Cyclic Cushing's Syndrome Research Articles

Cyclic Cushing Syndrome, an Enigma in Diagnosis- A Case Report

Cyclic Cushing syndrome is a rare disorder, characterized by repeated episodes of cortisol excess interspersed by periods of normal cortisol secretion. We report a 15-year-old boy with clinical Cushing syndrome and intermittent central Adrenocorticotropic hormone(ACTH) hypersecretion for a period of 8 years. Periods of hypercotisolemia as evidenced clinically and/or biochemically alternated with periods of eucortisolemia leading to much diagnostic dilemma. Ultimately, we were able to demonstrate the episodes of three peaks and two troughs of cortisol secretion favoring our diagnosis. His initial sellar MRI was negative, later high resolution dynamic sellar MRI unmasked a Pituitary micro-adenoma. In the absence of consensus for trans-sphenoidal adenomectomy (TSA) medical management in the form of sodium valproate was prescribed. At present he is on regular follow-up with marked clinical improvement.

Pitfalls in the diagnosis and differential diagnosis of Cushing's syndrome

Pitfalls in the diagnosis and differential diagnosis of <scp>C</scp>ushing's syndrome

Periodic hypokalemia associated with cyclic Cushing's syndrome.

A 69-year-old woman presented with periodic hypertension, edema, and hypokalemia that occurred within an interval of a few weeks. Her laboratory test values showed autonomously elevated plasma adrenocorticotropic hormone (ACTH) and cortisol concentrations. The patient's Cushingoid features were not evident on first admission. Several weeks later, in spite of constant oral potassium supplementation, severe hypokalemia recurred with Cushingoid features and worsening symptoms of leg edema and pigmentation, which spontaneously disappeared within a few days. Her periodic symptoms occurred in parallel with fluctuations of plasma ACTH and cortisol concentrations. A series of endocrinological and pituitary imaging findings led to a tentative diagnosis of cyclic Cushing's syndrome caused by ectopic ACTH secretion. However, chest and abdominal computed tomography did not reveal any candidate lesion. The patient's periodic hypercortisolemia and symptoms were well controlled after treatment with metyrapone plus dexamethasone. This is a very rare case of periodic hypokalemia and hypertension caused by cyclic Cushing's syndrome.

Urinary free cortisol in the diagnosis of Cushing′s syndrome: How useful?

Cushing's syndrome results from chronic exposure to excessive circulating levels of glucocorticoids. To confirm the clinical suspicion, biochemical tests are needed. These biochemical tests include the measurement of excess total endogenous cortisol secretion assessed by 24-hour urinary free cortisol (UFC), loss of the normal feedback of the hypothalamo-pituitary-adrenal axis assessed by suppressibility after dexamethasone testing, and disturbance of the normal circadian rhythm of cortisol secretion assessed by midnight serum or salivary cortisol. We searched the Medline, Pubmed, journal articles, WHO publications and reputable textbooks relating to Cushing's syndrome using publications from 1995 to 2011. UFC has been the classic screening test used to confirm hypercortisolemia as the first step in diagnostic work-up of Cushing's syndrome. Its long-term use in clinical practice has led to emergence of significant evidence regarding the utility of UFC in the diagnosis of Cushing's syndrome. UFC would have been a simple diagnostic tool to use but for the drawbacks in the sample collection, different laboratory methods of assay, not easily determined normal range. UFC use as a screening test is not strongly favoured because cortisol is not uniformly secreted during the day, and the increased prevalence of mild, preclinical or cyclic Cushing's syndrome. A very high level of UFC negates the need for other test procedures in patients with obvious symptoms and signs of Cushing's syndrome. We therefore suggest that UFC should be used with other screening tests for Cushing's syndrome to increase diagnostic yield.

