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1.  High Prevalence of Normal Tests Assessing Hypercortisolism in Subjects with Mild and Episodic Cushing’s Syndrome Suggests that the Paradigm for Diagnosis and Exclusion of Cushing’s Syndrome Requires Multiple Testing 
Many Endocrinologists believe that a single determination of eucortisolism or a single demonstration of appropriate suppression to dexamethasone excluded Cushing’s syndrome, except in what was previously thought to be the rare patient with episodic or periodic Cushing’s syndrome. We hypothesize that episodic Cushing’s syndrome is relatively common and a single test assessing hypercortisolism may not be sufficient to accurately rule out or diagnose Cushing’s syndrome and retrospectively examined the number of normal and abnormal tests assessing hypercortisolism performed on multiple occasions in 66 patients found to have mild and/or episodic Cushing’s syndrome compared to a similar group of 54 patients evaluated for, but determined not to have Cushing’s syndrome. We found that 65 of the 66 patients with Cushing’s syndrome had at least one normal test of cortisol status and most patients had several normal tests. The probability of having Cushing’s syndrome when one test was negative was 92 % for 23:00 h salivary cortisol, 88 % for 24-h UFC, 86 % for 24-h 17OHS, and 54 % for nighttime plasma cortisol. These results demonstrated that episodic hypercortisolism is highly prevalent in subjects with mild Cushing’s syndrome and no single test was effective in conclusively diagnosing or excluding the condition. Rather, the paradigm for the diagnosis should be a careful history and physical examination and in those patients in whom mild Cushing’s syndrome/disease is strongly suspected, multiple tests assessing hypercortisolism should be performed on subsequent occasions, especially when the patient is experiencing signs and symptoms of short-term hypercortisolism.
PMCID: PMC2978784  PMID: 20803415
Cushing’s syndrome; episodic; periodic; urinary free cortisol; salivary cortisol; cortisol-binding globulin; 17-hydroxycorticosteroids
2.  A Case of Congenital Adrenal Hyperplasia Mimicking Cushing's Syndrome 
Journal of Korean Medical Science  2012;27(11):1439-1443.
Congenital adrenal hyperplasia (CAH) is characterized by decreased adrenal hormone production due to enzymatic defects and subsequent rise of adrenocorticotrophic hormone that stimulates the adrenal cortex to become hyperplastic, and sometimes tumorous. As the pathophysiology is basically a defect in the biosynthesis of cortisol, one may not consider CAH in patients with hypercortisolism. We report a case of a 41-yr-old man with a 4 cm-sized left adrenal tumorous lesion mimicking Cushing's syndrome who was diagnosed with CAH. He had central obesity and acanthosis nigricans involving the axillae together with elevated 24-hr urine cortisol level, supporting the diagnosis of Cushing's syndrome. However, the 24-hr urine cortisol was suppressed by 95% with the low dose dexamethasone suppression test. CAH was suspected based on the history of precocious puberty, short stature and a profound suppression of cortisol production by dexamethasone. CAH was confirmed by a remarkably increased level of serum 17-hydroxyprogesterone level. Gene mutation analysis revealed a compound heterozygote mutation of CYP21A2 (I173N and R357W).
PMCID: PMC3492685  PMID: 23166432
Congenital Adrenal Hyperplasia; 21-Hydroxylase Deficiency; Hypercortisolism
3.  Five cases of cyclical Cushing's syndrome. 
Reported cases of cyclical Cushing's syndrome are rare. Of 14 successive patients with Cushing's syndrome nine collected sequential urine samples for the estimation of cortisol:creatinine ratio. Five had cyclical Cushing's syndrome while two had considerable variation in urinary cortisol excretion without a cyclical pattern being established. Two of the five patients with a cyclical syndrome had paradoxical responses to dexamethasone. In only one patient with a cyclical pattern did the cortisol:creatinine ratio fall after treatment with bromocriptine or cyproheptadine, or both. The high incidence of the cyclical form of Cushing's syndrome has important clinical implications. A high index of suspicion of the syndrome is required in patients with symptoms or signs of Cushing's syndrome but with normal cortisol values, in patients with fluctuating cortisol values, and in patients with anomalous responses to dexamethasone. Because of possible variations in steroidogenesis the results of drug studies in Cushing's syndrome must be interpreted cautiously.
