Cyclic Cushing's Disease Research Articles

Pregnancy in a lady with pre-existing cyclical cushing's disease

Pregnancy in a lady with pre-existing cyclical cushing's disease

PAM variants in patients with thyrotrophinomas, cyclical Cushing's disease and prolactinomas.

Germline loss-of-function variants in PAM, encoding peptidylglycine α-amidating monooxygenase (PAM), were recently discovered to be enriched in conditions of pathological pituitary hypersecretion, specifically: somatotrophinoma, corticotrophinoma, and prolactinoma. PAM is the sole enzyme responsible for C-terminal amidation of peptides, and plays a role in the biosynthesis and regulation of multiple hormones, including proopiomelanocortin (POMC). We performed exome sequencing of germline and tumour DNA from 29 individuals with functioning pituitary adenomas (12 prolactinomas, 10 thyrotrophinomas, 7 cyclical Cushing's disease). An unfiltered analysis was undertaken of all PAM variants with population prevalence <5%. We identified five coding, non-synonymous PAM variants of interest amongst seven individuals (six germline, one somatic). The five variants comprised four missense variants and one truncating variant, all heterozygous. Each variant had some evidence of pathogenicity based on population prevalence, conservation scores, in silico predictions and/or prior functional studies. The yield of predicted deleterious PAM variants was thus 7/29 (24%). The variants predominated in individuals with thyrotrophinomas (4/10, 40%) and cyclical Cushing's disease (2/7, 29%), compared to prolactinomas (1/12, 8%). This is the second study to demonstrate a high yield of suspected loss-of-function, predominantly germline, PAM variants in individuals with pathological pituitary hypersecretion. We have extended the association with corticotrophinoma to include the specific clinical entity of cyclical Cushing's disease and demonstrated a novel association between PAM variants and thyrotrophinoma. PAM variants might act as risk alleles for pituitary adenoma formation, with a possible genotype-phenotype relationship between truncating variants and altered temporal secretion of cortisol.

Cyclical Cushing's disease - challenges in diagnosis and management

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

PMON102 Utility of the Desmopressin Stimulation Test to Detect Cyclic Cushing's Disease

Abstract Background Arginine-vasopressin stimulates pituitary ACTH secretion after binding to arginine-vasopressin receptor 1B on corticotropes. Desmopressin (DDAVP), which preferentially binds to arginine-vasopressin receptor 2, stimulates the release of ACTH in most patients with pituitary corticotrope adenomas (Cushing's disease, CD), but not in most patients with ectopic ACTH-producing tumors or healthy people. Cyclic CD is characterized by periods of normal or low cortisol and ACTH, interspersed with hypercortisolism. We postulated that the DDAVP stimulation test, with measurement of ACTH and cortisol after a 10 mcg injection of DDAVP, might confirm the presence of an ACTH-producing pituitary adenoma even during periods without hypercortisolemia. Clinical Case A 27-year-old woman was diagnosed with Cushing's disease one year after developing weight gain, striae, intermittent acne, balding, irregular menses, a dorsal fat pad and facial rounding. Pituitary MRI revealed a right-sided 7 mm microadenoma; inferior petrosal sinus sampling confirmed a pituitary source of ACTH. Transsphenoidal resection was performed 6 months later. Histology showed an ACTH-positive adenoma and cortisol levels fell to 33nmol/L (1.2 ug/dL). Ten months later, due to intermittent symptoms, testing confirmed elevated UFC, with midnight cortisol of 565 nmol/L (20.3 ug/dL). Pituitary MRI showed a new right-sided lesion, interpreted as a residual adenoma or postoperative changes. Repeat surgical resection was recommended. She presented to our institution for a second opinion. On evaluation three weeks after recurrent hypercortisolism was confirmed, ACTH was low-normal (11.9 pg/mL, RR 5.0-46.0) and serum cortisol was undetectable. This rapid decrease was thought to signify apoplexy of the remaining adenoma or cyclic Cushing's disease. An MRI excluded apoplexy. However, surgery seemed inappropriate given hypocortisolism. To evaluate for the possibility of cyclic Cushing's disease due to residual adenoma, we performed a DDAVP stimulation test. This showed significant increases in ACTH and cortisol levels from 0 min to a 30-minute peak (ACTH 31.6 to 73.1 pg/mL, 131% increase, nl &amp;lt;50%; cortisol 2.6 to 8.1 mcg/dL [72 - 225 nmol/L], 212% increase, nl &amp;lt;20%). This led to transsphenoidal resection of a right-sided lesion. Cortisol levels were undetectable on post-operative day 3 and pathology showed an ACTH-producing adenoma. One week postoperatively, a repeat DDAVP stimulation test showed an insignificant rise in ACTH, and undetectable cortisol throughout (ACTH 11.1 to 12.4 pg/mL, 12% increase; cortisol &amp;lt;1.0 mcg/dL, 0% increase), which was deemed to indicate successful resection of the residual adenoma. She continues to lose weight and her clinical features of cortisol excess are involuting. Conclusion This case demonstrates how the DDAVP stimulation test can be used to both confirm the presence of ACTH-producing pituitary adenomas and assess the response to surgical resection. It may be particularly useful in the setting of cyclic Cushing's disease when cortisol and ACTH levels are not persistently elevated. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Factors Affecting Dexamethasone Suppression Test Results.