A Novel Tool in the Diagnosis and Follow-Up of (Cyclic) Cushing's Syndrome: Measurement of Long-Term Cortisol in Scalp Hair

Measurement of cortisol in 24-h urine collections and midnight saliva are standard screening tests for Cushing's syndrome (CS). These tests reflect cortisol levels during a maximum of 24 h and do not provide historical information. Therefore, they can yield normal results in case of cyclic CS, which is a rare disorder that is characterized by alternating episodes of endogenous cortisol excess and normal cortisol secretion. The measurement of cortisol in scalp hair is a novel tool that might be helpful to establish the diagnosis of (cyclic) CS. Our aim was to study whether hair cortisol timelines correspond with clinical course in patients with CS and whether we could create retrospective timelines of cortisol exposure that correspond with symptomatic periods in patients suspected of cyclic CS. Scalp hair was collected in 14 patients with confirmed CS and six patients suspected of cyclic CS. Cortisol was extracted from the hair samples with methanol, and an ELISA was used to measure cortisol levels in hair extracts. A group of 96 nonobese individuals were used as a control group. Hair cortisol levels were significantly elevated in CS patients (P<0.0001). Sensitivity and specificity of hair cortisol measurements for CS were 86 and 98%, respectively. Hair cortisol timelines of patients with CS and cyclic CS corresponded with clinical course. Hair samples can provide a historical timeline that corresponds with clinical course in patients with (cyclic) CS. This new diagnostic tool can contribute significantly to early recognition of patients suffering from cyclic CS.

A rare case of Cushing syndrome by cyclic ectopic-ACTH

ACTH-dependent Cushing syndrome (CS) due to ectopic ACTH production is most times difficult to manage. The identification of the source of ACTH may take many years. Surgery or chemotherapy for the primary tumor is not always possible. Control of Cushing symptoms is many times achieved using medication, or bilateral adrenalectomy in refractory cases. This case presents a Brazilian male who showed severe hypertension, mood changes, muscle weakness, darkening of skin, and increased abdominal fat. An investigation for Cushing syndrome was carried out and, after a four-year follow-up, a carotid glomus tumor (chemodectoma) was confirmed, a rare ectopic ACTH-producing tumor. Besides, the patient presented cyclic Cushing syndrome that was exacerbated by diverticulitis episodes. This case presents interesting pitfalls on diagnosis and management of ACTH-dependent CS. This is the only report of a chemodectoma that produced ACTH in the literature.

Pituitary Cyclic Cushing's Syndrome Concomitant with Solitary Cryptococcal Pneumonia Confused with Ectopic ACTH-producing Tumor

A 47-year-old man with Cushingoid appearance was admitted to our hospital showing excessive secretion of cortisol at intervals of a few days. Cyclic Cushing's disease was confirmed. Two years earlier, results of hormonal assessment had been within normal limits and macroadenoma had been incidentally detected in the pituitary. Dexamethasone suppression testing revealed various responses and a small lung tumor was detected, therefore his condition was misinterpreted as ectopic ACTH-producing tumor or pituitary cyclical Cushing's disease, leading to lung resection that confirmed cryptococcal pneumonia. The pituitary tumor was finally identified as the cause of cyclic Cushing's syndrome and fully removed, allowing remission.

Prolonged remission after long-term treatment with steroidogenesis inhibitors in Cushing's syndrome caused by ectopic ACTH secretion

Spontaneous remission is rare in ectopic ACTH syndrome (EAS). We describe four patients with presumed EAS in whom long-term treatment with steroidogenesis inhibitors was followed by prolonged remission of hypercortisolemia. Biochemical testing was consistent with EAS, but imaging failed to identify a tumor. Patients were treated with ketoconazole alone or with mitotane and/or metyrapone to control hypercortisolemia. Dexamethasone was added when a block and replace strategy was used. Treatment with steroidogenesis inhibitors for 3-10 years in these patients was followed by a prolonged period of remission (15-60 months). During remission, the first patient had an elevated ACTH, low cortisol and 24-h urinary free cortisol (UFC), and adrenal atrophy on computerized tomography scan during remission, suggesting a direct toxic effect on the adrenal glands. Cases 2 and 3 had normal to low ACTH levels and low-normal UFC, consistent with an effect at the level of the ectopic tumor. They did not have a history of cyclicity and case 3 has been in remission for ~5 years, making cyclic Cushing's syndrome less likely. Case 4, with a history of cyclic hypercortisolism, had normal to slightly elevated ACTH levels and low-normal UFC during remission. The most likely etiology of remission is cyclic production of ACTH by the ectopic tumor. Spontaneous and sustained remission of hypercortisolemia is possible in EAS after long-term treatment with steroidogenesis inhibitors; a drug holiday may be warranted during chronic therapy to evaluate this. The pathophysiology remains unclear but may involve several different mechanisms.