PMCID: PMC1418075  PMID: 2998540
4.  Metyrapone for Long-Term Medical Management of Cushing's Syndrome 
Case Reports in Endocrinology  2013;2013:782068.
Cushing's syndrome is characterized by any cause of excess cortisol in the blood and produces many physiologic consequences. Left untreated, Cushing's is associated with significant morbidity and mortality. Seventy percent of endogenous cases of Cushing's syndrome are secondary to a pituitary tumor; because of this, the primary mode of management is surgical resection of the tumor. Should hypercortisolism persist following surgical resection, further treatment options are limited. Metyrapone is an orphan medication that is often used in the diagnosis of the disease and occasionally for short-term treatment prior to surgery. Long-term treatment with metyrapone is usually discouraged due to the contradictory increase in ACTH production, acne, hirsutism, hyperkalemia, edema, and other mineralocorticoid effects. We present a patient with refractory Cushing's syndrome successfully treated for nearly 6 years with metyrapone with minimal adverse effects. This orphan medication may be a viable long-term treatment option for this difficult disease.
PMCID: PMC3876709  PMID: 24416602
5.  Hair Analysis Provides a Historical Record of Cortisol Levels in Cushing’s Syndrome 
The severity of Cushing’s Syndrome (CS) depends on the duration and extent of the exposure to excess glucocorticoids. Current measurements of cortisol in serum, saliva and urine reflect systemic cortisol levels at the time of sample collection, but cannot assess past cortisol levels. Hair cortisol levels may be increased in patients with CS, and, as hair grows about 1 cm/month, measurement of hair cortisol may provide historical information on the development of hypercortisolism. We attempted to measure cortisol in hair in relation to clinical course in six female patients with CS and in 32 healthy volunteers in 1 cm hair sections. Hair cortisol content was measured using a commercially available salivary cortisol immune assay with a protocol modified for use with hair. Hair cortisol levels were higher in patients with CS than in controls, the medians (ranges) were 679 (279–2500) and 116 (26–204) ng/g respectively (P <0.001). Segmental hair analysis provided information for up to 18 months before time of sampling. Hair cortisol concentrations appeared to vary in accordance with the clinical course. Based on these data, we suggest that hair cortisol measurement is a novel method for assessing dynamic systemic cortisol exposure and provides unique historical information on variation in cortisol, and that more research is required to fully understand the utility and limits of this technique.
PMCID: PMC2945912  PMID: 19609841
glucocorticoids; pituitary adenoma; cancer; adrenal gland; hormones; cushing hair
6.  Cortisol, obesity and the metabolic syndrome: A cross-sectional study of obese subjects and review of the literature 
Obesity (Silver Spring, Md.)  2013;21(1):E105-E117.
Circulating cortisol and psychosocial stress may contribute to the pathogenesis of obesity and metabolic syndrome. To evaluate these relationships, we performed a cross-sectional study of 369 overweight and obese subjects and 60 healthy volunteers and reviewed the previous literature.
Overweight and obese subjects had at least two other features of Cushing’s syndrome. They underwent measurements representing cortisol dynamics (24h urine cortisol excretion (UFC), bedtime salivary cortisol, 1 mg dexamethasone suppression test) and metabolic parameters (BMI, blood pressure (BP); fasting serum triglycerides, HDL, insulin, and glucose). Subjects also completed the Perceived Stress Scale (PSS). UFC, salivary cortisol and weight from 60 healthy volunteers were analyzed.
No subject had Cushing’s syndrome. UFC and dexamethasone responses were not associated with BMI or weight. However, salivary cortisol showed a trend to increase as BMI increased (P< 0.0001), and correlated with waist circumference (WC) in men (rs=0.28, P=0.02) and systolic BP in women (rs=0.24, P =0.0008). Post-dexamethasone cortisol levels were weak to moderately correlated with fasting insulin (rs=− 0.31, P=0.01) and HOMA-IR (rs=−0.31, P=0.01) in men and systolic (rs=0.18, P= 0.02) and diastolic BP (rs=0.20, P=0.009) in women. PSS results were higher in obese subjects than controls, but were not associated with cortisol or metabolic parameters. As expected, WC correlated with fasting insulin, HOMA-IR and systolic BP (adjusted for BMI and gender; P < 0.01). Literature showed inconsistent relationships between cortisol and metabolic parameters.
