Axis Cortisol Research Articles

Dysregulation of the Autonomic Nervous System Can Be a Link between Visceral Adiposity and Insulin Resistance

To evaluate the interplay among abdominal adipose tissue distribution, the cortisol axis, the autonomic nervous system, and insulin resistance. Two age-, sex-, and BMI-matched groups were studied. Fifteen subjects were first-degree relatives of patients with type 2 diabetes (R), and 15 had no family history of diabetes (controls, C). A hyperinsulinemic euglycemic clamp, cortisol measurements, and analysis of heart rate variability (HRV) were performed. Computed tomography was performed in a subgroup (n = 9 + 9) to determine abdominal adipose tissue distribution. R tended to be less insulin-sensitive than C (M value 9.2 +/- 1.0 vs 10.3 +/- 0.7 mg/kg per minute, not significant). Stimulation with tetracosactin or corticotropin releasing hormone yielded lower peak serum cortisol levels in R (p = 0.03 and p = 0.06, respectively). The amount of visceral abdominal fat (VAT) tended to be greater in R. In all subjects, VAT was negatively correlated to insulin sensitivity (r = -0.93, p < 0.001). There was a positive association between VAT and resting heart rate (r = 0.70, p = 0.003) and sympathetic/parasympathetic ratio in HRV assessment after tilt (r = 0.53, p = 0.03). Subcutaneous abdominal tissue was not associated with insulin sensitivity or any of the hormonal or HRV assessments. Subjects genetically predisposed for type 2 diabetes had a tendency toward a larger amount of VAT and to lower insulin sensitivity compared with control subjects. The amount of visceral fat was strongly associated with insulin resistance and signs of a high ratio of sympathetic vs. parasympathetic reactivity. A large amount of visceral fat may act in concert with sympathetic/parasympathetic imbalance to promote the development of insulin resistance, and this may be partly independent of genetic background.

Early stroke: a dynamic process.

In the acutely infarcted brain, cytokines are released into cerebrospinal fluid and blood. Interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, among others, may play a role in the acute increases in plasma adrenocorticotropic hormone, cortisol, epinephrine, norepinephrine, and vasopressin.1–6 Increases in cytokines and hormones may in turn induce changes in other variables. When recorded on admission in acute stroke patients, many variables have been found to be associated with poor outcome in acute stroke. Body temperature7 is one such variable, blood glucose another,8–18 and C-reactive protein (CRP)19–22 and white blood cell count (WBC)20,23 serum cortisol and ferritin24 are further examples. Elevated plasma and cerebrospinal fluid levels of glutamate, glycine,25 ferritin,26 and IL-627 were also associated with deteriorating stroke. It seems plausible that these variables generally are unaffected at stroke onset and then increase in the early hours after onset, depending on the severity of the stroke. We found this to be the case with temperature,28 which in a large series of patients was normal when measured within 2 hours of stroke onset, but which rose at 4 to 6 hours after stroke onset in patients with severe neurological deficits. At 8 to 10 hours after stroke onset, elevated temperature was associated with poor outcome. This association arose several hours after onset of severe stroke. Thus, the initial severity of the stroke …

Higher basal cortisol predicts verbal memory loss in postmenopausal women: Rancho Bernardo Study.

In animals, higher endogenous or exogenous corticosteroids cause neuronal dysfunction, damage, and loss, especially in the hippocampus. In humans, high cortisol levels have been linked to memory impairment. To prospectively examine the relation between morning basal cortisol level and change in cognitive performance during an average follow-up of 2 years. Longitudinal cohort. Geographic community in southern California. Between 1984 and 1987, blood for basal morning cortisol was obtained along with pertinent medical, behavioral, and physical covariates from 749 post-menopausal women, mean age 72 years, who were not taking corticosteroids or postmenopausal hormones. Cognitive function was assessed in 502 women in the period from 1988 to 1991 and repeated in 136 women in the period from 1991 to 1993. In both age- and multiply adjusted linear regression models, higher baseline cortisol was a significant predictor of worsened category fluency. No other cognitive domain tested was related to cortisol. These results support the hypothesis that subtle dysregulation of cortisol axis is related to memory loss. Interventions that block this pathway may provide new therapeutic options to prevent cognitive decline.

