The present study has established that physiological concentrations of estradiol can modulate stress-induced increases in plasma epinephrine (EPI). In anesthetized female rats, insulin-induced hypoglycemia (0.25 U/kg) increased plasma EPI concentration to a significantly greater extent in 14-day ovariectomized (OVEX) rats compared to sham-operated controls. In 17-estradiol (E2)-replaced OVEX rats, the hypoglycemia-induced rise in plasma EPI was significantly reduced compared to OVEX rats. This suppression was due to both decreased adrenal medullary output and increased clearance of EPI. Adrenal venous EPI concentration was significantly reduced in OVEX+E2 rats, suggesting that EPI secretion from the adrenalmedulla was decreased by E2 replacement. The underlying mechanism(s) of this apparent E2-mediated reduction in secretion could not be established since 1) the expression levels of the biosynthetic enzymes tyrosine hydroxylase and phenylethanolamine N-methyltransferase were not affected in OVEX+E2 rats, suggesting that EPI biosynthesis is similar in these and OVEX rats; and 2) agonist-induced increases in intracellular CaP2+P were identical in isolated adrenal medullary chromaffin cells exposed to E2 (10 nM) or vehicle for 48 hr, suggesting that stimulus secretion coupling is unaffected by E2 treatment. In contrast, plasma clearance of EPI was significantly increased in OVEX+E2 rats. Although 48 hr exposure to E2 had no effect on intracellular signaling in chromaffin cells, acute (3 min) exposure to micromolar concentrations of E2 dose-dependently and reversibly inhibited agonist-induced CaP 2+Ptransients. Consistent with this observation, acute (30 min) infusions of E2 also significantly reduced the insulin-induced increase in plasma EPI in OVEX rats. These data demonstrate that physiological levels of circulating E2 can modulate hypoglycemia-induced increases in plasma EPI. This effect appears to be mediated by the steroids influence on adrenal medullary EPI output and plasma EPI clearance; however the mechanism(s) underlying these E2-mediated modulations remain undetermined. This study has also established that acute exposure to supra-physiological levels of E2 can suppress hypoglycemia-induced increases in plasma EPI, due at least in part to inhibition of stimulus-secretion coupling.

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Exactly where in the hypothalamus is the adrenal-pituitary response to X-irradiation "triggered" or initiated? Moreover, does ionizing radiation act directly on specific centers in the brain or does it act indirectly via the production of some humoral agents? Finally, what role does the hypothalamus play in the radiation-syndrome? The purpose of the present study was to attempt to answer these questions by determining the effects of two stressor agents, X-irradiation and electrical stimulation applied either singly or together, on the activity of the adrenal-pituitary axis. The parameters measured were changes in plasma corticosterone, in circulating eosinopihils, and in adrenal gland weight.

The effects of a lethal dose (1380 r) of X-irradiation on plasma and adrenal tissue histamine levels of rats were studied. The plasma histamine response was triphasic (increase at 1-3 hours, decrease at 5 and 9 hours and return to control at 24 hours post-irradiation). The adrenal tissue histamine response was found to be biphasic (decrease at 1 to 9 hours and a return to control level at 24 hours post-irradiation).

Abstract Introduction: Tuberculosis carries a high mortality in the days immediately after treatment. It is also the commonest cause of adrenal insufficiency in the developing world. Rifampicin is a potent hepatic enzyme inducer, and may contribute to adrenal insufficiency by accelerating cortisol breakdown. The aim of the study was to determine whether rifampicin induced accelerated catabolism of corticosteroids. Methods: A prospective, randomised study comparing adrenal function in 20 patients with pulmonary tuberculosis in the first five days treated with two different antituberculosis regimens, one containing rifampicin, and the other ciprofloxacin. Results: Demographic, clinical and laboratory results were similar in both groups. Both groups showed a statistically significant and similar decrease in morning cortisol, with similar responses to ACTH stimulation at both 30 and 60 minutes before and after four days of treatment. In the entire cohort, 40% demonstrated an incremental cortisol rise of <250nmol/l after ACTH stimulation on day 1. Mean basal cortisol concentrations were substantially elevated and DHEA-S levels were consistently subnormal, resulting in a high cortisol:DHEA-S ratio. No patient demonstrated overt adrenal insufficiency. There were no significant differences between the two groups before or during therapy for any electrolytes, hormones or calculated serum osmolality. Conclusions: Rifampicin did not additionally impair adrenocortical function during the initial period of therapy.