Dexamethasone suppression tests are basic tools in diagnostics of hypercortisolemia. Low-dose tests play major role in screening and initial assessment. High-dose tests are aimed at more elaborate diagnostics, however their clinical value is questionable. Dexamethasone is a highly potent, synthetic steroid. It is metabolized by cytochrome P450 3A4 (CYP3A4), and so are various other xenobiotics. Due to wide spectrum of substances processed by CYP3A4, interferences and interactions are not uncommon. Physicians should be familiar with drugs modifying dexamethasone metabolism, and therefore the results of dynamic tests. Other important concerns are: drugs enhancing cortisol-binding globulin production, organ dysfunction, pseudo-Cushing states, pregnancy and other physiological conditions leading to elevated blood cortisol, cyclic Cushing disease. To properly assess and assist patients, it is crucial for health professionals to understand and be able to overcome such clinical dilemmas.

Cushing disease in children and adolescents - assessment of the clinical course, diagnostic process, and effects of the treatment - experience from a single paediatric centre.

Adrenocorticotropic hormone-dependent Cushing syndrome, known as Cushing disease (CD), is a rare disease in paediatric patients, the signs and symptoms of which differ from those seen in adult patients. The objective of the study was to present the diagnostics and treatment results of CD in children and adolescents. We included four consequent patients in the study, 7-15 years old, with CD confirmed by laboratory tests and finally by histology ex-aminations after surgery. The data were retrospectively retrieved from the medical records of all the patients from the years 2012-2018. The median time from the onset of clinical symptoms to CD diagnosis was 1.5 years. All patients presented with rapid weight gain ac-companying growth retardation, and behavioural, puberty, or menstruation disorders. The diagnostic process was carried out in accord-ance with the current standard. Diagnostic difficulties regarded the cyclic CD. All patients underwent transsphenoidal complete resection of the pituitary adenoma, and they all required transient glucocorticoid substitution for a period that correlated with the time from onset of symptoms to diagnosis. All subjects achieved normalisation of hormonal results and resolution of clinical symptoms, but all are still obese. Currently the patients are in remission, but there is a suspicion of the regrowth of the tumour mass in the eldest patient. In each case of the coexistence of growth velocity inhibition (not necessarily short stature) with the weight gain (not necessarily obesity) and the appearance of hyperandrogenism and depressive-anxiety disorders, biochemical diagnostics of CS should be performed. Obesi-ty could be a chronic complication of CD in childhood, even after effective neurosurgery treatment.

Characterization of cyclic Cushing's disease using late night salivary cortisol testing.