Taken together, these data do not support a strong relationship between systemic cortisol or stress and obesity or metabolic syndrome.
PMCID: PMC3602916  PMID: 23505190
cortisol; metabolic syndrome; insulin resistance; obesity
7.  Cushing’s Syndrome: All variants, detection, and treatment 
Cushing’s syndrome is caused by prolonged exposure to excess glucocorticoids. Diagnosis of Cushing’s syndrome involves a step-wise approach and establishing the cause can be challenging in some cases. Hypertension is present in about 80% of patients with Cushing’s syndrome and can lead to significant morbidity and mortality. Several pathogenic mechanisms have been proposed for glucocorticoid-induced hypertension including a functional mineralocorticoid excess state, up-regulation of the renin angiotensin system and deleterious effects of cortisol on the vasculature. Surgical excision of the cause of excess glucocorticoids remains the optimal treatment for Cushing’s syndrome. Anti-glucocorticoid and antihypertensive agents and steroidogenesis inhibitors can be used as adjunctive treatment modalities in preparation for surgery, and in cases where surgery is contraindicated or has not led to cure.
PMCID: PMC3095520  PMID: 21565673
Cushing’s syndrome; hypertension; glucocorticoids; ectopic ACTH secretion; 11-beta hydroxysteroid dehydrogenase; hypercortisolemia
8.  Crossing the other side of the algorithm: a challenging case of adrenal Cushing’s syndrome 
BMJ Case Reports  2011;2011:bcr0820114694.
The diagnosis of endogenous Cushing’s syndrome and its aetiology involved documenting the hypercotisolism and then determining whether that hypercortisolism is adrenocorticotropic hormone-dependent (ACTH-dependent) or not. Hence, following the algorithm, an undetected ACTH level points to an adrenal Cushing’s while a detectable or elevated ACTH level points to either a pituitary or ectopic Cushing’s syndrome. The authors present a case of florid adrenal Cushing’s syndrome initially presenting with a normal ACTH level, which led to the investigation for an ACTH-secreting tumour. Adding to the confusion, a MRI done showed an intrasellar focus. Knowledge of how ACTH-dependent (versus ACTH-independent) Cushing’s syndrome manifests clinically, supported by results of repeat laboratory tests, led to the true diagnosis. This case illustrates that a detectable ACTH does not rule out an adrenal Cushing’s syndrome nor does a positive pituitary imaging confirm Cushing’s disease.
PMCID: PMC3229338  PMID: 22674941
9.  A case of ectopic ACTH syndrome treated with intermittent administration of dopamine agonists 
ACTH-dependent Cushing's syndrome includes Cushing's disease and ectopic ACTH syndrome (EAS). The differential diagnosis of Cushing's disease from EAS in cases of ACTH-dependent Cushing's syndrome is a challenging problem. We report here a case of EAS with an unknown source of ACTH secretion. Extensive imaging procedures, involving computed tomography (neck to pelvis), pituitary magnetic resonance imaging, and whole-body 18F-fluorodeoxyglucose-positron emission tomography, failed to reveal the source of ACTH secretion. Intermittent administration of bromocriptine, a short-acting and nonselective dopamine agonist, has afforded adequate suppression of plasma ACTH and cortisol levels over the long term.
Learning points
Tumor excision is the primary treatment for EAS. However, when surgery is impossible, medical therapy is needed to treat hypercortisolism.In cases where the source of ACTH secretion is unknown, inhibitors of steroidogenesis, such as metyrapone, mitotane, ketoconazole, and etomidate, are mostly used to suppress cortisol secretion.Medications that suppress ACTH secretion are less effective, therefore less popular, as standard treatments.In the present case, short-term treatment with dopamine agonists was effective for the long-term suppression of both ACTH and cortisol levels.
PMCID: PMC3965275
10.  Circadian rhythm of salivary cortisol, plasma cortisol, and plasma ACTH in end-stage renal disease 
Endocrine Connections  2012;2(1):23-31.