Is urinary free cortisol of value in the diagnosis of Cushingʼs syndrome?

Cushing's syndrome results from prolonged and inappropriately high exposure of tissues to glucocorticoids. Biochemical tests are always needed to confirm the clinical suspicion: these include measurement of excess total endogenous cortisol secretion assessed by 24-h urinary free cortisol (UFC), loss of the normal feedback of the hypothalamo-pituitary-adrenal axis assessed by suppressibility after dexamethasone testing, and disturbance of the normal circadian rhythm of cortisol secretion assessed by midnight serum or salivary cortisol. This review focuses on recent data emerging on the value of UFC as a screening test for Cushing's syndrome. Considerable evidence has emerged regarding the utility of UFC in the diagnosis of Cushing's syndrome because of its long-term use in clinical practice. Despite the fact that UFC assesses the active (free) component of cortisol, the methodological difficulties in 24-h urine collection and in assay precision have rendered this screening technique increasingly unpopular. Furthermore, the increased prevalence of mild, preclinical or cyclic Cushing's syndrome along with the fact that cortisol is not uniformly secreted during the day do not support its use as a screening test, although strikingly high levels can be useful. Since the sensitivity and specificity of UFC are less than ideal when compared with other diagnostic modalities, we suggest the use of other more novel tests as first-step diagnostic tests to screen for hypercortisolaemia.

Cyclic Cushing's syndrome

The cyclic Cushing's syndrome is a rare disease characterized by multiple episodes of elevated cortisol levels alternating with periods of its normal secretion. The so-called hypercorticism cycles may be either regular or episodic with intercycle intervals as long as a few days to several years. Most researchers agree that the reliable diagnosis of cyclic Cushing's syndrome should be based on laboratory detection of 3 peaks and 2 falls of plasma cortisol level. Cyclic Cushing's syndrome may be either ACTH dependent or independent. A review of 65 verified cases indicates that this condition may be caused by pituitary corticotropinoma (54%), ectopic ACTH-producing tumour (26%), and adrenal tumour (roughly 11%). The cause of the disease remains uncertain in 9% of the patients. Pathophysiological mechanisms of cyclic Cushing's syndrome are poorly known. In certain cases of bilateral macronodular adrenal hyperplasia or adrenal corticosteroma, it may be associated with the presence of ectopic receptors or anomalous expression of normally located receptors. The majority of the patients presenting with cyclic Cushing's syndrome exhibit symptoms of classical hypercorticism that manifest themselves either on a permanent or cyclic basis. In a small number of patients, clinical signs of cyclic Cushing's syndrome are virtually absent. Variations of the clinical picture and conflicting results of hormonal assays taken together make cyclic Cushing's syndrome difficult to diagnose. Therefore, physicians must be aware of this condition and actively search for it in all patients believed to have an enhanced cortisol production despite normal results of laboratory analysis. Frequent changes of urinary or salivary free cortisol levels are reliable and convenient criteria for cyclic Cushing's syndrome in patients suspected to have this condition. Results of cortisol stimulation or suppression tests are likely to lead to a false conclusion due to spontaneous falls and rises in serum cortisol levels at the time of analysis. Given laboratory confirmation of cyclic Cushing's syndrome, subsequent studies should be focused on the elucidation of its cause. The average life expectancy of patients with cyclic Cushing's syndrome remains to be determined.