Dynamic interactions of behavior-related traits and the physiological stress response bear upon the beef industry by impacting animal welfare, health, and productivity. The specific mechanisms of hypothalamic-pituitary-adrenal (HPA) axis dysfunction as related to cattle temperament remain unclear. To further characterize endophenotypes associated with the complex interaction of environment and genotype, the following experiments focused on stimulation and regulation of the pituitary gland in cattle of differing genetic background and temperament. Using serial blood sampling, via jugular cannula, the pituitary and subsequent adrenal response to exogenous vasopressin (VP) was characterized for steers of an excitable or calm temperament. Exit velocity (EV) measured at weaning was used to determine steer temperament. Endocrine parameters were measured for 6 h before and 6 h after the VP administration to quantify the stress response to both the handling associated with the experimental procedures and pharmacological challenge. Elevated concentrations of cortisol in excitable steers during the pre-challenge period reflected an increased initial adrenal reactivity to interactions with humans. Subsequent acclimation to the experimental surroundings yielded greater baseline cortisol concentrations in the cattle with an excitable temperament. Pituitary stimulation with VP resulted in a greater adrenocorticotropic hormone (ACTH) output from the excitable compared to the calm animals. A separate experiment employed the same 12-h blood sampling protocol with a different pituitary secretagogue, corticotrophin-releasing hormone (CRH), in order to evaluate pituitary-adrenal responsiveness in cattle with differing temperaments and genetic backgrounds. Measures of EV at weaning identified the calmest and most excitable steers from two separate calf crops; one Angus and the other Brahman. Within breed, adrenal medullary response to initial handling was influenced by temperament as concentrations of epinephrine and norepinephrine were higher in the excitable steers of both breedtypes. Additionally, concentrations of cortisol also differed by temperament in the Angus steers at this time point. An effect of temperament on pituitary responsiveness to exogenous CRH was observed in the Angus but not the Brahman steers. Unlike what was observed with the previously described VP challenge, the pituitary responsiveness to CRH was blunted in the excitable steers. The specific endophenotypes which have been identified or reinforced through these experiments suggest that there are aspects of HPA dysfunction associated with bovine temperament.

In the human adrenal cortex, adrenocorticotropin (ACTH) activates steroid hormone biosynthesis by acutely increasing cholesterol delivery to the mitochondria and chronically up-regulating the transcription of steroidogenic genes (including CYP17). Sphingolipids are a diverse family of phospholipids and glycolipids that mediate a wide variety of cellular processes, including apoptosis, proliferation, and survival. Sterol regulatory element binding proteins (SREBPs) are a family of transcription factors that regulate genes that are involved in cholesterol biosynthesis and fatty acid metabolism. In this study, we investigated the role of sphingolipids in ACTH-dependent steroidogenesis. H295R human adrenocortical cells were treated with ACTH or dibutyryl cAMP (Bt2cAMP) for various time periods and the content of several sphingolipid species was quantified by mass spectrometry. Both ACTH and Bt2cAMP decreased cellular amounts of sphingomyelin, ceramides, sphingosine (So) and sphingosine-1-phosphate (S1P). However, both ACTH and Bt2cAMP increased the activity of sphingosine kinase and the amounts of S1P released into the media. Both So and S1P increased CYP17 mRNA expression and increased cortisol biosynthesis. This increase in CYP17 transcription occurs by promoting SREBP binding to an SRE at -450/-436 basepairs upstream of the transcription initiation site. Furthermore, chromatin immunoprecipitation (ChIP) assays revealed that Bt2cAMP and S1P treatment results in an increase in acetylation of histone H3 and SREBP1 binding to CYP17 promoter. Additionally, transient transfection studies using wild type or mutated hCYP17 promoters and RNA interference (RNAi) assays confirmed the role of SREBP1 in mediating the stimulatory effect of S1P on CYP17 transcription. In summary, our studies demonstrate a link between sphingolipid metabolism and ACTH-dependent steroidogenesis which requires the activation of SREBP1 in human adrenal cortex.