Impaired Glucose Tolerance and Elevated Blood Pressure in Low Birth Weight, Nonobese, Young South African Adults: Early Programming of Cortisol Axis

Impaired Glucose Tolerance and Elevated Blood Pressure in Low Birth Weight, Nonobese, Young South African Adults: Early Programming of Cortisol Axis

Impact of Age on Cortisol Secretory Dynamics Basally and as Driven by Nutrient-Withdrawal Stress*

The present study tests the clinical hypothesis that aging impairs homeostatic adaptations of cortisol secretion to stress. To this end, we implemented a short-term 3.5-day fast as an ethically acceptable metabolic stressor in eight young (ages 18-35 yr) and eight older (ages 60-72 yr) healthy men. Volunteers were studied in randomly ordered fed vs. fasting sessions. To capture the more complex dynamics of cortisol's feedback control, blood was sampled every 10 min for 24 h for later RIA of serum cortisol concentrations and quantitation of the pulsatile, entropic, and 24-h rhythmic modes of cortisol release using deconvolution analysis, the approximate entropy statistic, and cosine regression, respectively. The stress of fasting elevated the mean (24-h) serum cortisol concentration equivalently in the two age cohorts [i.e. from 7.2 +/- 0.35 to 11.6 +/- 0.71 microg/dL in young men and from 7.7 +/- 0.39 to 12.6 +/- 0.59 microg/dL in older individuals (P < 10(-7))]. The rise in integrated cortisol output was driven mechanistically by selective augmentation of cortisol secretory burst mass (P = 0.002). The resultant daily (pulsatile) cortisol secretion rate increased significantly but equally in young (from 94 +/- 6.3 to 151 +/- 15 microg/dL x day) and older (from 85 +/- 5.4 to 145 +/- 7.3 microg/dL x day) volunteers (P < 10(-4)). Nutrient restriction also prompted a marked reduction in the quantifiable regularity of (univariate) cortisol release patterns in both cohorts (P < 10(-4)). However, older men showed loss of joint synchrony of cortisol and LH secretion even in the fed state, which failed to change with metabolic stress (P < 10(-6)). In addition, older individuals maintained a premature (early-day) cortisol elevation in the fed state and unexpectedly evolved an anomalous further cortisol phase advance of 99 +/- 16 min during fasting (P < 10(-5)). Caloric deprivation in aging men also disproportionately elevated the mesor of 24-h rhythmic cortisol release (P = 10(-7)) and elicited a greater increment in the mean day-night variation in cortisol secretory-burst mass (P < 0.01 vs. young controls). Lastly, short-term caloric depletion in older subjects paradoxically normalized their age-associated suppression of the 24-h rhythm in cortisol interburst intervals. In summary, acute metabolic stress in healthy aging men (compared with young individuals) unmasks distinct, albeit complex, disruption of cortisol homeostasis. These dynamic anomalies impact the feedback-dependent and time-sensitive coupling of pulsatile and 24-h rhythmic cortisol secretion. Nutrient-withdrawal stress in the older male heightens the cortisol phase disparity already evident in fed elderly individuals. Conversely, the stress of fasting in young men paradoxically reproduces selected features of the aging unstressed (fed) cortisol axis; viz., abrogation of joint cortisol-LH synchrony and suppression of the normal diurnal variation in cortisol burst frequency. Whether fasting would unveil analogous disruption of feedback-dependent control of the corticotropic axis in healthy aging women is not yet known.

Cortisol axis abnormalities early after stroke--relationships to cytokines and leptin.

To assess the relationships between circulating levels of proinflammatory cytokines and adrenocortical hormones and leptin early after stroke. Blood samples were collected four times daily the first two days after stroke, twice daily the next 4 days and four times at day 7. Cognitive function and functional outcome was measured at admittance and at day 7. Consecutive inclusion of patients admitted to the stroke unit at Umeâ University Hospital. Eight men and 4 women with acute stroke and 10 healthy volunteers. Levels and diurnal variations of plasma proinflammatory cytokines interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha), serum adrenocortical hormones (cortisol and DHEA) and leptin, and MMSE, SSS, and ADL scores. A significant correlation was present between IL-6 and cortisol levels the first two days after stroke (P < 0.05). In patients with a disturbed diurnal rhythm of cortisol, cortisol and leptin levels were increased (68% and 81% increase, respectively), whilst DHEA levels were unaltered. Half of the patients displayed an abnormal diurnal rhythmicity of leptin at the end of the week. Median TNF-alpha levels for the first two days after stroke also correlated to median leptin levels at the end of the week (P < 0.05). Median IL-6 levels correlated to severity of paresis on days 1 and 7 and to MMSE scores on day 7 (P < 0.05). Neuroendocrine disturbances are common and often profound early after stroke. Cytokines seem to be important modulators of these disturbances, including diurnal rhythmicity of cortisol and leptin.