Cyclic Cushing syndrome due to an ectopic pituitary adenoma

A 39-year-old man was referred to an endocrinology clinic for evaluation of his Cushing syndrome. He had gained 20 kg over 5 years and complained of intermittent headaches and easy bruisability. His medical history included a left foot fracture associated with minimal trauma 2 years earlier, hypertension, and stable Crohn disease with no use of exogenous glucocorticoids for at least 10 years. Measurements of plasma adrenocorticotropic hormone, 24 h urine free cortisol excretion, late-night salivary cortisol, serum cortisol levels before and after corticotropin-releasing hormone administration during a dexamethasone suppression/corticotropin-releasing hormone-stimulation test, pituitary MRI, and inferior petrosal sinus sampling. Cyclic Cushing syndrome secondary to an ectopic pituitary adenoma. The cyclic nature of Cushing syndrome was suggested by the absence of hypercortisolemia during inferior petrosal sinus sampling, and was confirmed by multiple 24 h urine free cortisol measurements. The patient underwent transsphenoidal surgery, during which a 5 mm firm, round, midline sphenoid sinus lesion was identified and resected. In preoperative imaging studies, this lesion had been interpreted as being a mucosal polyp. At microscopic examination, the lesion was found to be a pituitary adenoma, which stained diffusely with antiadrenocorticotropic-hormone antibodies. Explorations of the sella and pituitary did not reveal any abnormalities. Postoperatively, the patient became hypocortisolemic and his cushingoid features resolved. His adrenal function normalized 3 months after surgery. At 18 months, the patient continued to be symptom-free with normal levels of urinary-free cortisol and midnight salivary cortisol.

Operative management of Cushing Syndrome secondary to micronodular adrenal hyperplasia

We reviewed our experience with micronodular adrenal hyperplasia (MAH), its pigmented variant primary pigmented nodular adrenocortical disease (PPNAD), and the association with Carney's complex (CNC) to better characterize these disorders. This retrospective study analyzes clinical data and operative reports of 34 patients identified with MAH and/or PPNAD who underwent resection between 1969 and 2006 at the Clinical Research Center, an inpatient research hospital at the National Institutes of Health. Symptoms and anthropometric and biochemical data were used to evaluate effect of resection. Fifteen patients (44%) presented as adults and 19 (56%) as children. Twenty-five patients (74%) presented with noncyclic Cushing syndrome and 9 patients (26%) presented with cyclic Cushing syndrome. Thirty-one patients underwent bilateral resection; this was curative biochemically in 30 patients. Fourteen operations were performed laparoscopically (41%), and 20 were performed as open resections (59%). There was 1 postoperative complication in the laparoscopic group (7%) and 6 complications in the open group (30%; P = .20). Follow-up was available for 25 patients (74%). Statistically significant improvements in anthropometrics were observed for both adults and children. The most frequent manifestation of CNC requiring additional operation was cardiac myxoma, which was associated strongly with an atypical (cyclic) presentation of Cushing syndrome (P = .009). Cushing syndrome due to MAH and PPNAD may be cured by bilateral adrenal resection. All patients should be screened for manifestations of CNC at the time of adrenal diagnosis with particular attention to cardiac disease.

Cyclic Cushing's syndrome: an overview

Cyclic Cushing's syndrome (CS) is a disorder in which glucocorticoid levels are alternately normal and high, the latter occurring in episodes that can last from a few days to several months. It is more common in children than in adults. Cyclic CS may be either of the two different forms of CS (ACTH-dependent or -independent CS). Clinically, it may present with one or many symptoms, depending on the duration of disease activity and the timing of the fluctuations. A serotoninergic influence, cyclic changes in central dopaminergic tone, spontaneous episodic hemorrhage in the tumor, and the action of inflammatory cytokines with antitumor properties are some of the mechanisms suggested to explain the physiopathology of this phenomenon but the exact mechanism remains to be clarified. The cyclic pattern of hypercortisolism can delay the final diagnosis of CS and make it difficult to interpret the results of dynamic tests. Patients may have paradoxical responses to dexamethasone that can reflect increasing or decreasing levels of endogenous activity. Hormone assessments have to be repeated periodically when a diagnosis of CS is suspected. The cyclic pattern can also interfere with medical treatment because patients may show unexpected clinical and biochemical signs of hypocortisolism when cortisol secretion cyclically returns to normal, so an accurate follow-up is mandatory in these patients.

Cyclic Cushing syndrome: definitions and treatment implications

Endogenous Cushing syndrome (CS) results from hypercortisolemia caused by excess adrenocorticotropic hormone production in a pituitary adenoma or ectopic tumor, or by an adrenal tumor that directly produces excess cortisol. The diagnosis can usually be ascertained with a reasonable degree of certainty based on clinical and laboratory findings of hypercortisolism. There are patients, however, in whom the production of excess cortisol exhibits a cyclic or intermittent pattern, and, as a result, the clinical symptoms may be quite complex and varied. In these patients the hypothalamic-pituitary-adrenal axis may be normal between cycles, and dexamethasone suppression testing may produce a paradoxical response. In the present article, the authors provide a definition of cyclic Cushing syndrome, review the causes and its potential pathophysiological mechanisms, and discuss the treatment options based on a review of the available literature.