Patients with end-stage renal disease (ESRD) can display the features of endogenous hypercortisolism but are difficult to evaluate for Cushing's syndrome. We evaluated the circadian rhythm of plasma compared with salivary cortisol in subjects with ESRD.
Plasma and salivary cortisol and plasma ACTH samples were drawn frequently over 24 h in an inpatient research unit in stable ESRD subjects on daytime chronic hemodialysis (n=16) vs controls (n=8).
Plasma cortisol was measured every 2 h from 0800 to 0600 h the following day. Salivary cortisol was measured every 2 h, except between 2400 and 0400 h (sleep time). Plasma ACTH measured in a subset of samples and C-reactive protein (CRP) was measured as a marker of a subclinical inflammatory state in all subjects.
ESRD subjects had a discernable circadian rhythm in plasma and salivary cortisol, but with a significantly higher nadir (1800–2400 h) compared with the controls (P=0.016–<0.001). After excluding four ESRD subjects without a normal circadian rhythm, the ESRD subjects still had higher nadir plasma and salivary cortisol and plasma ACTH compared with controls. There was no difference in the correlation of salivary and plasma cortisol in control vs ESRD subjects. ESRD subjects had higher CRP levels compared with controls.
ESRD subjects had increased late-night plasma and salivary cortisol and plasma ACTH levels. Late-night salivary cortisol is a reliable index of plasma cortisol in ESRD patients.
PMCID: PMC3680964  PMID: 23781315
cortisol; circadian rhythm; ACTH; C-reactive protein; end-stage renal disease
11.  Clinical Usefulness of Corticotropin Releasing Hormone Testing in Subclinical Cushing's Syndrome for Predicting Cortisol Replacement after Adrenalectomy 
Korean Journal of Urology  2012;53(6):414-418.
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.
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.
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.
PMCID: PMC3382692  PMID: 22741051
Adrenalectomy; Corticotropin-releasing hormone; Cushing syndrome
12.  Adrenocortical carcinoma initially presenting with hypokalemia and hypertension mimicking hyperaldosteronism: a case report 
BMC Research Notes  2013;6:405.
Adrenocortical carcinoma is a rare malignancy and rare cause of Cushing’s syndrome.
Case presentation
A 65-year-old seemingly well male patient was referred to our clinic under the suspicion of hyperaldosteronism due to hypertension combined with hypokalemia. However, his serum aldosterone and plasma renin activity were within normal limits. Instead, Cushing’s syndrome was diagnosed by elevated urine free cortisol and a non-suppressible dexamethasone test. Abdominal computed tomography showed a 7.8 × 4.8 cm mass lesion at the right adrenal gland with liver invasion. Etomidate infusion was performed to reduce his cortisol level before the patient received a right adrenalectomy and liver wedge resection. The pathology report showed adrenocortical carcinoma with liver and lymph node metastasis. According to the European Network for the Study of Adrenal Tumors (ENSAT) staging system, the tumor was classified as T4N1M1, stage IV. Recurrent hypercortisolism was found shortly after surgery. The patient died of Fournier’s gangrene with septic shock on the 59th day after diagnosis.
We report a case of rapidly progressive stage IV adrenocortical carcinoma with initial presentations of hypokaelmia and hypertension, mimicking hyperaldosteronism.
PMCID: PMC3852253  PMID: 24103295
Adrenocortical carcinoma; Cushing’s syndrome; Hyperaldosteronism
13.  The ectopic adrenocorticotropic hormone syndrome in carcinoid tumors 
Ectopic production of adrenocorticotropic hormone by carcinoid tumors is relatively uncommon and may not be recognized by physicians. This report describes a woman who had Cushing syndrome from the ectopic secretion of adrenocorticotropic hormone by a carcinoid tumor. Her cause of death was a pneumonia that may have been secondary to her untreated hypercortisolism. There are threeinstructive elements of this case: 1) the recognition of Cushing syndrome, 2) the association of Cushing syndrome with low-grade (carcinoid tumors) as well as with high-grade (small cell carcinoma) neuroendocrine tumors, and 3) the need to treat the hypercortisolism as well as the tumor.