Adrenal steroid dysregulation in dystrophia myotonica.

To evaluate circulating adrenal steroid hormones, cortisol diurnal rhythm and the negative feedback function of the cortisol axis in patients with dystrophia myotonica (DyM), a disease where metabolic disturbances, peripheral insulin insensitivity and cognitive dysfunction are common features. Morning serum levels of dehydroepiandrosterone sulphate, androstenedione, 17 alpha-hydroxy progesterone and cortisol; morning serum levels of testosterone and insulin; diurnal rhythm of saliva cortisol; and an overnight dexamethasone suppression test, together with a cognitive screening test in men with DyM and in controls. Outpatient clinic in co-operation with Umeå University Hospital. Fifteen men with DyM and 13 age-matched controls. Adrenal steroid hormone levels, diurnal rhythm of saliva cortisol, dexamethasone suppression test and Mini Mental State Examination scores. Morning serum levels of dehydroepiandrosterone sulphate, androstenedione and 17 alpha-hydroxy progesterone were significantly decreased in DyM after inclusion of age and body mass index in multiple regression analyses (48, 26 and 32% decreases, respectively). An abnormal diurnal rhythm of saliva cortisol was present in all patients, mean saliva cortisol levels being significantly increased (33%) in DyM patients. Dexamethasone suppressibility did not differ between groups. DyM patients scored significantly lower on the Mini Mental State Examination (P < 0.001). These results indicate an abnormal adrenal steroid hormone secretion in DyM, which may contribute to peripheral insulin sensitivity as well as cognitive impairment in these patients.

Repeat administration of the GH secretagogue MK-0677 increases and maintains elevated IGF-I levels in beagles.

We have reported that MK-0677 is a novel, orally active GH secretagogue that stimulates an immediate and long-lasting increase in serum GH levels in dogs. Significant elevations in IGF-I levels were associated with the increased GH secretion. Cortisol secretion was also increased following MK-0677 administration. In the current study, we determined the effect of repeat oral administration of MK-0677 on GH, IGF-I and cortisol levels; we also investigated if the GH and cortisol responses to MK-0677 are influenced by circulating IGF-I concentrations. Following the initial oral administration of MK-0677, GH secretion (area under the time-response curve (AUC) ng/ml per h) was increased 7.9- to 9.8-fold (1.0 mg/kg), 5.6-fold (0.5 mg/kg) or 3.9-fold (0.25 mg/kg). With repeat MK-0677 administration, the GH response was decreased by 41-77%; GH concentrations remained significantly above control in the 0.5 mg/kg and 1.0 mg/kg groups. Individual beagle GH profiles indicated that the increased GH concentration was associated with an amplified GH pulsatile profile. Serum IGF-I levels were significantly increased over control levels at all dosage levels by 480 min on the first day of MK-0677 administration. With repeated administration, IGF-I levels were increased up to 126% and remained elevated through 14 days, the longest treatment period evaluated. While daily MK-0677 administration appeared to increase IGF-I levels over 24 h, as evidenced by significant increases in the pretreatment IGF-I levels on days 4-14, no such increase was noted with alternate day MK-0677 administration; thus the dosage regimen modulated circulating IGF-I levels. MK-0677 stimulated increases in cortisol secretion (AUC microgram/dl per h) on the first day of treatment. A decreased cortisol response was observed following repeated daily treatment with MK-0677; in contrast, with alternate day treatment, no decrease in cortisol response to MK-0677 occurred. A marked increase in circulating IGF-I concentrations following administration of exogenous GH resulted in a significant decrease in both the GH and cortisol response to MK-0677 compared with control animals. Our findings suggested, therefore, that circulating IGF-I concentrations regulate GH and cortisol response to MK-0677. In summary, chronic oral administration of MK-0677 was associated with significant increases in GH and IGF-I levels that were maintained for the duration of the treatment. The GH profile following MK-0677 administration consisted of episodic increases above control. Compared with day 1, repeated daily treatment with MK-0677 resulted in an attenuated GH response that was associated with an increase in circulating IGF-I levels. The cortisol response was similarly reduced during chronic MK-0677 treatment, suggesting that IGF-I mediated negative feedback on both the GH and cortisol axes. The fact that similar attenuation of the GH and cortisol responses to MK-0677 on day 1 was observed if IGF-I levels were increased by treating animals with exogenous GH suggested that the attenuated response to MK-0677 that occurred during chronic treatment was mediated by increases in IGF-I rather than desensitization to MK-0677. Thus, a regulatory feedback loop apparently prevents hyperstimulation of the GH axis by MK-0677. We conclude that MK-0677 offers the potential of an orally active GH secretagogue that can maintain elevated IGF-I levels when administered chronically.

