63) found a 3.3% prevalence of SH due to an adrenal adenoma in one patient and a pituitary adenoma in two patients using 1-mg DST above 5.1 g/dl (140 nmol/liter) as a screening test.”

What the sources say

• Not checked yetcites [63] Leibowitz, 1996, Pre-clinical Cushing's syndrome: an unexpected frequent cause of poor glycaemic control in obese diabetic patients., Clin Endocrinol (Oxf) source

In the paper

“Overall in this study, the prevalence of SH could be estimated to be almost 5.5%, with a pituitary and adrenal origin of 1.5 and 4.0%, respectively.”

What the sources say

• Not checked yetcites [82] Catargi, 2003, Occult Cushing's syndrome in type-2 diabetes., J Clin Endocrinol Metab source

In the paper

“Indeed, somatostatin analogs have been used to control food-dependent cortisol hypersecretion due to the presence of aberrant glucose-dependent insulinotropic peptide receptors (100, 101); propranolol has been proposed in patients with adrenal hypercortisolism (102) and leuprolide acetate in LH-dependent Cushing's syndrome (103).”

What the sources say

• Not checked yetcites [100] Libé, 2010, 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., Eur J Endocrinol source
• Not checked yetcites [101] de Herder, 1996, Food-dependent Cushing's syndrome resulting from abundant expression of gastric inhibitory polypeptide receptors in adrenal adenoma cells., J Clin Endocrinol Metab
• Not checked yetcites [102] Lacroix, 1997, Propranolol therapy for ectopic β-adrenergic receptors in adrenal Cushing's syndrome., N Engl J Med source
• Not checked yetcites [103] Lacroix, 1999, Leuprolide acetate therapy in luteinizing hormone-dependent Cushing's syndrome., N Engl J Med source

In the paper

“However, to date, the small sample size of the available studies and the lack of a large prospective randomized trial could not allow us to draw any firm conclusion about this point.”

In the paper

“The difficulties in defining a protocol are related to the variability of cortisol secretion in these patients (3,22) because even a 2-yr follow-up may be too short to ascertain the presence of SH (79).”

What the sources say

• Not checked yetcites [3] Grumbach, 2003, Management of the clinically inapparent adrenal masses (“incidentaloma”)., Ann Intern Med source
• Not checked yetcites [22] Terzolo, 2005, Midnight serum cortisol as a marker of increased cardiovascular risk in patients with a clinically inapparent adrenal adenoma., Eur J Endocrinol source
• Not checked yetcites [79] Donadio, 2009, Role of adrenal gland scintigraphy in patients with incidentally discovered adrenal mass and subclinical hypercortisolism., J Endocrinol Invest source

In the paper

“These uncertainties, in turn, bring into question the real clinical importance of SH itself and the need of a surgical treatment in these patients instead of the optimization of medical therapy (61).”

What the sources say

• Not checked yetcites [61] Chiodini, 2010, Beneficial metabolic effects of prompt surgical treatment in patients with an adrenal incidentaloma causing biochemical hypercortisolism., J Clin Endocrinol Metab source

In the paper

“Moreover, it must be considered that the optimization of the medical therapy is not completely free of adverse events and that adrenal surgery is becoming increasingly safer by endoscopic procedures.”