PMCID: PMC2277348  PMID: 18382753
14.  Adrenal incidentaloma: A case of pheochromocytoma with sub-clinical Cushing's syndrome 
Adrenal incidentalomas (AIs) are a cluster of different pathologies, but AIs with dual functional aspects are very rare. We report a case of AI with the evidence of both pheochromocytoma and sub-clinical Cushing's syndrome. A 42-year-old female patient presented with the history of abdominal pain. Abdominal computed tomography revealed right adrenal mass suggestive of pheochromocytoma. On endocrine evaluation, she admitted history of intermittent headache and palpitations for 4 years and was on treatment for hypertension and diabetes. There were no signs and symptoms suggestive of Cushing's syndrome. The laboratory data demonstrated 10 times raised 24-h urinary fractionated metanephrines with non-suppressible serum cortisol after 2-day low-dose dexamethasone suppression test. She underwent right-sided adrenalectomy with subsequent resolution of both pheochromocytoma and hypercortisolism. Patient was discharged in good clinical condition.
PMCID: PMC3830320  PMID: 24251174
Adrenal incidentaloma; Cushing's syndrome; pheochromocytoma
15.  Management Strategies for Aggressive Cushing's Syndrome: From Macroadenomas to Ectopics 
Journal of Oncology  2012;2012:685213.
Cushing's syndrome (CS) is a rare but severe clinical condition represented by an excessive endogenous cortisol secretion and hence excess circulating free cortisol, characterized by loss of the normal feedback regulation and circadian rhythm of the hypothalamic-pituitary axis due to inappropriate secretion of ACTH from a pituitary tumor (Cushing's disease, CD) or an ectopic source (ectopic ACTH secretion, EAS). The remaining causes (20%) are ACTH independent. As soon as the diagnosis is established, the therapeutic goal is the removal of the tumor. Whenever surgery is not curative, management of patients with CS requires a major effort to control hypercortisolemia and associated symptoms. A multidisciplinary approach that includes endocrinologists, neurosurgeons, oncologists, and radiotherapists should be adopted. This paper will focus on traditional and novel medical therapy for aggressive ACTH-dependent CS. Several drugs are able to reduce cortisol levels. Their mechanism of action involves blocking adrenal steroidogenesis (ketoconazole, metyrapone, aminoglutethimide, mitotane, etomidate) or inhibiting the peripheral action of cortisol through blocking its receptors (mifepristone “RU-486”). Other drugs include centrally acting agents (dopamine agonists, somatostatin receptor agonists, retinoic acid, peroxisome proliferator-activated receptor γ “PPAR-γ” ligands) and novel chemotherapeutic agents (temozolomide and tyrosine kinase inhibitors) which have a significant activity against aggressive pituitary or ectopic tumors.
PMCID: PMC3425913  PMID: 22934113
16.  Treatment Options in Cushing’s Disease 
Endogenous Cushing’s syndrome is a grave disease that requires a multidisciplinary and individualized treatment approach for each patient. Approximately 80% of all patients harbour a corticotroph pituitary adenoma (Cushing’s disease) with excessive secretion of adrenocorticotropin-hormone (ACTH) and, consecutively, cortisol. The goals of treatment include normalization of hormone excess, long-term disease control and the reversal of comorbidities caused by the underlying pathology. The treatment of choice is neurosurgical tumour removal of the pituitary adenoma. Second-line treatments include medical therapy, bilateral adrenalectomy and radiation therapy. Drug treatment modalities target at the hypothalamic/pituitary level, the adrenal gland and at the glucocorticoid receptor level and are commonly used in patients in whom surgery has failed. Bilateral adrenalectomy is the second-line treatment for persistent hypercortisolism that offers immediate control of hypercortisolism. However, this treatment option requires a careful individualized evaluation, since it has the disadvantage of permanent hypoadrenalism which requires lifelong glucocorticoid and mineralocorticoid replacement therapy and bears the risk of developing Nelson’s syndrome. Although there are some very promising medical therapy options it clearly remains a second-line treatment option. However, there are numerous circumstances where medical management of CD is indicated. Medical therapy is frequently used in cases with severe hypercortisolism before surgery in order to control the metabolic effects and help reduce the anestesiological risk. Additionally, it can help to bridge the time gap until radiotherapy takes effect. The aim of this review is to analyze and present current treatment options in Cushing’s disease.
