SAT-263 A Vicious Cycle of Hypercortisolism - Cyclical Cushing’s Syndrome

Abstract Background: Cyclical Cushing’s syndrome (CS) is described as periods of excess cortisol secretion interspersed with low or normal cortisol. The generally acceptable criteria for diagnosis is demonstration of 3 peaks and 2 troughs in cortisol secretion but, in practice, patterns and duration of cycles are unpredictable and can present a significant diagnostic challenge. Here, we present a case series of three patients who did not meet the published criteria but had pathological confirmation of ACTH-dependent CS. Clinical Case: Two women (A: 30 year-old, B: 40 year-old), and one man (C: 30 year-old) presented to the Pituitary Center for second/third opinions regarding CS. All patients had significant central weight gain. Patient A described cycles of rapid weight gain and loss, fluctuating facial and leg swelling, anxiety and darkening of stretch marks or scars punctuated with episodes of fatigue, lightheadedness and nausea. Patients B and C reported cyclical leg swelling, facial redness and acne. These patients had additional clinical signs of Cushingoid facies, dorsocervical and supraclavicular fat pads. Patient C had violaceous striae. Multiple tests for CS were performed: 1 mg overnight dexamethasone suppression test, two midnight salivary cortisols, and 24h urine free cortisol (UFC). All testing was normal, with a few exceptions. Patient A had an isolated midnight salivary cortisol elevated to 0.426 (<0.112 ug/dL). Patient C had two mildly elevated 24h UFC collections of 1.4 times upper limit of normal corresponding with his cycles of peripheral edema and acne. Patient B had completely negative testing. In all 3 patients, ACTH levels were not suppressed but also not elevated. Random serum DHEA-S levels were elevated in patients A and B. Patients A and C were found to have possible pituitary microadenomas on MRI with dynamic contrast. Patient B’s MRI was negative but inferior petrosal sinus sampling revealed a markedly elevated tumoral level of ACTH of >62,500 pg/mL with CRH stimulation. All 3 patients underwent endoscopic transsphenoidal resection by an expert pituitary surgeon with no post-operative complications in patients A & B, but development of partial diabetes insipidus in patient C. In patients A & C, pathology revealed corticotroph hyperplasia while patient B was found to have a corticotroph adenoma. Patients A & B persisted to have symptoms of hypercortisolism, opted to undergo bilateral adrenalectomy and pathology showed diffuse adrenocortical hyperplasia for both. Conclusion: Cyclical CS is likely underdiagnosed because of difficulty in obtaining biochemical confirmation even with strong clinical suspicion of CS. DHEA-S has a long half-life as well as minimal diurnal variation, and could be an additional clue in patients with suspected pituitary source of cyclical hypercortisolism. Ultimately, clinical concern should drive further diagnostic imaging and management.

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Long-term low-dose ketoconazole treatment in bilateral macronodular adrenal hyperplasia

Endocrinology Diabetes and Metabolism Case Reports ◽

10.1530/edm-14-0083 ◽

2014 ◽

Vol 2014 ◽

Author(s):

Sophie Comte-Perret ◽

Anne Zanchi ◽

Fulgencio Gomez

Keyword(s):