Cyclic Cushing syndrome: definitions and treatment implications

Cyclic Cushing syndrome: definitions and treatment implications

Cyclic Cushing syndrome: definitions and treatment implications

✓ Endogenous Cushing syndrome (CS) results from hypercortisolemia caused by excess adrenocorticotropic hormone production in a pituitary adenoma or ectopic tumor, or by an adrenal tumor that directly produces excess cortisol. The diagnosis can usually be ascertained with a reasonable degree of certainty based on clinical and laboratory findings of hypercortisolism. There are patients, however, in whom the production of excess cortisol exhibits a cyclic or intermittent pattern, and, as a result, the clinical symptoms may be quite complex and varied. In these patients the hypothalamic-pituitary-adrenal axis may be normal between cycles, and dexamethasone suppression testing may produce a paradoxical response. In the present article, the authors provide a definition of cyclic Cushing syndrome, review the causes and its potential pathophysiological mechanisms, and discuss the treatment options based on a review of the available literature.

Cyclic Cushing syndrome: definitions and treatment implications

Cyclic Cushing syndrome: definitions and treatment implications

Cyclic Cushing's Syndrome: An Overview

Cyclic Cushing's syndrome (CS) involves rhythmic fluctuations in ACTH secretion resulting in a cyclic variation of adrenal steroid production. In the majority of cases, cyclic CS is caused by an ACTH-secreting pituitary adenoma, but it can also be due to ectopic ACTH production or an adrenal adenoma. This condition should be strongly suspected in patients with symptoms or signs of hypercortisolism but normal cortisol levels and paradoxical responses to the dexamethasone test, that may reflect an increasing or decreasing endogenous hormone activity. Dynamic tests are best interpreted if they are performed during a sustained period of hypercortisolism. Sometimes, it is necessary to confirm the diagnosis over lengthy periods of observation. Responses to treatment must be closely monitored, interpreted and evaluated with caution because of the potential variations in steroidogenesis. An original case report of a cyclic Cushing's syndrome is presented in this review.

Cyclic Cushing's Syndrome Caused by Periodic Secretion of ACTH From a Bronchial Carcinoid Tumor

INTRODUCTION: Ectopic production of adrenocotropic hormone (ACTH) accounts for approximately 15% of cases of Cushing's syndrome. Several types of malignant and non-malignant tumors of neuroendocrine origin have been implicated in ectopic ACTH production. Bronchial carcinoids account for approximately one quarter of such cases. Periodic hormonogenesis by ectopic ACTH producing tumors other than bronchial carcinoid is an unusual phenomenon that has been reported in the endocrine literature. The following represents what is believed to be the first reported case of a bronchial carcinoid with periodic ACTH production causing cyclic Cushing's syndrome.

Variable Hormonogenesis in Cushing's Syndrome

Four patients with Cushing's syndrome and variable cyclic hormonogenesis are reported and 40 other cases from the literature are reviewed. These cases were divided into four categories depending on regular or irregular cyclic adrenal hypersecretion and presence or absence of concomitant fluctuations in the clinical course. The manifestations of cyclic adrenal hypersecretion in these patients varied from daily to yearly intervals. Cyclic activity persisted for as long as 25 years, with cycle lengths varying from 12 hours to 85 days. Some patients demonstrated complex biochemical cyclic patterns. Clinical presentations varied from a single outstanding symptom, such as recurring oedema, to a complex clinical syndrome. The aetiology in these patients varied: 12 appeared to be pituitary dependent, 11 had corticotropin-producing tumours and another eight were described as showing 'adrenal hyperplasia'. A hypothalamic disorder was found in four, a benign adrenal adenoma in two, and an adrenal 'mass' and adrenocortical nodular dysplasia in single patients. Evaluation during the intercyclic phase may reveal normal pituitary function. Inconsistent responsiveness to administration of dexamethasone in different phases of cyclic activities may suggest the presence of cyclic Cushing's syndrome.