scholarly journals Displacement of PKA catalytic subunit from AKAP signaling islands drives pathology in Cushing's syndrome

2021 ◽  
Author(s):  
Mitchell H. Omar ◽  
Dominic P. Byrne ◽  
Kiana N. Jones ◽  
Tyler M. Lakey ◽  
Kerrie B. Collins ◽  
...  
Keyword(s):  
Cushing’S Syndrome ◽  
Cushing's Syndrome ◽  
Catalytic Subunit ◽  
Endocrine Function ◽  
Hippo Signaling ◽  
Stress Hormone ◽  
Kinase Activation ◽  
Anchoring Protein ◽  
Erk Activity ◽  
Cortisol Release

Mutations in the catalytic subunit of protein kinase A (PKAc) drive the stress hormone disorder adrenal Cushing's syndrome. Here we define mechanisms of action for the PKAc-L205R and W196R variants. Both Cushing's mutants are excluded from A kinase anchoring protein (AKAP) signaling islands and consequently diffuse throughout the cell. Kinase-dead experiments show that PKA activity is required for cortisol hypersecretion. However, kinase activation is not sufficient, as only cAMP analog drugs that displace native PKAc from AKAPs enhance cortisol release. Rescue experiments that incorporate mutant PKAc into AKAP signaling islands abolish cortisol overproduction, indicating that kinase anchoring restores normal endocrine function. Phosphoproteomics show that PKAc-L205R and W196R engage different mitogenic signaling pathways. ERK activity is elevated in adrenal-specific PKAc-W196R knock-in mice. Conversely, PKAc-L205R attenuates Hippo signaling, thereby upregulating the YAP/TAZ transcriptional co-activators. Thus, aberrant localization of each Cushing's variant promotes the transmission of a distinct downstream pathogenic signal.

Long-term morphological, hormonal, and clinical follow-up in a single unit on 118 patients with adrenal incidentalomas

2010 ◽  
Vol 162 (4) ◽  
pp. 779-785 ◽  
Author(s):  
R Giordano ◽  
E Marinazzo ◽  
R Berardelli ◽  
A Picu ◽  
M Maccario ◽  
...  
Keyword(s):  
Cushing’S Syndrome ◽  
Cumulative Risk ◽  
Cushing's Syndrome ◽  
Endocrine Function ◽  
Adrenal Incidentalomas ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Significant Clinical Improvement

ObjectiveTo evaluate long-term morphological, functional, and clinical outcome in adrenal incidentalomas.Design and methodsA total of 118 patients (77 F and 47 M; age 62.3±1.0 years) with adrenal incidentalomas were evaluated at baseline and followed-up for median 3 years (range 1–10 years) by clinical, biochemical, hormonal, and morphological evaluation. Among them, six patients with diagnosis of subclinical Cushing's syndrome (SCS) underwent surgery.ResultsAt entry, 86% (n=102) of tumors were nonfunctioning (NF) and 14% (n=16) showed SCS. Comparing NF with SCS patients, a significantly higher percentage of dyslipidemia was found in the group of SCS patients (50 vs 23%,P=0.033). During follow-up, adrenal function remained normal in all NF patients, none of them developed subclinical or overt endocrine disease. The cumulative risk of mass enlargement was globally low (25%), but progressive up to 8 years. SCS was confirmed in all patients, and none of them shifted to overt Cushing's syndrome. The cumulative risk of developing metabolic–cardiovascular abnormalities was globally low (22%), but progressive up to 8 years and new diseases were recorded in the group of NF patients only (three patients with dyslipidemia, four with impaired fasting glucose/impaired glucose tolerance, and three with diabetes mellitus). SCS patients who underwent surgery did not show any significant clinical improvement.ConclusionsThe risk of mass enlargement, hormonal, and metabolic impairment over time is globally low. Conservative management seems to be appropriate, but further prospective studies are needed to establish the long-term outcome of such patients, especially for metabolic status, cardiovascular risk profile and their relationship with endocrine function.

Adrenal Incidentaloma and Subclinical Cushing’s Syndrome: A Longitudinal Follow-Up Study by Endoscopic Ultrasound

2015 ◽  
Vol 38 (04) ◽  
pp. 411-419 ◽  
Author(s):  
Maike Collienne ◽  
Nina Timmesfeld ◽  
Simona Bergmann ◽  
Joachim Goebel ◽  
Peter Kann
Keyword(s):  
Growth Rate ◽  
Cushing’S Syndrome ◽  
Endoscopic Ultrasound ◽  
Adrenal Incidentaloma ◽  
Cushing's Syndrome ◽  
Endocrine Function ◽  
Maximum Diameter ◽  
Subclinical Cushing’S Syndrome ◽  
The Mean