To characterize a cohort of patients with cyclic Cushing's disease (CD) in comparison with noncyclic CD using late night salivary cortisol (LNSC) and examine the diagnostic sensitivity of LNSC in comparison with that of 24-hour urine-free cortisol (UFC) in this population. Retrospective study of patients with CD seen in our institution between 2008 and 2017. A total of 205 patients, including 17 (8%) with cyclic CD (based on a minimum of 3 peaks and 2 troughs in cortisol levels). In a secondary analysis, 38 patients (19%) with cyclic CD were identified (based on a criterion of at least 2 peaks and 1 trough). Data on presentation, laboratory tests and outcomes were extracted. The diagnostic sensitivity of LNSC vs UFC in establishing cyclic CD was calculated. Kaplan-Meier analyses of recurrence after transsphenoidal pituitary surgery (TSS) were performed. The interval between presentation and TSS was significantly longer in patients with cyclic CD (P<.0001) in comparison with those with noncyclic CD. The sensitivity of LNSC in establishing cyclic CD was 88% and was higher than that of UFC (12%, P=.007). There were no differences in remission and recurrence rates between patients with cyclic CD and those with noncyclic CD. Patients with cyclic CD account only for a minority of those with CD, but may require a lengthier diagnostic evaluation. The use of LNSC on multiple occasions provides a more sensitive method of detecting cyclic CD than UFC. Outcomes of TSS in cyclic CD are comparable to those with noncyclic disease.

An unusual case of possible cyclic Cushing's disease in a young man with Klinefelter syndrome

An unusual case of possible cyclic Cushing's disease in a young man with Klinefelter syndrome

Desmopressin test in the diagnosis and follow-up of cyclical Cushing's disease

To assess the utility of the desmopressin (DDAVP) test in the diagnosis and follow-up of a cyclical Cushing's disease (CCS) case. Laboratory tests included morning and midnight serum cortisol levels, 24 h urine free cortisol excretion, midnight salivary cortisol levels, serum cortisol levels after low (1 mg) and high (8 mg) dexamethasone, plasma ACTH and serum cortisol levels after DDAVP. Magnetic resonance imaging (MRI) was used to assess the presence of a pituitary adenoma. The resected tumor specimen was studied by histological, immunohistochemical and cell biology techniques. A patient was referred to our unit with a diagnosis of Cushing's syndrome (CS) for further evaluation and treatment. However, no biochemical evidence of hypercortisolism was observed in the follow-up evaluations. Furthermore, the typical features of CS fluctuated throughout this period. A consistent positive response to the DDAVP stimulation test was observed during the diagnostic work-up, even when overt clinical features of CS were not apparent, raising suspicion for CCS. After two years of follow-up a definitive diagnosis of hypercortisolism was established. An MRI scan revealed a pituitary adenoma, as the source of ACTH production. After transphenoidal surgery, clinical signs of CS resolved and the response to DDAVP became negative. DDAVP induced a significant increase in ACTH levels in cultured pituitary adenoma cells, consistent with the in vivo DDAVP test results. Our case illustrates the utility of the DDAVP test in the evaluation of patients with suspected CCS. The DDAVP test could facilitate the management of CCS by shortening the time of diagnosis. Evaluar la utilidad de la prueba de la desmopresina (DDAVP) en el diagnóstico y seguimiento de un caso de enfermedad de Cushing cíclica (ECC). Se realizaron mediciones de cortisol sérico diurno y nocturno, cortisol libre en orina de 24 h, cortisol en saliva nocturno, cortisol sérico tras dosis elevadas y bajas de dexametasona, ACTH plasmática y cortisol tras la DDAVP, y resonancia magnética (RM) para valorar la presencia de un adenoma hipofisario. El tumor extirpado fue analizado mediante técnicas histológicas, inmunohistoquímicas y de biología celular. Se presenta una paciente enviada a nuestra unidad con el diagnóstico de síndrome de Cushing (SC) para evaluación más completa y tratamiento. No obstante durante un periodo de seguimiento de 2 años no se encontró evidencia alguna de hipercortisolismo en los análisis realizados en nuestro laboratorio. Durante este tiempo, la paciente mostró fluctuaciones de los síntomas y signos típicos del SC. De manera interesante, la prueba de DDAVP mostró hiperrespuesta de cortisol y ACTH en todas las evaluaciones. La exploración por RM mostró un adenoma hipofisario que tras extirpación resultó ser positivo para ACTH. El SC se resolvió tras la cirugía y la respuesta a la prueba de DDAVP desapareció en las evaluaciones de seguimiento posquirúrgico. Se incubaron muestras del tumor mostrando este un aumento en la secreción in vitro de ACTH. Este caso ilustra la utilidad de la prueba de DDAVP en la evaluación de pacientes con sospecha de SCC. Esta prueba podría facilitar el manejo del SCC acortando el tiempo de diagnóstico.