PMCID: PMC3273924  PMID: 22346367
Cushing’s disease; operative treatment; medical therapy; bilateral adrenalectomy; radiotherapy
17.  "Osler's phenomenon": misdiagnosing Cushing's syndrome 
Postgraduate Medical Journal  2003;79(936):594-596.
Four cases of Cushing's syndrome are described that were associated with deteriorating morbidity because of the considerable delay from first presentation to a secondary care physician to eventual diagnosis. The clinical diagnosis was delayed in all the four patients, although they had symptoms and signs that were missed by a number of primary and secondary care physicians. Trans-sphenoidal surgery resulted in biochemical cure as well as improvement in the accompanying co-morbidity.
Although still rare, the prevalence of Cushing's syndrome is increasing. Increasing clinical awareness and the use of appropriate screening tests should facilitate earlier diagnosis with reduced morbidity and mortality. Although the syndrome is named after Harvey Cushing, Sir William Osler was probably the first to describe it. Therefore, in deference to Osler's contribution to Cushing's syndrome and the work of Harvey Cushing, it is suggested that to the list of the other eponymous conditions of Osler-Weber-Rendu and Osler's nodes, should be added the delay or misdiagnosis of Cushing's syndrome—"Osler's phenomenon".
PMCID: PMC1742858  PMID: 14612605
18.  Screening for Cushing’s Syndrome in Obese Patients 
Clinics  2010;65(1):9-13.
The aim of this study was to examine the frequency of Cushing’s syndrome (CS) in obese patients devoid of specific clinical symptoms of Cushing’s syndrome.
A total of 150 obese patients (129 female, 21 male; mean age 44.41 ± 13.34 yr; mean BMI 35.76 ± 7.13) were included in the study. As a first screening step, we measured 24-h urinary free cortisol (UFC). An overnight 1-mg dexamethasone suppression test was also performed on all patients. Urinary free cortisol levels above 100 μg/24 h were considered to be abnormal. Suppression of serum cortisol <1.8 μg/dL after administration of 1 mg dexamethasone was the cut-off point for normal suppression. The suppression of the serum cortisol levels failed in all of the patients.
Measured laboratory values were as follows: ACTH, median level 28 pg/ml, interquartile range (IQR) 14–59 pg/ml; fasting glucose, 100 (91–113) mg/dL; insulin, 15.7 (7.57–24.45) mU/ml; fT4, 1.17 (1.05–1.4) ng/dL; TSH, 1.70 (0.91–2.90) mIU/L; total cholesterol, 209 (170.5–250) mg/dL; LDL-c, 136 (97.7–163) mg/dL; HDL-c, 44 (37.25–50.75) mg/dL; VLDL-c, 24 (17–36) mg/dL; triglycerides, 120.5 (86–165) mg/dL. The median UFC level of the patients was 30 μg/24 h (IQR 16–103). High levels of UFC (>100 μg/24 h) were recorded in 37 patients (24%). Cushing’s syndrome was diagnosed in 14 of the 150 patients (9.33%). Etiologic reasons for Cushing’s syndrome were pituitary microadenoma (9 patients), adrenocortical adenoma (3 patients), and adrenocortical carcinoma (1 patient).
A significant proportion (9.33%) of patients with simple obesity were found to have Cushing’s syndrome. These findings argue that obese patients should be routinely screened for Cushing’s syndrome.
PMCID: PMC2815288  PMID: 20126340
Cushing’s syndrome; Obesity; Screening; Cortisol; Adrenocorticorticotropic hormone
19.  Long-Term Follow-Up of Cushing’s Disease: A Case Report 
Cushing’s disease is a condition in which hypercortisolism develops due to excessive hypophyseal adrenocorticotropic hormone production. It is rare in childhood. In this paper, we report the case of a 10-year-old male patient with hypophyseal microadenoma-related Cushing’s disease who presented with obesity and was found to show poor height growth at follow-up. The diagnosis was confirmed with inferior petrosal sinus sampling, and the adenoma was successfully removed by transsphenoidal surgery. While adrenal axis suppression continued for approximately 1 year, clinical improvement was clearly observed after the third month following surgery. The findings in this patient demonstrate that decreased growth rate despite rapid weight gain in children can be early sign of Cushing’s disease and emphasize the importance of monitoring of growth in obese children.