Medical Therapy ◽

Cushing’S Syndrome ◽

Clinical Signs ◽

Cushing's Syndrome ◽

List Type ◽

Adrenal Hyperplasia ◽

Benign Condition ◽

Steroid Secretion ◽

Free Cortisol

Summary Medical therapy for Cushing's syndrome due to bilateral macronodular adrenal hyperplasia (BMAH) is generally administered for a limited time before surgery. Aberrant receptors antagonists show inconsistent efficacy in the long run to prevent adrenalectomy. We present a patient with BMAH, treated for 10 years with low doses of ketoconazole to control cortisol secretion. A 48-year-old woman presented with headaches and hypertension. Investigations showed the following: no clinical signs of Cushing's syndrome; enlarged lobulated adrenals; normal creatinine, potassium, and aldosterone; normal urinary aldosterone and metanephrines; elevated urinary free cortisol and steroid metabolites; and suppressed plasma renin activity and ACTH. A screening protocol for aberrant adrenal receptors failed to show any illegitimate hormone dependence. Ketoconazole caused rapid normalisation of cortisol and ACTH that persists over 10 years on treatment, while adrenals show no change in shape or size. Ketoconazole decreases cortisol in patients with Cushing's syndrome, and may prevent adrenal overgrowth. Steroid secretion in BMAH is inefficient as compared with normal adrenals or secreting tumours and can be controlled with low, well-tolerated doses of ketoconazole, as an alternative to surgery. Learning points Enlarged, macronodular adrenals are often incidentally found during the investigation of hypertension in patients harboring BMAH. Although laboratory findings include low ACTH and elevated cortisol, the majority of patients do not display cushingoid features. Bilateral adrenalectomy, followed by life-long steroid replacement, is the usual treatment of this benign condition, and alternative medical therapy is sought. Therapy based on aberrant adrenal receptors gives disappointing results, and inhibitors of steroidogenesis are not always well tolerated. However, ketoconazole at low, well-tolerated doses appeared appropriate to control adrenal steroid secretion indefinitely, while preventing adrenal overgrowth. This treatment probably constitutes the most convenient long-term alternative to surgery.

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Values for Urinary Free Cortisol during Treatment with Amino-Glutethimide for Cushing’s Syndrome

Clinical Chemistry ◽

10.1093/clinchem/19.9.1067 ◽

1973 ◽

Vol 19 (9) ◽

pp. 1067-1068 ◽

Cited By ~ 1

Author(s):

Karl W Schmitt ◽

Roger Juselius ◽

James Hanlon ◽

David Steed

Keyword(s):

Cushing’S Syndrome ◽

Urinary Free Cortisol ◽

Cushing's Syndrome ◽

Sensitive Indicator ◽

Cortisol Secretion ◽

Clinical Correlation ◽

Free Cortisol ◽

Amino Glutethimide

Abstract Of the chemical tests used, we found that values for urinary free cortisol had the best clinical correlation and were the most sensitive indicator of cortisol secretion in a patient with Cushing’s syndrome who was treated with amino-glutethimide.

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Spontaneous resolution of avascular necrosis of femoral heads following cure of Cushing’s syndrome

Endocrinology Diabetes and Metabolism Case Reports ◽

10.1530/edm-16-0015 ◽

2016 ◽

Vol 2016 ◽

Cited By ~ 1

Author(s):

A Pazderska ◽

S Crowther ◽

P Govender ◽

K C Conlon ◽

M Sherlock ◽

...

Keyword(s):

Femoral Head ◽

Avascular Necrosis ◽

Cushing’S Syndrome ◽

Cushing's Syndrome ◽

Leg Pain ◽

List Type ◽

Rapid Weight Gain ◽

Free Cortisol ◽

Femoral Heads ◽

Adrenal Disease

Summary Avascular necrosis (AVN) is a rare presenting feature of endogenous hypercortisolism. If left untreated, complete collapse of the femoral head may ensue, necessitating hip replacement in up to 70% of patients. The majority of the described patients with AVN due to endogenous hypercortisolaemia required surgical intervention. A 36-year-old female, investigated for right leg pain, reported rapid weight gain, bruising and secondary amenorrhoea. She had abdominal adiposity with violaceous striae, facial plethora and hirsutism, atrophic skin, ecchymosis and proximal myopathy. Investigations confirmed cortisol excess (cortisol following low-dose 48h dexamethasone suppression test 807nmol/L; 24h urinary free cortisol 1443nmol (normal<290nmol)). Adrenocorticotrophic hormone (ACTH) was <5.0pg/mL. CT demonstrated subtle left adrenal gland hypertrophy. Hypercortisolaemia persisted after left adrenalectomy. Histology revealed primary pigmented micronodular adrenal disease. Post-operatively, right leg pain worsened and left leg pain developed, affecting mobility. MRI showed bilateral femoral head AVN. She underwent right adrenalectomy and steroid replacement was commenced. Four months after surgery, leg pain had resolved and mobility was normal. Repeat MRI showed marked improvement of radiological abnormalities in both femoral heads, consistent with spontaneous healing of AVN. We report a case of Cushing’s syndrome due to primary pigmented nodular adrenocortical disease, presenting with symptomatic AVN of both hips. This was managed conservatively from an orthopaedic perspective. Following cure of hypercortisolaemia, the patient experienced excellent recovery and remains symptom free 4 years after adrenalectomy. This is the first report of a favourable outcome over long-term follow-up of a patient with bilateral AVN of the hip, which reversed with treatment of endogenous hypercortisolaemia. Learning points AVN of femoral head can be a presenting feature of hypercortisolism, both endogenous and exogenous. Rarely, treatment of hypercortisolaemia can reverse AVN without the need for orthopaedic intervention. Primary pigmented nodular adrenal disease is a rare cause of ACTH-independent Cushing’s syndrome.

