Peripheral Cortisol Concentrations Research Articles

Peripheral cortisol concentration during adrenal vein sampling for primary aldosteronism

Peripheral cortisol concentration during adrenal vein sampling for primary aldosteronism

Peripheral cortisol administration blunts reward arousal but heightens anxiety-like arousal in marmosets

AimsExcess hypothalamic-pituitary-adrenal (HPA) axis activation is common in people with major depression and generalised anxiety disorder. We sought to determine whether higher circulating levels of the glucocorticoid cortisol are causally related to the expression of anhedonia-like and anxiety-like behaviours in marmosets.MethodFour marmosets (two male, two female) took part in the study. Cortisol and saline control injections were administered intramuscularly and salivary cortisol samples were taken before and after injections to determine if circulating cortisol levels changed from pre- to post-injection. To measure anhedonia-like behaviours, we trained marmosets on an appetitive Pavlovian conditioning paradigm, where animals learn to associate two anticipatory auditory cues (conditioned stimulus + or conditioned sitmulus -, CS+ or CS-) with the presence or absence of food reward (unconditioned stimulus + or unconditioned stimulus -, US+ or US-). Using cardiovascular telemetry probes and video cameras, we recorded animals' cardiovascular and behavioural arousal in freely moving conditions, comparing the injection of saline control versus 5mg/kg, 10mg/kg or 20mg/kg intramuscular cortisol. To measure anxiety-like behaviours, we used a human intruder (HI) paradigm, where marmosets are confronted with an unfamiliar human in their home cage. We recorded their behaviour on video cameras after saline control or 20mg/kg intramuscular cortisol. We used an exploratory-factor analysis (EFA) to determine how marmosets' behaviours towards the intruder loaded onto an 'anxiety-like' score. We then compared these scores under saline control versus cortisol conditions. Significance was set at p < 0.05.ResultUnlike saline control, we found that subcutaneous injections of 20 mg/kg cortisol successfully elevated peripheral cortisol concentrations to levels equivalent to peak circadian concentrations (p = 0.023). In the appetitive setting, 5 mg/kg, 10 mg/kg and 20 mg/kg cortisol injections blunted anticipatory (CS+ induced) increases in behavioural arousal (p = 0.004) but did not alter anticipatory cardiovascular arousal. Consummatory behavioural and cardiovascular arousal also remained intact. In the HI test, 20 mg/kg cortisol injections moderately increased anxiety towards the intruder as measured by an increase in marmosets' EFA-derived anxiety-like scores (p = 0.035).ConclusionIn marmosets, elevated peripheral cortisol levels are causally related to the behavioural features of blunted reward anticipation together with elevated anxiety-like behaviours characteristic of mood and anxiety disorders. Future work will characterise the neuroimaging changes induced by elevated peripheral cortisol levels and identify the regions of the prefrontal cortex contributing to HPA axis regulation and dysregulation.

Intraprocedural Cortisol Levels in the Evaluation of Proper Catheter Placement in Adrenal Venous Sampling

Purpose Adrenal venous sampling (AVS) is limited by technical failures that result from incorrect catheter placement or failure to catheterize the right adrenal vein. The existence of an inadequate sample may not be recognized at the time of the procedure, which can lead to nondiagnostic results. Rapid assay of serum cortisol levels allows for intraprocedural evaluation of the ratio of adrenal and peripheral cortisol concentrations and confirmation of adequate sampling. Materials and Methods Retrospective review was performed of 64 AVS procedures, 36 performed with digital subtraction venography (DSV) guidance alone and 28 performed with DSV guidance plus intraprocedural quantitative determinations of plasma cortisol levels. Results Technical success was achieved in 26 of 28 procedures (93%) that included intraprocedural cortisol measurements in addition to DSV. Analysis of cortisol ratios (adrenal vein cortisol level divided by inferior vena cava cortisol level) revealed technical success in 29 of 36 procedures (81%) that used DSV alone ( P = .16). Procedure note indication of successful/unsuccessful sampling coincided with cortisol ratios in 28 of 28 cases (100%) that included cortisol measurement and 29 of 36 cases (81%) that did not ( P = .01).The feedback provided by the measurement of cortisol levels allowed the operator to salvage three of five inadequate AVS procedures (60%), increasing the overall technical success rate from 82% to 93%. Conclusions Intraprocedural measurement of cortisol with rapid results allows for prediction of successful adrenal vein catheterization, which may increase the technical success rate of AVS.