Abstract Purpose Adrenal incidentaloma (AI) and adrenal masses in cases of subclinical Cushing’s syndrome (SCS) initially require follow-up imaging. In this study we used endoscopic ultrasound (EUS) as a method for high-resolution imaging. The aim was to evaluate the growth rate of AI and SCS by EUS. Materials and Methods This retrospective analysis included 93 out of 229 patients with AI or SCS who were investigated longitudinally by EUS in our university hospital between 1997 and 2013. The longitudinal follow-up required at least two investigations by EUS and evaluation of endocrine function. Plasma renin, serum aldosterone, 24 h urinary catecholamines and 2 mg dexamethasone suppression test were performed. EUS was performed at baseline and during follow-up. Each time, the maximum diameter was measured. Three groups were defined: non-functioning adenomas (NFA), non-functioning nodular hyperplasias (NFH) and SCS. Results 86 patients had non-functioning masses [NFM] (59 NFA, 48 NFH) and 7 patients had SCS (10 masses). At baseline the mean diameter was 19.4 (± 9.3) mm (NFM) and 19.6 (± 9.2) mm (SCS). The mean follow-up period was 31.6 ± 28.7 months. The estimated mean growth rates per year were low: They were 0.35 mm/yr [NFA], 0.02 mm/yr [NFH] and 0.53 mm/yr [SCS]. Furthermore, there was no malignant progression of any mass. Conclusion The growth rate as determined by EUS was low for all tumor entities observed in this study. There was no difference in tumor growth between the groups.

scholarly journals Constitutive Activation of PKA Catalytic Subunit in Adrenal Cushing's Syndrome

2014 ◽  
Vol 370 (11) ◽  
pp. 1019-1028 ◽  
Author(s):  
Felix Beuschlein ◽  
Martin Fassnacht ◽  
Guillaume Assié ◽  
Davide Calebiro ◽  
Constantine A. Stratakis ◽  
...  
Keyword(s):  
Cushing’S Syndrome ◽  
Cushing's Syndrome ◽  
Catalytic Subunit ◽  
Constitutive Activation ◽  
Pka Catalytic Subunit

The 24-h cortisol secretory pattern in Cushing's syndrome

1986 ◽  
Vol 112 (2) ◽  
pp. 230-237 ◽  
Author(s):  
J. Tourniaire ◽  
D. Chalendar ◽  
B. Rebattu ◽  
M. Fevre-Montange ◽  
L. Bajard ◽  
...  
Keyword(s):  
Cushing’S Syndrome ◽  
Cushing’S Disease ◽  
Plasma Cortisol ◽  
Adrenal Adenoma ◽  
Cushing's Syndrome ◽  
Cushing's Disease ◽  
Acth Secretion ◽  
Ectopic Acth ◽  
Ectopic Acth Secretion ◽  
Cortisol Release

Abstract. The 24-h plasma cortisol profile was obtained at 20-min intervals in 18 patients with Cushing's syndrome (10 with Cushing's disease, 5 with adrenal adenoma, 2 with ectopic ACTH secretion and 1 of questionable aetiology). The mean cortisol level was maximum in the case of ectopic ACTH secretion. The coefficient of variation of cortisol levels was subnormal in all except 2 subjects. Periodogram calculations, providing a best-fit curve (B F C) for each profile, showed that the existence of a significant baseline variation is a frequent feature. In certain cases, it is compatible with the persistance of a true circadian rhythm (2 patients with Cushing's disease; 1 patient with adrenal adenoma). The alteration of plasma cortisol pulsatility is much more pronounced in patients with adrenal adenoma than in patients with Cushing's disease. This is consistent with the hypothesis of a predominantly tonic secretion blunting the episodic hormone release. In 9 patients with Cushing's disease, the plasma cortisol pattern was suggestive of a combination of episodic cortisol release under CRF control and of continuous cortisol secretion due to constant stimulation from an autonomous ACTH source. Two cases were possibly of hypothalamic origin, as suggested by the presence of enhanced cortisol pulsatility and of a normal circadian amplitude. The analysis of the 24-h profile of plasma cortisol in Cushing's syndrome contributes to our understanding of the physiopathological mechanisms underlying this disorder and may help the diagnosis of its aetiology.

Effects of cortisol on catabolism of canine myocardium and mitral valve

Impact ◽  
2020 ◽  
Vol 2020 (6) ◽  
pp. 65-67
Author(s):  
Sachiyo Tanaka ◽  
Shuji Suzuki ◽  
Yasushi Hara
Keyword(s):  
Cushing’S Syndrome ◽  
Cardiovascular Effects ◽  
Assistant Professor ◽  
Cushing's Syndrome ◽  
The Body ◽  
Stress Hormone ◽  
Main Stress ◽  
Sugar Levels ◽  
The Brain ◽  
Canine Myocardium