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Cyclic Cushing's syndrome

Problems of Endocrinology ◽

10.14341/probl201056444-51 ◽

2010 ◽

Vol 56 (4) ◽

pp. 44-51

Author(s):

E I Marova ◽

I A Voronkova

Keyword(s):

Cushing’S Syndrome ◽

Clinical Signs ◽

Serum Cortisol ◽

Cushing's Syndrome ◽

Plasma Cortisol Level ◽

Average Life Expectancy ◽

Ectopic Acth ◽

Number Of Patients ◽

Free Cortisol ◽

Cortisol Levels

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.

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Incidentally discovered ACTH-dependent adrenal adenoma presenting as 'Pre-Cushing's syndrome'

Acta Endocrinologica ◽

10.1530/acta.0.1110089 ◽

1986 ◽

Vol 111 (1) ◽

pp. 89-92 ◽

Cited By ~ 27

Author(s):

U. Bogner ◽

U. Eggens ◽

J. Hensen ◽

W. Oelkers

Keyword(s):

Cushing’S Syndrome ◽

Adrenal Mass ◽

Adrenal Adenoma ◽

Clinical Signs ◽

Cushing's Syndrome ◽

Cortisol Secretion ◽

Adrenal Tumour ◽

Urinary Cortisol

Abstract. An adrenal tumour was incidentally discovered with no clinical signs of Cushing's syndrome. The endocrine evaluation revealed the unique hormonal constellation of an increased urinary cortisol excretion rate, unequivocal suppressibility of plasma and urinary cortisol by dexamethasone, but only to a residual level in the low normal range which probably reflected ACTH-independent 'autonomous' cortisol secretion. After removal of the adrenal mass, urinary cortisol secretion and dexamethasone suppressibility were normalized. In vitro, the tumour cells were as sensitive towards ACTH as 'normal' human adrenal cells, but showed a reduced cortisol production rate per cell. We suppose that the adrenal mass participated in the diurnal rhythm of ACTH-mediated cortisol secretion in vivo, which resulted in an increased cortisol secretion. During the night, when ACTH levels were low, the cortisol production decreased and the hormone levels were probably too low to suppress ACTH. We regard the hormonal findings in our patients as 'Pre-Cushing's syndrome', although the absence of clinical features of Cushing's syndrome remains unclear. We suggest that every patient with an incidentally discovered adrenal mass should have an endocrinological evaluation because the results may help to decide whether or not the adrenal tumour should be removed.

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Primary adrenocortical micronodular adenomatosis causing Cushing's syndrome. Effects of ketoconazole on steroid production and in vitro performance of adrenal cells

Acta Endocrinologica ◽

10.1530/acta.0.1130370 ◽

1986 ◽

Vol 113 (3) ◽

pp. 370-377 ◽

Cited By ~ 26

Author(s):

W. Oelkers ◽

V. Bähr ◽

J. Hensen ◽

H. Pickartz ◽

P. Exner ◽

...

Keyword(s):