The contribution of omental adipose tissue to adipokine concentrations in patients with the metabolic syndrome

To examine differences in peripheral vascular endothelial growth factor (VEGF), interleukin-6 (IL6) and cortisol concentrations between patients with both visceral obesity and metabolic syndrome, and lean controls. In a subsample of metabolic patients underwent abdominal surgery, the adipokine concentrations were measured in venous blood from the omentum to determine information on some processes of synthesis. Forty-two healthy lean controls and 46 overweight-obese patients with central adiposity and stigmata of metabolic syndrome were studied. In a subsample of 11 metabolic patients undergoing non-bariatric surgery, blood samples from omental and peripheral veins were taken intraoperatively to determine VEGF, IL6 and cortisol concentrations. Median levels (range) of peripheral VEGF and IL6 were higher in patients than in controls [31.5 (3-112) pg/mL vs 21.35 (9-41.9) pg/mL (P < 0.05) and 5.50 (1.40-13) pg/mL vs 1.15 (0.3-1) pg/mL (P < 0.0001)]. On the other hand, concentrations of VEGF and IL6 from the omental and peripheral veins were similar in the surgery sub-group. Peripheral cortisol concentrations were not higher in patients than in controls, nor were omental concentrations different from the peripheral. Omental and peripheral VEGF and cortisol values were correlated, whereas no association was found between omental and peripheral IL6. In the presence of abdominal obesity, VEGF and IL6 concentrations are increased in the systemic circulation. The contribution of visceral adipose tissue to circulating levels of VEGF and IL6 was modest.

Lower birth weight and attenuated adrenocortical response to ACTH in offspring from sows that orally received cortisol during gestation

Prenatal stress is known to affect several offspring characteristics, but its effects depend among other factors on the period of gestation in which it is applied. In the present study, oral administration of hydrocortisone-acetate (HCA) was used to elevate cortisol concentrations in pregnant sows to levels also observed after psychological stress. HCA was administered during three different periods of gestation (115 days in pigs): period 1: 21–50 (P1, n = 10), period 2: 51–80 (P2, n = 10) and period 3: 81–110 (P3, n = 10) days after insemination. Control sows ( n = 11) received vehicle from 21–110 days after insemination. When P1-, P2- and P3-sows did not receive HCA, they also received vehicle. During gestation, weekly saliva samples were taken from the sows to determine salivary cortisol concentrations. Treatment effects on sow, litter and piglet characteristics were determined. In addition, two female piglets per litter were subjected to an ACTH-challenge test at 6 weeks of age to determine the adrenocortical response to ACTH. Pigs were slaughtered at 6 months of age and slaughter weight, back fat thickness and percentage of lean meat were analysed. During the period of treatment with HCA, salivary cortisol concentrations were increased in P1-, P2- and P3-sows compared to control sows ( P < 0.01). The total number of piglets born per litter did not differ among treatment groups ( P > 0.30), but pooled HCA-litters had a higher percentage of live born piglets ( P < 0.05) and fewer mummies than control litters ( P < 0.05). Gestation length did not differ among treatment groups ( P = 0.21), but did affect treatment effects on birth weight. Overall, HCA-piglets weighed less at birth, and remained lighter until weaning ( P < 0.05). The salivary cortisol concentrations after i.m. injection of ACTH (2.5 IU/kg) were lower in P1- and P3-piglets compared to control piglets. At slaughter, HCA-treatment indirectly decreased lean meat percentage and increased back fat thickness. In conclusion, elevated peripheral cortisol concentrations in pregnant sows affect both litter characteristics and piglet physiology, the latter depending on the period of gestation during which concentrations were elevated. Underlying mechanisms require further investigation.