Different linkage of depression to hypercortisolism early versus late after stroke. A 3-year longitudinal study.

Using the dexamethasone suppression test, we studied the suppressibility of the cortisol axis and its clinical determinants at various time points after stroke. A major aim was to examine the dexamethasone test as a diagnostic tool for the diagnosis of major depression in stroke patients. The dexamethasone suppression test, major depression, functional ability, and disorientation were assessed in a cohort of 70 patients with acute stroke and after 3 months (n = 63) and 3 years (n = 43). Early after stroke, 24% of the patients were nonsuppressors, with about the same proportion at 3 months (22%) and 3 years (21%). None of the controls (17 healthy elderly volunteers) were nonsuppressors. High cortisol levels early after stroke were significantly associated with functional impairment (r = 0.35; p = 0.003) and disorientation (r = 0.27; p = 0.03). Three years after stroke, high postdexamethasone cortisol levels were significantly associated with major depression (r = 0.57; p < 0.001). The sensitivity of the dexamethasone test was 70% and the specificity 97%. In a longitudinal analysis of the long-term survivors (n = 42), postdexamethasone cortisol values at 3 months predicted major depression at 3 years. Hypercortisolism is associated with major depression late (3 years) but not early (0-3 months) after stroke. Patients with hypercortisolism 3 months after stroke are at risk of major depression later in the course and warrant careful follow-up from a psychiatric viewpoint.

Abnormalities at different levels of the hypothalamic-pituitary-adrenocortical axis early after stroke.

Hypercortisolism is common in stroke patients. The aim of this study was to investigate possible disturbances at different sites within the hypothalamic-pituitary-adrenal axis. We also studied possible associations between hypercortisolism and clinical manifestations of brain dysfunction. Patients with an acute ischemic stroke (n = 16; mean +/- SD age, 71 +/- 11 years) were compared with healthy elderly subjects (n = 9). We performed a short adrenocorticotropic hormone (ACTH) test with 0.25 mg 1-24 ACTH injected intravenously and an overnight dexamethasone suppression test with 1 mg dexamethasone given orally at 11 PM. Serum cortisol levels after dexamethasone at 8 AM were significantly higher in stroke patients (p = 0.003). The area under the curve for the cortisol response to ACTH was elevated in seven (47%) of stroke patients, and the centered cumulative cortisol response was elevated in three (20%) patients. The area under the curve response correlated significantly to the presence of an acute confusional state and male sex in stroke patients (rs = 0.63 and rs = 0.62, respectively; p < 0.05), whereas the centered cumulative cortisol response diminished with increasing age (rs = -0.62; p < 0.05). Postdexamethasone cortisol levels were significantly correlated to the presence of an acute confusional state and to extensive limb paresis (rs = 0.66 and rs = 0.62, respectively; p < 0.05). There are abnormalities in the cortisol axis both at the central level and at the adrenal level early after stroke. Hypercortisolism is closely associated with cognitive disturbances and extensive motor impairment.

Urinary free Cortisol excretion shortly after ischaemic stroke

The cortisol axis and catecholamine excretion were studied in 20 patients within the first week after acute ischaemic stroke. Urine free cortisol and plasma cortisol levels after dexamethasone were significantly higher in stroke patients than in 80-year-old volunteers (n = 32; P = 0.03 and P = 0.003, respectively). Catecholamine excretion was found to be significantly correlated with urine cortisol concentration (r = 0.54, P less than 0.05) and limb paresis (r = 0.52, P less than 0.05). In a multiple regression analysis, urine cortisol values were shown to be positively associated with limb paresis (P = 0.003), disorientation (P = 0.03) and body temperature (P = 0.03). High cortisol excretion was associated with a poorer functional outcome in a discriminant analysis (P = 0.001). Thus acute ischaemic stroke is associated with an increased activity in the cortisol axis. This may have a number of negative effects on organ functioning, and is a predictor of a poorer functional outcome.