For clinical follow-up, features of SDHB mutation-associated disease include a later age of onset, extraadrenal (abdominal or thoracic) tumors, and a higher rate of malignancy. In contrast, SDHD mutation carriers, in addition to head and neck paragangliomas, should be observed for multifocal tumors, infrequent malignancy, and the possibility of extraadrenal pheochromocytoma.

No abstract

This study clearly shows that even within the clinically relevant range of temperatures found in humans, CBG acts as a protein thermocouple that is exquisitely sensitive to temperature change and will release cortisol in response to fever or external sources of heat. This has major implications for our understanding of cortisol regulation in febrile patients.

Objectives-To characterize the dynamics of the pituitary-adrenal interaction during the course of coronary artery bypass grafting (CABG) both on and off pump. Since our data pointed to a major change in adrenal responsiveness to ACTH we used a reverse translation approach to investigate the molecular mechanisms underlying this change in a rat model of critical illness. Measurements and Results-Clinical studies: Blood samples were taken for 24 hours from placement of the first venous access. Cortisol and ACTH were measured every 10 and 60 minutes respectively, and corticosteroid binding globulin (CBG) was measured at the beginning and end of the 24 hour period and at the end of operation. There was an initial rise in both levels of ACTH and cortisol to supra-normal values at around the end of surgery. ACTH levels then returned towards pre-operative values. Ultradian pulsatility of both ACTH and cortisol was maintained throughout the peri-operative period in all individuals. The sensitivity of the adrenal gland to ACTH increased markedly at around 8 hours after surgery maintaining very high levels of cortisol in the face of 'basal' levels of ACTH. This sensitivity began to return towards pre-operative values at the end of the 24-hour sampling period.Animal studies: Adult, male Sprague-Dawley rats were either given lipopolysaccharide (LPS) or sterile saline via a jugular vein cannula. Hourly blood samples were subsequently collected for ACTH and corticosterone measurement. Rats were sacrificed 6 hours after the injection and the adrenal glands were collected for measurement of StAR, SF-1 and DAX1 mRNA and protein using RTqPCR and Western immunoblotting, respectively. Adrenal levels of the ACTH receptor (MC2R) mRNA and its accessory protein (MRAP) were also measured by RTqPCR. In response to LPS, rats showed a pattern of ACTH and corticosterone that was similar to patients undergoing CABG. We were also able to demonstrate increased intra-adrenal corticosterone levels and an increase in StAR, SF-1 and MRAP mRNAs and StAR protein, and a reduction in DAX1 and MC2R mRNAs, 6h after LPS injection.Conclusions-Severe inflammatory stimuli activate the HPA axis resulting in increased steroidogenic activity in the adrenal cortex and an elevation of cortisol levels in the blood. Following CABG there is a massive increase in both ACTH and cortisol secretion. Despite a subsequent fall of ACTH to basal levels, cortisol remains elevated and co-ordinated ACTHcortisol pulsatility is maintained. This suggested that there is an increase in adrenal sensitivity to ACTH, which we confirmed in our animal model of immune activation of the HPA axis. Using this model we were able to show that this increased adrenal sensitivity results from changes in the regulation of both stimulatory and inhibitory intra-adrenal signaling pathways. Increased understanding of the dynamics of normal HPA responses to major surgery will provide us with a more rational approach to glucocorticoid therapy in critically ill patients.Gibbison et al.

Untreated compared to treated OSA is associated with marked disturbances in ACTH and cortisol secretory dynamics, resulting in prolonged tissue exposure to disordered, elevated hormone levels.

A complex dynamic ultradian rhythm underlies the hypothalamic-pituitary-adrenal (HPA) circadian rhythm. We have investigated in normal human male subjects the importance, site of action, and receptor-mediated processes involved in rapid basal corticosteroid feedback and its interaction with corticotrophin releasing hormone (CRH) drive. Pro-opiomelanocortin (POMC), ACTH, and cortisol were measured every 10 min from healthy males during the awakening period or late afternoon using an automated blood sampling system. Mathematical modeling into discrete pulses of activity revealed that intravenous infusion of the synthetic mixed glucocorticoid/ mineralocorticoid agonist prednisolone produced rapid inhibition of ACTH and cortisol pulsatility within 30 min in the morning and afternoon. Any pulse that had commenced at the time of injection was unaffected, and subsequent pulsatility was inhibited. Prednisolone also inhibited ACTH and cortisol secretion in response to exogenous CRH stimulation, inferring rapid feedback inhibition at the anterior pituitary. Circulating POMC peptide concentrations were unaffected, suggesting that the rapid corticosteroid inhibitory effect specifically targeted ACTH secretion from pituitary corticotrophs. Prednisolone fast feedback was only reduced by glucocorticoid receptor antagonist pretreatment and not by mineralocorticoid receptor antagonism, suggesting a glucocorticoid receptor-mediated pathway. The intravenous prednisolone suppression test provides a powerful new tool to investigate HPA abnormalities underlying metabolic and psychiatric disease states.

No abstract

Testosterone and gonadotropins have been associated with cognitive decline in men and the modulation of β amyloid (Aβ) metabolism. The relatively few studies that have investigated whether changes in one or a combination of these hormones influence Aβ levels have focused primarily on plasma Aβ(1-40) and not on the more pathogenic Aβ(1-42). Currently, no study has investigated whether these hormones are associated with an increase in brain amyloid deposition, ante mortem. Through the highly characterised Australian imaging, biomarkers and lifestyle study, we have determined the impact of these hormones on plasma Aβ levels and brain amyloid burden (Pittsburgh compound B (PiB) retention). Spearman's rank correlation and linear regression analysis was carried out across the cohort and within subclassifications. Luteinizing hormone (LH) was the only variable shown, in the total cohort, to have a significant impact on plasma Aβ(1-40) and Aβ(1-42) levels (beta=0.163, P<0.001; beta=0.446, P<0.001). This held in subjective memory complainers (SMC) (Aβ(1-40); beta=0.208, P=0.017; Aβ(1-42); beta=0.215, P=0.017) but was absent in mild cognitive impairment (MCI) and Alzheimer's disease (AD) groups. In SMC, increased frequency of the APOE-ɛ4 allele (beta=0.536, P<0.001) and increasing serum LH levels (beta=0.421, P=0.004) had a significant impact on PiB retention. Whereas in MCI, PiB retention was associated with increased APOE-ɛ4 allele copy number (beta=0.674, P<0.001) and decreasing calculated free testosterone (beta=-0.303, P=0.043). These findings suggest a potential progressive involvement of LH and testosterone in the early preclinical stages of AD. Furthermore, these hormones should be considered while attempting to predict AD at these earliest stages of the disease.