Enhanced glucocorticoid sensitivity of cytokine release from circulating leukocytes stimulated with lipopolysaccharide in healthy male smokers

Smoking is a strong cardiovascular risk factor that promotes inflammation. The source of elevated pro-inflammatory cytokines in the circulation of smokers is not fully understood. We investigated the release of pro-inflammatory cytokines from circulating leukocytes stimulated with lipopolysaccharide (LPS) and its inhibition by glucocorticoids in smokers and non-smokers. Ninety-three middle-aged apparently healthy men were categorized as smokers (>10 cigarettes/day; n=41) or life-long non-smokers ( n=52). Peripheral cortisol was assessed from overnight urine. C-reactive protein (CRP) and tumor necrosis factor (TNF)-α were measured in plasma. LPS-stimulated interleukin (IL)-6 and TNF-α release from harvested circulating leukocytes were assessed using an in vitro whole blood assay with and without co-incubation of increasing concentrations of either dexamethasone or hydrocortisone. Glucocorticoid sensitivity was defined as the concentration of glucocorticoids required that inhibits LPS-stimulated cytokine release by 50%. Smokers had higher CRP levels ( p=.005) and a trend for higher basal TNF-α levels ( p<.07), and they also showed lower IL-6 and TNF-α release after LPS-stimulation than non-smokers ( p’s < .001). While peripheral cortisol concentration showed no significant group difference, inhibition of LPS-stimulated leukocyte IL-6 and TNF-α release by either glucocorticoid was enhanced in smokers as compared to non-smokers ( p’s < .022). The finding suggests that, in spite of a low-grade systemic inflammation, smokers have decreased LPS-stimulated cytokine release from circulating leukocytes and greater glucocorticoid sensitivity of this cytokine release than non-smokers. Circulating leukocytes unlikely contribute to the elevated pro-inflammatory cytokine levels in the blood of smokers.

Experimental Inoculations with Ostertagia ostertagi or Exposure to Artificial Illumination Alter Peripheral Cortisol in Dairy Calves ( Bos taurus)

A series of experiments were conducted on dairy calves ( Bos taurus) to assess, by way of circulating cortisol, the impact of a parasitic infection as a systemic stressor. The first study was designed to assess the effects of chronic stress on dairy calves resulting from a large bolus inoculation of the nematode parasite, Ostertagia ostertagi. Peripheral cortisol concentrations and adrenal cortical competency to adrenocorticotropic hormone (ACTH) challenge were utilized as indicators of chronic stress for 5 weeks. Calves were cleared of nematodes by anthelminthic treatment after the third week of infection. Calves were challenged with ACTH on weeks 0 and 2, and blood samples were obtained at a 12 × 10-min bleeding schedule. Cortisol concentrations were significantly higher ( P < 0.05) in the infected calves than in the uninfected calves. The maximal response level to the ACTH challenge was also higher while the calves were infected. Two additional experiments were conducted to investigate the effects of experimental procedures that became evident during Experiment 1. Firstly, calves that had previously been fitted with jugular cannulae were sampled from 3 hr predawn until 5 hr after dawn under red- or white-light incandescent illumination. Calves under red lights had lower initial cortisol concentrations but increased to the concentrations in calves under white lights, indicating a compounding effect of lighting with the procedures of blood-sample acquisition. Secondly, 12 calves were inoculated with 10,000, 100,000, or 200,000 third-stage, infective larvae of O. ostertagi. Blood samples were obtained similarly to the regimen in Experiment 1. Cortisol concentrations were elevated only in the 200,000-dose group during week 3, correlating with the period immediately after emergence of the young adult parasites from the gastric glands. Continuous emergence of these parasites might induce chronic hyperadrenocorticism and the concomitant negative consequences on metabolic and immunological processes.