Desmopressin test in the diagnosis and follow-up of cyclical Cushing's disease

To assess the utility of the desmopressin (DDAVP) test in the diagnosis and follow-up of a cyclical Cushing's disease (CCS) case. Laboratory tests included morning and midnight serum cortisol levels, 24h urine free cortisol excretion, midnight salivary cortisol levels, serum cortisol levels after low (1 mg) and high (8 mg) dexamethasone, plasma ACTH and serum cortisol levels after DDAVP. Magnetic resonance imaging (MRI) was used to assess the presence of a pituitary adenoma. The resected tumor specimen was studied by histological, immunohistochemical and cell biology techniques. A patient was referred to our unit with a diagnosis of Cushing's syndrome (CS) for further evaluation and treatment. However, no biochemical evidence of hypercortisolism was observed in the follow-up evaluations. Furthermore, the typical features of CS fluctuated throughout this period. A consistent positive response to the DDAVP stimulation test was observed during the diagnostic work-up, even when overt clinical features of CS were not apparent, raising suspicion for CCS. After two years of follow-up a definitive diagnosis of hypercortisolism was established. An MRI scan revealed a pituitary adenoma, as the source of ACTH production. After transphenoidal surgery, clinical signs of CS resolved and the response to DDAVP became negative. DDAVP induced a significant increase in ACTH levels in cultured pituitary adenoma cells, consistent with the in vivo DDAVP test results. Our case illustrates the utility of the DDAVP test in the evaluation of patients with suspected CCS. The DDAVP test could facilitate the management of CCS by shortening the time of diagnosis.

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.

Long-term Remission of Cyclic Cushing's Disease that was Diagnosed and Treated Surgically in Non-active Phase

Cyclic Cushing's disease is a rare clinical entity that is defined as a periodic excessive production of adrenocorticotropic hormone (ACTH) and cortisol. Only 42 cases with cyclic Cushing's disease have been reported in the literature. The diagnosis is very difficult because of the fluctuating secretion of ACTH and cortisol. We report a 78-year-old woman with a pituitary adenoma presenting with cyclic Cushing's disease. In the present case, several interesting issues are pointed out: 1) MRI study detected the presence of an adenoma and selective venous sampling in the cavernous sinus disclosed the hypersecretion of ACTH from a pituitary adenoma. These neuroimaging and endocrinological studies were helpful for the diagnosis, even in the remission phase. 2) The disease was in the long-term remission phase after transsphenoidal surgery despite the high recurrence rate in this clinical entity, although it recurred four years later. Even in the remission phase of cyclic Cushing's disease, meticulous endocrinological and neuroimaging examinations can reveal the presence of a pituitary adenoma, which should be treated surgically.