Cortisol can be thought of as the body's main stress hormone, where it works with specific parts of the brain to control moods, motivations and fears. Cortisol is a hormone that many animals produce too, including dogs - in which it can help control weight, fight infections and keep blood sugar levels in check. However, if the body produces too much cortisol - in humans and in dogs - it can cause many problems. Cushing's syndrome is the name for the condition where dogs produce too much cortisol. The incidence is one or two cases in every 1,000 dogs per year, making it the most common endocrine disorder in dogs. Humans can also be diagnosed with Cushing's syndrome, where excessive exposure to cortisol is known to cause myocardial hypertrophy and cardiac dysfunction. It has also been reported that humans can experience hypertrophy of the cardiomyocytes and an increase in myocardial fibre. A team of researchers based at the Nippon Veterinary and Life Science University in Japan is investigating the cardiovascular effects of hyperglycocorticoidemia. Dr Sachiyo Tanaka is working with Professor Yasushi Hara and Assistant Professor Shuji Suzuki, to conduct research in order to elucidate the histopathological changes that occur in the heart organ when there is hyperglucocorticoidemia.

Abnormalities of endocrine function in patients with clinically "silent" adrenal masses

1995 ◽  
Vol 132 (4) ◽  
pp. 422-428 ◽  
Author(s):  
Bruno Ambrosi ◽  
Susanna Peverelli ◽  
Elena Passini ◽  
Tiziana Re ◽  
Riccardo Ferrario ◽  
...  
Keyword(s):  
Cushing’S Syndrome ◽  
Normal Subjects ◽  
Cushing's Syndrome ◽  
Endocrine Function ◽  
Type I ◽  
Unilateral Adrenalectomy ◽  
Free Cortisol ◽  
Adrenal Masses ◽  
Cortisol Levels ◽  
Secondary Hypoadrenalism

Ambrosi B, Peverelli S, Passini E, Re T, Ferrario R, Colombo P, Sartorio A, Faglia G. Abnormalities of endocrine function in patients with clinically "silent" adrenal masses. Eur J Endocrinol 1995;132:422–8. ISSN 0804–4643 Because, in recent years, patients with incidentally discovered adrenal masses have been encountered increasingly, their endocrine function was investigated in basal conditions and after dynamic tests. Thirty-two patients (23 women and 9 men, aged 28–74 years) were studied. Lesion diameter, as documented by computed tomography and/or nuclear magnetic resonance imaging, ranged between 5 and 65 mm; the tumors were localized on the right in 22 patients, on the left in 5 and bilaterally in 5 cases. In basal conditions, urinary free cortisol (UFC) excretion, plasma adrenocorticotropin (ACTH) and cortisol levels were normal, except for 4 patients who showed high UFC and ACTH levels in the low–normal range. Ovine corticotropin-releasing hormone (CRH, 1 μg/kg iv) was given to 18 patients, inducing normal ACTH and cortisol responses in 12, blunted responses in 4 and no response in 2 cases. No reduction in ACTH and cortisol levels after suppression tests was observed in 4 of 29 patients after dexamethasone (1 mg overnight) or in 6 of 29 after loperamide. The 4 patients who were unresponsive to both tests did not show any further inhibition after high-dose dexamethasone administration, had low plasma ACTH levels and showed impaired or absent responses to the CRH test: they were diagnosed as affected with preclinical Cushing's syndrome. An exogenous ACTH test performed in 30 patients caused a normal cortisol rise. Basal mean 17-hydroxyprogesterone (17-OHP) levels were not different from those in normal subjects. After ACTH the 17-OHP rate increase was higher than in normal subjects (17-OHP(30–)/30 min = 0.31 ±0.04 vs 0.07 ± 0.01 nmol·1−1·min−1; mean±SEM, p < 0.01); in particular, this parameter was elevated in 18 of 30 patients (17-OHP(30–0)/30 min range = 0.23–1.07 vs 0.01–0.19 nmol·1−1·min−1 in normal subjects). In a subset of 11 patients, serum markers of bone (bone-GLA protein (BGP) and carboxyterminal cross-linked telopeptide of type I collagen (ICTP) and collagen turnover (aminoterminal propeptide of type III procollagen (PIIINP)) were significantly (p < 0.01) lower than in normal subjects: in particular, in 2 preclinical Cushing's patients they were markedly reduced and rose after unilateral adrenalectomy. Of these 2 patients who underwent surgery, 1 showed a secondary hypoadrenalism. The histological study in 7 operated patients revealed the presence of benign adenoma in 4 cases and carcinoma, myelolipoma and hematoma in the others. In conclusion, in patients with incidentalomas endocrine testing is recommended because about two-thirds of them show subtle signs of adrenal overactivity. In patients with enzymatic defects of steroidogenesis a surgical approach is not suggested. On the contrary, the existence of a preclinical Cushing's syndrome has to be investigated carefully and followed up in order to disclose the possible appearance of clinical and/or metabolic features induced by the hypercortisolism and to suggest a surgical treatment. B Ambrosi, Institute of Endocrine Sciences, Ospedale Maggiore, IRCCS, via F Sforza 35, 20122 Milan, Italy

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