Cushing’S Syndrome ◽

Plasma Cortisol ◽

Venous Blood ◽

Clinical Signs ◽

Cushing's Syndrome ◽

Cortisol Secretion ◽

Urinary Cortisol ◽

Adrenal Cells

Abstract. Mild Cushing's syndrome was diagnosed in a 35 year old woman. Elevated plasma and urinary cortisol levels were unsuppressible with up to 32 mg dexamethasone per day. Aldosterone, 18-OH-corticosterone and testosterone in plasma were normal and dehydroepiandrosterone-sulphate was low. No adrenal tumour was found by CT or adrenal venography, and bilateral cortisol secretion was demonstrated by steroid measurements in adrenal venous blood. A circadian rhythm of plasma cortisol was absent. Plasma ACTH was suppressed, even after injection of CRH, during insulininduced hypoglycaemia and after metyrapone administration, which led to a large fall in plasma cortisol but to a subnormal rise of plasma 11-deoxy-cortisol. The clinical diagnosis of primary micronodular adenomatosis of the adrenal gland was histologically confirmed, when the patient finally underwent bilateral adrenalectomy. In vitro, the adrenal cells did not produce more cortisol and aldosterone than adrenal cells from cadaver kidney donors. In vivo and in vitro, cortisol was slightly less than normally responsive to ACTH. Intermittent treatment of the patient with 800 mg/day of ketoconazole led to a rapid fall of cortisol secretion and clinical signs of adrenocortical insufficiency. Treatment for 7 weeks with 200–400 mg ketoconazole per day reduced plasma and urinary cortisol less dramatically into the normal range. This case unequivocally documents autonomous dysfunction of the adrenal cortex in this rare form of Cushing's syndrome and the efficacy of ketoconazole in the treatment of ACTH-independent hypercortisolism.

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Aberrant Membrane Hormone Receptors in Incidentally Discovered Bilateral Macronodular Adrenal Hyperplasia with Subclinical Cushing’s Syndrome

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.86.11.8062 ◽

2001 ◽

Vol 86 (11) ◽

pp. 5534-5540 ◽

Cited By ~ 2

Author(s):

Isabelle Bourdeau ◽

Pierre D’Amour ◽

Pavel Hamet ◽

Jean-Marie Boutin ◽

André Lacroix

Keyword(s):

Cushing’S Syndrome ◽

Plasma Cortisol ◽

Hormone Receptors ◽

Gastric Inhibitory Polypeptide ◽

Urinary Free Cortisol ◽

Cushing's Syndrome ◽

Cortisol Secretion ◽

Adrenal Hyperplasia ◽

Free Cortisol ◽

Cortisol Levels

Cortisol secretion in adrenal Cushing’s syndrome can be regulated by the aberrant adrenal expression of receptors for gastric inhibitory polypeptide, vasopressin, catecholamines, LH/human CG (LH/hCG), or serotonin. Four patients with incidentally discovered bilateral macronodular adrenal hyperplasia without clinical Cushing’s syndrome were evaluated for the possible presence of aberrant adrenocortical hormone receptors. Urinary free cortisol levels were within normal limits, but plasma cortisol levels were slightly elevated at nighttime and suppressed incompletely after dexamethasone administration. Plasma ACTH was partially suppressed basally but increased after administration of ovine CRH. A 51-yr-old woman had ACTH-independent increases of plasma cortisol after 10 IU AVP im (292%), 100 μg GnRH iv (184%), or 10 mg cisapride orally (310%); cortisol also increased after administration of NaCl (3%), hCG, human LH, and metoclopramide. In a 61-yr-old man, cortisol was increased by AVP (349%), GnRH (155%), hCG (252%), and metoclopramide (191%). Another 53-yr-old male increased plasma cortisol after AVP (171%) and cisapride (142%). Cortisol secretion was also stimulated by vasopressin in a 54-yr-old female. This study demonstrates that subclinical secretion of cortisol can be regulated via the aberrant function of at least V1-vasopressin, LH/hCG, or 5-HT4 receptors in incidentally identified bilateral macronodular adrenal hyperplasia.

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SUN-187 A Case of Adrenal Mass with Elevated ACTH and Cortisol in a Woman with No Cushingoid Features

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.849 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Tara Rajiyah ◽

Susan Sam

Keyword(s):