Circadian and Ultradian Rhythms of Peripheral Cortisol Concentrations in Lactating Dairy Cows

To investigate possible circadian and ultradian periodicities for plasma cortisol in lactating dairy cows, integrated 15-min blood samples taken sequentially over 48h from six cows were analyzed by radioimmunoassay. The cows were housed in an environmental chamber at about 19°C, 50% relative humidity, and 16h of light and 8h of darkness (lights on at 0700h); fed daily at 0900h; and milked at 0830 and 2000h. Peripheral concentrations of cortisol for all six cows exhibited weak circadian rhythms—average minima were 3.1ng/ml at 1800h, maxima were 4.5ng/ml at 0530h—and strong ultradian rhythms with periods around 120min. Peak to trough amplitudes of ultradian rhythms, 1 to 17ng/ml, varied among and within cows over time. No direct relation between ultradian peaks and milking or feeding was apparent. Spectral analysis indicated that most power (variation) was centered around 1 cycle every 2h, i.e., around a period of 120min. This very strong, easily observable, ultradian rhythm indicates that an oscillation with a period around 120min is probably intrinsic to mechanisms regulating peripheral glucocorticoid concentrations.

Effects of pretreatment with adrenocorticotropin on endocrine and behavioral responses of bulls to sexual activity

Peripheral concentrations of cortisol, growth hormone and testosterone were determined in two experiments which examined the endocrine and behavioral responses of sexually mature Angus bulls to an estrous female (Experiment 1) and to female exposure 5 hours following an adrenocorticotropin (ACTH) injection (Experiment 2). Sexual activity of bulls in Experiment 1 significantly increased levels of cortisol when compared with concentrations before exposure to a female. Administration of ACTH in Experiment 2 consistently elevated levels of cortisol by 30-fold (P<0.01) when compared with pre-ACTH concentrations. This heightened level of cortisol persisted throughout the period of exposure to an estrous cow, although a gradual decline in cortisol concentrations occurred over time (P<0.05). In Experiment 1, growth hormone profiles tended to increase in response to sexual activity (P<0.10), whereas in Experiment 2, growth hormone increased in response to ACTH administration (P<0.01) and to female exposure (P<0.01). Concentrations of testosterone were unaffected (P>0.10) by mating activity in Experiment 1. In Experiment 2, acute suppression (P<0.01) in testosterone concentrations 5 hours after ACTH administration coincided with the exposure period to the estrous female. Frequencies of mounting behavious (penis extension, mounting, intromission and ejaculation) exhibited by ACTH-treated bulls were significantly lower compared with the frequencies two days earlier. Exogenous ACTH administration suppressed reproductive behaviors of bulls and altered secretion of cortisol, growth hormone and testosterone. Furthermore, these data provide evidence that specific mating behaviors of the bull can be influenced by circulating steroids.

Cortisol, growth hormone, and testosterone concentrations during mating behavior in the bull and boar.

Two experiments were conducted to evaluate peripheral concentrations of cortisol (C), growth hormone (GH), and testosterone (T) in bulls and boars during mating and to correlate mating behaviors with endocrine secretion in the presence of an estrous female. In Exp. 1, six sexually inexperienced mature bulls were bled every 15 min for 2 h before and 2 h after a 30-min exposure to a single, restrained, estrous cow; sampling occurred every 5 min during exposure. In Exp. 2, six sexually experienced boars were bled similarly before and after exposure to a sow and every 5 min during a 15-min exposure to a freely moving, estrous sow. Behavioral events recorded during exposure to a female included the following: flehmen responses (bulls only), mounts, penis extensions, intromissions, ejaculations, and time to first mount and first ejaculation. Of the six bulls, four completed at least one service (intromission + ejaculation), and three of six mounted the estrous cow eight or more times. Completion of one or more services resulted in significant elevations in serum C and GH concentrations, but not T concentrations, during the exposure period. Bulls mounting eight or more times also experienced significant elevations in C concentrations during exposure. Three of six boars completed at least one service. Servicing and mounting the sow fewer than five times were both associated with significant elevations in serum C concentrations. Serum concentrations of T were also elevated as a result of exposure to an estrous sow. Collectively, these data support the suggestion that specific events during natural mating activity can alter endocrine secretions of C and GH in bulls and C and T in boars.