Cyclic Cushing’s disease with paradoxical response to dexamethasone

Cyclic Cushing's disease is an unusual disorder characterised by ACTH-dependent periodical increase of serum cortisol levels, clinically accompanied by peripheral edema, abnormalities of cardiac rhythm and hypokalemia. The condition may be unrecognised for years, since the typical features of Cushing's disease are usually absent due to the intermittent and brief duration of cortisol hypersecretion. We describe the case of a 42-yr-old man with Cyclic Cushing's disease due to an ACTH-producing pituitary macroadenoma, who presented two episodes of hypercortisolism in a 3-yr-period, clinically characterised by peripheral edema, hypokalemia and arrhythmia. The diagnosis was suspected because of a paradoxical increase of plasma ACTH and cortisol after dexamethasone administration during an asymptomatic period and was confirmed by pituitary imaging and by final histology after transphenoidal resection of the pituitary adenoma. After surgery, the patient resumed a normal pituitary-adrenal function with restoration of the normal ACTH and cortisol suppression after dexamethasone. Cyclic Cushing's disease should be considered in the differential diagnosis of several conditions characterised by recurrent episodes of idiopathic edema, hypokalemia or unexplained cardiac arrhythmia. In such patients, the pituitary-adrenal axis should be tested possibly during the acute phase of their disease or using the dexamethasone suppression test during asymptomatic intervals.

Cyclical Cushing's disease causing recurrent oedema and knee effusions

Internal Medicine JournalVolume 35, Issue 3 p. 201-202 Cyclical Cushing's disease causing recurrent oedema and knee effusions M. D. Reed, M. D. Reed Rheumatology, Royal Melbourne Hospital, Parkville, Victoria, AustraliaSearch for more papers by this authorP. G. Colman, P. G. Colman Departments of Diabetes and EndocrinologySearch for more papers by this author D. Barraclough, D. Barraclough Rheumatology, Royal Melbourne Hospital, Parkville, Victoria, AustraliaSearch for more papers by this author M. D. Reed, M. D. Reed Rheumatology, Royal Melbourne Hospital, Parkville, Victoria, AustraliaSearch for more papers by this authorP. G. Colman, P. G. Colman Departments of Diabetes and EndocrinologySearch for more papers by this author D. Barraclough, D. Barraclough Rheumatology, Royal Melbourne Hospital, Parkville, Victoria, AustraliaSearch for more papers by this author First published: 25 February 2005 https://doi.org/10.1111/j.1445-5994.2005.00780.xRead the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Volume35, Issue3March 2005Pages 201-202 RelatedInformation

Periodic Secretion of Adrenocorticotropin in a Patient with Cushing's Disease Manifested during Pregnancy

We report the case of 19-year-old woman with cyclical Cushing's disease, in whom plasma adrenocorticotropin (ACTH) was secreted periodically after her first pregnancy. Since the 33rd week of pregnancy, hypertension and proteinuria became clinically remarkable. She gave normal birth at 36th week of pregnancy; however she continued to gain body weight even after delivery and developed typical Cushingoid features. Her ACTH secretion lacked normal daily fluctuation but exhibited periodic change during 1-year observation, showing 119 pg/ml, 34.6 pg/ml and 115 pg/ml at the 4th, 7th and 13th months after delivery. Plasma ACTH levels were increased by corticotropin releasing hormone and metyrapone, while low-dose dexamethasone suppressed cortisol secretion. Gel filtration analysis of the patient's plasma detected big ACTH molecules being eluted with a peak of authentic 1-39 ACTH. Cranial magnetic resonance imaging revealed a 1-cm pituitary mass in right cavernous sinus. The pituitary tumor was removed by transsphenoidal surgery at 13th month after delivery and was pathologically compatible with ACTH-producing pituitary adenoma by immunohistochemistry. This case includes clinically rare subsets of Cushing's syndrome showing periodic ACTH secretion and aberrant ACTH molecules.