Cushing’S Syndrome ◽

Adrenal Mass ◽

Correct Diagnosis ◽

Fasting Blood Glucose ◽

Clinical Signs ◽

Case Series ◽

Pituitary Surgery ◽

Cushing's Syndrome ◽

T Score ◽

History Of

Abstract Background Adrenal incidentalomas can present with subclinical Cushing’s Syndrome (SCS), which is defined as elevated cortisol levels without overt clinical signs or symptoms. Inaccuracies in ACTH levels due to issues with the assay and non-classic presentation of Cushing’s Syndrome (CS) can delay appropriate diagnosis and timely intervention. Clinical Case A 50-year-old female with a history of an incidentally discovered 3.4 x 1.8 cm adrenal mass was referred for evaluation of hypercortisolism (midnight salivary cortisol 0.17 μg/dL, normal < 0.09 μg/dL) with lack of suppression of both ACTH (19 pg/mL, normal 6-50 pg/mL) and cortisol (13.1 μg/dL, normal 6.0-18.4 μg/dL) on overnight 1-mg dexamethasone suppression test (DST). Pheochromocytoma work up was negative. Her medical history was remarkable for premature ovarian failure at age 40 and osteoporosis at age 48 (Lumbar spine T-score -3.6, Femoral neck T-score -3.7, Hip T-score -2.7). She denied alcohol abuse and depression screening was negative. She reported high levels of stress and insomnia. She denied muscle weakness, acne, or change to body habitus. Fasting blood glucose was intermittently as high as 212 mg/dl but HbA1c was 5.5%. She did not have a history of hypertension or glucocorticoid use. Her BMI was 20 kg/m2 and she did not appear Cushingoid. A pitutiary MRI showed no evidence of pituitary lesions or enlargement. Discussion and Follow up A non-suppressed ACTH made an adrenal source of cortisol unlikely. The working diagnosis was pseudo-CS secondary to stress, loss of diurnal rhythm due to insomnia, or overlooked depression. She was taking supplements, including biotin, and was asked to discontinue these for two weeks. Repeat 1-mg DST revealed an elevated cortisol of 9.8 μg/dL with a once again non-suppressed ACTH of 20 pg/mL. Her dexamethasone level was 109 ng/dL (normal after 1 mg dexamethasone 180-950 ng/dL), which may suggest slightly faster metabolism. All ACTH levels were run on Immulite assays, which has recently been suggested to be unreliable (1). When repeated using the Roche Assay, ACTH was low at 1.6 pg/mL. Given suppressed ACTH in conjunction with hypercortisolemia and osteoporosis, an adrenal source of CS was confirmed. Diagnosis was further solidified by a DHEA-S level of 11.4 μg/dL (normal 35.4 - 256 ug/dL). She underwent adrenalectomy and pathology revealed adrenal cortical adenomas. Conclusion The correct diagnosis of adrenal CS in this patient was delayed due to erroneously higher ACTH result by the Immulite assay. Similar cases have been reported in the literature with the use of Immulite assays for measurement of ACTH leading to invasive diagnostic procedures and even unnecessary pituitary surgery (1). 1. Greene LW, Geer EB, Page-Wilson G, Findling JW, Raff H. Assay-Specific Spurious ACTH Results Lead to Misdiagnosis, Unnecessary Testing, and Surgical Misadventure-A Case Series. J Endocr Soc. 2019;3(4):763-72.

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How useful is 24 hour Urinary Free Cortisol as a screening tool for Cushing's syndrome?

Endocrine Abstracts ◽

10.1530/endoabs.59.p028 ◽

2018 ◽

Author(s):

Ahmed Hanafy ◽

Chinnadorai Rajeswaran ◽

Saad Saddiq ◽

Warren Gillibrand ◽

John Stephenson

Keyword(s):

Cushing’S Syndrome ◽

Screening Tool ◽

Urinary Free Cortisol ◽

Cushing's Syndrome ◽

Free Cortisol

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Correction to: Levoketoconazole improves clinical signs and symptoms and patient-reported outcomes in patients with Cushing’s syndrome

Pituitary ◽

10.1007/s11102-020-01116-1 ◽

2020 ◽

Author(s):

Eliza B. Geer ◽

Roberto Salvatori ◽

Atanaska Elenkova ◽

Maria Fleseriu ◽

Rosario Pivonello ◽

...

Keyword(s):

Cushing’S Syndrome ◽

Patient Reported Outcomes ◽

Clinical Signs ◽

Signs And Symptoms ◽

Cushing's Syndrome ◽

Original Version ◽

Patient Reported ◽

Author Group ◽

Clinical Signs And Symptoms

The original version of the article unfortunately contained an error in the first name and the surname of one of the authors in the author group. The last author name was incorrectly published as ‘F. Pecori Giraldi’ and the corrected name is ‘Francesca Pecori Giraldi’ (First name: Francesca; Surname: Pecori Giraldi).

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