Conflict of interest:None declared.
PMCID: PMC3814537  PMID: 24072091
obesity; growth rate; Cushing’s disease
20.  Cushing’s disease 
Cushing’s disease, or pituitary ACTH dependent Cushing’s syndrome, is a rare disease responsible for increased morbidity and mortality. Signs and symptoms of hypercortisolism are usually non specific: obesity, signs of protein wasting, increased blood pressure, variable levels of hirsutism. Diagnosis is frequently difficult, and requires a strict algorithm. First-line treatment is based on transsphenoidal surgery, which cures 80% of ACTH-secreting microadenomas. The rate of remission is lower in macroadenomas. Other therapeutic modalities including anticortisolic drugs, radiation techniques or bilateral adrenalectomy will thus be necessary to avoid long-term risks (metabolic syndrome, osteoporosis, cardiovascular disease) of hypercortisolism. This review summarizes potential pathophysiological mechanisms, diagnostic approaches, and therapies.
PMCID: PMC3458990  PMID: 22710101
21.  Diagnosis and Multimodality Management of Cushing's Disease: A Practical Review 
Cushing's Disease is caused by oversecretion of ACTH from a pituitary adenoma and results in subsequent elevations of systemic cortisol, ultimately contributing to reduced patient survival. The diagnosis of Cushing's Disease frequently involves a stepwise approach including clinical, laboratory, neuroimaging, and sometimes interventional radiology techniques, often mandating multidisciplinary collaboration from numerous specialty practitioners. Pituitary microadenomas that do not appear on designated pituitary MRI or dynamic contrast protocols may pose a particularly challenging subset of this disease. The treatment of Cushing's Disease typically involves transsphenoidal surgical resection of the pituitary adenoma as a first-line option, yet may require the addition of adjunctive measures such as stereotactic radiosurgery or medical management to achieve normalization of serum cortisol levels. Vigilant long-term serial endocrine monitoring of patients is imperative in order to detect any recurrence that may occur, even years following initial remission. In this paper, a stepwise approach to the diagnosis, and various management strategies and associated outcomes in patients with Cushing's Disease are discussed.
PMCID: PMC3562580  PMID: 23401686
22.  Spot urine cortisol–creatinine ratio – A useful screening test in the diagnosis of Cushing's syndrome 
Although, there are several tests available, not one of them fulfils the criteria of being an ideal screening test. Continuing the search for an ideal screening test, we explored the use of urine spot cortisol-creatinine ratio as a novel method of evaluating patients with Cushing's syndrome.
A total of 35 subjects were studied and divided into 3 groups - 15 having cushings syndrome, 15 patients with obesity and 5 normal weight subjects. All patients with cushings syndrome were positive for the other screening tests.
The mean (standard deviation) of cortisol:creatinine ratio among the 3 groups (cushings, obese and control subjects) was 36.00(24.74), 7.01(2.73) and 3.49(2.68) respectively. Using the cutoff of 12.27 nano mol/ micro mol(based on data of normal subjects) for the urine cortisol creatinine ratio we get a sensitivity of 93.75% and a specificity of 100%. Also the positive and negative predictive value as calculated with this cutoff is 100% and 93.3% respectively.
In this study we found that UCCR is similar in both Obese and Non Obese subjects who did not have cushings syndrome. UCCR is significantly elevated in individuals with Cushing's syndrome as compared to those who do not have cushings syndrome. Also when a cut off of 12.27 nano mol/ micro mol was used this test had a higher sensitivity, however this test had a higher specificity at a cut off of 15.35.
PMCID: PMC3603083  PMID: 23565435
Urine Cortisol creatinine ratio; cushings syndrome; endogenous
23.  Functioning Adrenocortical Tumors in Children-Secretory Behavior 
Objective: Adrenocortical tumors are rare childhood neoplasms. More than 95% are functional and present with virilization, Cushing’s syndrome, hypertension, or hyperestrogenism. The objective of this paper is to present the clinical, laboratory and pathological findings of this rare disease and to highlight the secretory behavior of these tumors.