A case of cyclical Cushing's disease associated with corticosteroidbinding globulin deficiency: a rare pitfall in the diagnosis of Cushing's disease

We experienced an extremely unusual combination of Cushing's disease and corticosteroid-binding globulin (CBG) deficiency that has been reported in only one similar case to date. A 53-year-old woman presented at a medical clinic with clinical Cushing's disease. However, her plasma levels of adrenocorticotropin (ACTH) and cortisol were in the normal range. Six months later, during a second visit, a high urinary excretion of 17-hydroxycorticosteroids was found, but plasma ACTH and cortisol levels were normal again. Further investigation revealed a decreased CBG concentration. Free plasma cortisol levels were clearly elevated. Furthermore, the Cushing's disease of our patient was complicated by periodic secretion of ACTH and cortisol, with high or normal outputs of corticosteroids occurring alternately every 1-3 days, which explained the occasionally normal plasma ACTH and cortisol levels. A combination of a decreased serum CBG concentration and periodic secretion of ACTH can be an important pitfall in the diagnosis of Cushing's disease.

Cyclical Cushing's Disease: A Case Report

A 41-year-old man with clinical Cushing's syndrome and intermittent central ACTH hypersecretion for a period of 9 1/2 years follow-up is described. Episodes of biochemical and clinical remission alternated with periods of florid Cushing's disease, characterized by circadian hyperpulsatile ACTH and cortisol secretion. Responses to metyrapone and inhibition of ACTH and cortisol hypersecretion after high dose dexamethasone during active phases of the disease favored a central origin of ACTH hypersecretion, confirmed by simultaneous bilateral venous sampling of the sinus petrosus inferior. Prolonged clinical remission followed near total anterior hypophysectomy. However, on anatomopathological examination of the pituitary neither corticotroph cell hyperplasia nor a microadenoma could be documented. The possibility of a functional ACTH hypersecretion is discussed.

Cortisol-suppressible dexamethasone-nonsuppressible cyclic Cushing's disease with evidence of clinical and biochemical remission with bromocriptine.

We report a rare case of a 57-year-old female patient with Cushing's disease who had clinically and biochemically proven cyclicity. There were periodic increases in plasma ACTH and cortisol and urinary free cortisol and 17-OHCS. Plasma CRH was undetectable and plasma ACTH responded to exogenous CRH when basal plasma cortisol was relatively low. Neither plasma ACTH nor cortisol responded to dexamethasone (oral and intravenous) but plasma ACTH was clearly suppressed by cortisol infusion. With 40 mg/day bromocriptine, the periodic hypercortisolemia disappeared and the patient was maintained on remission. The response of plasma cortisol to dexamethasone suppression test was also normalized.

Cyclic Cushingʼs Disease in Association With a Pituitary Stone

We have documented what we believe to be the first reported case of a pituitary stone in a patient with pituitary-dependent Cushing's disease. Pituitary stones have been reported exclusively in growth-hormone-producing or prolactin-producing pituitary adenomas. Our patient's ACTH and serum cortisol levels cycled for 15 months and then resolved spontaneously. A CT scan of the head showed calcification of pituitary tissue. Pituitary stones may occur in association with Cushing's disease. We hypothesize that the spontaneous resolution of the cyclic Cushing's disease was due to destruction and ultimate calcification of abnormal pituitary tissue.

Cyclical Cushing's Disease: Two Distinct Rhythms in a Patient with a Basophil Adenoma

A 71-yr-old woman with clinical signs of Cushing's syndrome was studied continuously for an extended period after demonstration of a paradoxical response to dexamethasone. She proved to have a corticotroph cell adenoma of the pituitary which caused secretion of ACTH and cortisol in two distinct rhythms. One rhythm consisted of a period of 40 days of excess cortisol production, followed by a period of 60-70 days of normal production. During the period of excess cortisol production there was a second rhythm, consisting of peaks of cortisol production every 3-6 days with intervening troughs of normal cortisol production. Prolonged clinical remission followed transphenoidal surgery, but the pituitary still has the ability to provoke abnormal amounts of cortisol secretion, as occurred during a postoperative dexamethasone suppression test. The long duration of normal cortisol production phases in this patient demonstrates the difficulty in excluding Cushing's syndrome in patients with suggestive clinical symptoms but normal serum and urinary cortisol levels if these tests are measured for a single short phase of several days.