Increased urinary excretion of free 20 alpha- and 20 beta-dihydrocortisol in a hypercortisolemic but hypocortisoluric patient with Cushing's disease.

We identified non-metabolized, non-conjugated 20 alpha- and 20 beta-dihydrocortisol (20 alpha- and 20 beta-DHF) in urine from a patient with Cushing's disease, by use of three different liquid-chromatographic systems and by gas chromatography-mass spectrometry. We document that these 20-isomers of dihydrocortisol may strongly contribute to unspecific interferences with the immunological assessment of urinary free cortisol (F). The urinary excretion rates of 20 alpha- and 20 beta-DHF were quantified radioimmunologically with use of a cross-reacting cortisol antiserum after effective purification by liquid chromatography. The patient with Cushing's disease had mean peripheral cortisol concentrations of 1018 nmol/L. The urinary excretion rates (nmol/24 h) were 1455 for 20 alpha-DHF, 330 for 20 beta-DHF, and 18 for F. The corresponding reference values (median in nmol/24 h) were 174 for 20 alpha-DHF, 111 for 20 beta-DHF, and 68 for F (n = 22). We conclude that (a) specific estimation of urinary free F is not as highly sensitive for diagnosis of chronic hypercortisolemic states as is generally assumed; and (b) measurement of urinary free 20 alpha- and 20 beta-DHF or of the corresponding 20-DHF:F ratios may be more sensitive.

Quantitative relations of fetal and maternal pitiutary-adrenal systems.

Even though certain aspects of the fetal pituitary-adrenal system have been extensively studied, much remains to be learned of its basic development and function. In the present work, the effect of maternal hypophysectomy upon quantitative pituitary-adrenal relations in mother and fetus was investigated in pregnant beagle dogs. At 57 days gestation in each of seven normal animals and seven animals 3 wk posthypophysectomy, a cannula for collection of adrenal effluent was placed in a single fetus in utero under halothane anesthesia. A timed fetal adrenal sample was obtained; ACTH (10 mU) was injected into the fetus; 3 min thereafter a second fetal adrenal sample was collected and fetal and maternal peripheral arterial samples were drawn. All fetuses and their adrenal glands were weighed. Concentrations of cortisol and corticosterone were determined by a modification of the double-isotope dilution derivative method of Kliman and Peterson. Mean peripheral cortisol concentrations in mother and fetus were 92 and 94 ng/ml, respectively (ratio 1.0), in normal pregnancies and 11 and 54 ng/ml, respectively (ratio 0.2), in maternal hypophysectomy pregnancies. Weights of fetal adrenal gland pairs of 32 and 44 mg, respectively, in normal and hypophysectomy pregnancies indicate increased fetal ACTH secretion in response to lowered circulating cortisol in the fetus secondary to maternal hypophysectomy. These data demonstrate the presence of an active pituitary-adrenal feedback mechanism in the dog fetus which is partly influenced by maternal pituitary-adrenal function. The shift in the maternal-fetal ratio of peripheral cortisol concentrations from 1.0 to 0.2 occasioned by maternal hypophysectomy neither supports nor rules out the presence of specific placental mechanisms affecting relative concentrations of cortisol in mother and fetus. It does suggest, however, that the relative steroid input into maternal and fetal compartments is one of the factors which influences such concentration ratios. Concentrations of cortisol were significantly higher in fetal adrenal effluent (pre-ACTH) than in fetal peripheral plasma in normal pregnancies, which demonstrates secretion of cortisol by the fetus and shows that corticosteroid of maternal origin does not lead to complete suppression of fetal pituitary-adrenal function. Cortisol secretion rates in response to exogenous ACTH were essentially the same in fetuses in normal and hypophysectomy pregnancies (132 and 128 ng/min, respectively). Thus, fetal adrenal responsiveness to ACTH, i.e., maximum secretory capacity, is not enhanced by increased ACTH stimulation sufficient to induce adrenal hypertrophy in the same fetuses.