Methods: Clinical and laboratory data of seven Iranian children and adolescents aged between 2 and 16 years with functioning adrenocortical tumors are presented. Five patients had virilization and two had Cushing’s syndrome at the time of diagnosis. In all subjects, the tumors were removed successfully by open surgery, during which a blood sample was drawn from the corresponding adrenal vein for hormonal evaluation.
Results: Peripheral blood evaluation revealed that in addition to the dominant hormone (testosterone in the cases presenting with virilization and cortisol in those with Cushing’s syndrome), significant amounts of other hormones were secreted from these tumors. Adrenal vein evaluation revealed that testosterone, dehydroepiandrosterone sulfate, estradiol, ?17(OH) progesterone, and cortisol were directly released from the tumor. The tumors weighed between 36-103 grams. The patients have since been followed for 5 to 20 years, and there have been no signs or symptoms of relapse in any of the patients.
Conclusions: The study shows that functioning adrenocortical tumors should be considered in children and adolescents presenting with hyperandrogenism, Cushing’s syndrome, or hyperestrogenism. A diagnosis of a functioning adrenocortical tumor requires surgical removal as early as possible to prevent the untoward effects of virilization or corticosteroid excess. Evaluation of adrenal vein hormones showed that the steroids are secreted directly from the tumor and peripheral conversion has little contribution to the serum levels.
Conflict of interest:None declared.
PMCID: PMC3628389  PMID: 23367496
Adrenocortical tumors; child; virilism; feminization; Cushing’s syndrome
24.  Classification, diagnosis and treatment of ACTH-independent macronodular adrenal hyperplasia 
Canadian Urological Association Journal  2013;7(9-10):E594-E597.
ACTH-independent macronodular adrenal hyperplasia (AIMAH) is a distinctive subtype of Cushing’s syndrome (CS), with different clinical manifestations according to the level of serum cortisol. Based on clinical manifestations and serum cortisol, we divide AIMAH into three types, subclinical AIMAH, clinical AIMAH and high-risk AIMAH, with varied treatment methods being adapted to different subtypes. At the same time, we describe 3 patients who represent these subtypes of this disease, and review some cases of AIMAH which have been previously reported in the English literature. To our knowledge, this is the first article discussing classification, diagnosis and treatment of this disease and should be useful for future therapy of AIMAH.
PMCID: PMC3776036  PMID: 24069103
25.  Benign adrenal adenomas secreting excess mineralocorticoids and glucocorticoids 
Objective: To recognize that benign adrenal adenomas can co-secrete excess aldosterone and cortisol, which can change clinical management.
Methods: We reviewed the clinical and histological features of an adrenal tumor co-secreting aldosterone and cortisol in a patient. Biochemical testing as well as postoperative immunohistochemistry was carried out on tissue samples for assessing enzymes involved in steroidogenesis.
Results: A patient presented with hypertension, hypokalemia, and symptoms related to hypercortisolism. The case demonstrated suppressed renin concentrations with an elevated aldosterone:renin ratio, abnormal dexamethasone suppression test results, and elevated midnight salivary cortisol concentrations. The patient had a right adrenal nodule with autonomous cortisol production and interval growth. Right adrenalectomy was carried out. Postoperatively, the patient tolerated the surgery, but he was placed on a short course of steroid replacement given a subnormal postoperative serum cortisol concentration. Long-term follow-up of the patient showed that his blood pressure and glucose levels had improved. Histopathology slides showed positive staining for 3β-hydroxysteroid dehydrogenase, 11β-hydroxylase, and 21 hydroxylase.
Conclusion: In addition to the clinical manifestations and laboratory values, the presence of these enzymes in this type of tumor provides support that the tumor in this patient was able to produce mineralocorticoids and glucocorticoids. The recognition of patients with a tumor that is co-secreting aldosterone and cortisol can affect decisions to treat with glucocorticoids perioperatively to avoid adrenal crisis.
Learning points
Recognition of the presence of adrenal adenomas co-secreting mineralocorticoids and glucocorticoids.Consideration for perioperative and postoperative glucocorticoid use in the treatment of co-secreting adrenal adenomas.
PMCID: PMC3922398  PMID: 24616772

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