Rise In Cortisol Concentrations Research Articles

The Cortisol Levels, Histology, and Fine Structure of Various Tissues of Fish Gambusia affinis (Baird and Girard, 1853) after Exposure to Lead.

Aquatic organisms demonstrate a high vulnerability to mortality when exposed to Pb, even at low concentrations. The objective of this investigation is to ascertain the histopathological alterations and cortisol concentrations in diverse tissues of Gambusia affinis, with a specific focus on the eggs and larvae, following exposure to varying concentrations of PbCl2. Adult specimens of G. affinis measuring 5-6 cm in length were obtained from a commercial fish breeding facility. A total of 8 fish with a 1 : 1 ratio of 4 pairs of broodstock were placed in an 8-liter aquarium. Following the adaptation phase, the broodstock underwent a spawning process that lasted for a duration of 7 days. Throughout the spawning process, assessments were conducted on the progression of the abdominal growth of the broodstock. Eggs ready to hatch and Gambusia larvae were taken and exposed to 0.1 mg/L PbCl2, 1 mg/L PbCl2, and control (without PbCl2) for 24 hours, with three replications. At the end of the experiment, histopathological analysis was conducted using the hematoxylin Ehrlich-eosin staining method and scanning electron microscopic (SEM) observation. The levels of Pb in gills were determined by employing atomic absorption spectrophotometer. The cortisol concentration in organ samples of fish was determined through the utilization of a cortisol ELISA Kit. The findings of this investigation demonstrated an important bioaccumulation occurrence of Pb within the gills of Gambusia fish that were specifically subjected to 0.1 and 1 mg/L PbCl2. The histological structures of eggs and larvae that were subjected to PbCl2 exhibited impairment in comparison to the control group. The present study observed a significant elevation in cortisol levels among fish specimens that were subjected to PbCl2 exposure. The findings of this investigation suggest that the occurrence of Pb is linked to a rise in cortisol concentrations in various organs of G. affinis larvae. Furthermore, the research indicates that the exposure to Pb has a notable impact on the histological alterations in the eggs and larvae of Gambusia fish, implying that they are undergoing stress as a result of the Pb exposure.

Hyperadrenocorticism in Dogs: Impact on Reproduction and Diagnostic Insights from Ultrasonography

Canine Cushing's syndrome, also known as hyperadrenocorticism (HAC), is one of the most prevalent endocrinopathies observed in dogs, characterized by elevated cortisol levels. The majority of cases are associated with pituitary tumors, leading to excessive production of corticotrophin (ACTH), thereby stimulating the adrenal glands to secrete cortisol. Clinical manifestations arise from the rise in cortisol concentration and encompass diabetes mellitus, polyuria, and polydipsia. Additionally, prolonged administration of glucocorticoids (iatrogenic) can also contribute to the development of Cushing's syndrome. The surplus cortisol resulting from this condition not only impacts the affected dog's health but also exerts adverse effects on various endocrine systems, leading to anestrus, infertility, premature labor, and high fetal mortality in canines. Therefore, a comprehensive understanding of these reproductive implications is essential to manage this syndrome effectively. The diagnosis of canine hyperadrenocorticism can be done by patient history, clinical signs, specific endocrine tests, and ultrasonography. Despite its significance, knowledge regarding the reproductive implications associated with Cushing's syndrome remains limited. Hence, this review aims to provide a thorough examination of the changes and challenges related to hyperadrenocorticism in canines, with a particular focus on its impact on the reproductive system. By shedding light on this aspect, the review intends to contribute valuable insights to the existing scientific literature and promote better management of this complex syndrome in dogs.

The cortisol awakening response and the late positive potentials evoked by unpleasant emotional pictures in healthy adults

The cortisol awakening response (CAR) refers to a sharp rise in cortisol concentrations within the 45 min following morning awakening. Alterations in CAR have been associated with various internalizing symptoms and brain function. The current study aimed to investigate the association between CAR and neural activity in response to unpleasant emotional pictures. A total of 46 healthy adults (22.55 years ± 1.69) collected saliva samples at 0, 30, and 45 min post-awakening on two days to assess the CAR. In the afternoon after CAR measurement on the first day, electroencephalograms were recorded when the participants completed a passive viewing task. The results showed that a greater CAR was associated with a decreased late positive potential difference score between unpleasant and neutral stimuli. This finding indicates that a larger CAR may be associated with decreased attentional engagement to unpleasant emotional information in healthy adults.

SUN-739 Next Generation AR Antagonists Increase Systemic Active Glucocorticoid Exposure by Altering Glucocorticoid Metabolism

Enzalutamide and apalutamide are potent next-generation androgen receptor (AR) antagonists used in metastatic and non-metastatic prostate cancer. Despite the increased survival benefits of these agents, resistance normally occurs and the disease transitions to its lethal form. We hypothesized that enzalutamide and apalutamide suppress 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2), which normally converts cortisol to cortisone, leading to elevated cortisol concentrations and increased ratio of active to inactive glucocorticoids. We measured cortisol and cortisol/cortisone ratio (substrate/product of 11β-HSD2) in serum using mass spectrometry before and 1 month on-treatment in 3 clinical trials: 1) neoadjuvant apalutamide + leuprolide (n=25) 2) enzalutamide +/- PROSTVAC for metastatic castration-resistant prostate cancer (n=54) and 3) enzalutamide +/- PROSTVAC for non-metastatic castration-sensitive prostate cancer (n=38 patients). Progression-free survival (PFS) was determined in the metastatic CRPC study of enzalutamide +/- PROSTVAC for those with glucocorticoid changes above and below the median. A statistically significant rise in cortisol concentration and cortisol/cortisone ratio with AR antagonist treatment occurred uniformly across all 3 clinical trials. For example, a rise in cortisol/cortisone ratio occurred in 23/25 (92%) patients (p < 0.001), 36/54 (67%) patients (p < 0.001), and 30/38 (79%) patients (p = 0.051), in the 3 respective trials. In the trial of enzalutamide +/- PROSTVAC for metastatic CRPC, high cortisol/cortisone ratio in the enzalutamide arm was associated with significantly improved PSA progression-free survival and radiographic progression-free survival. However, in the enzalutamide + PROSTVAC arm, the opposite trend was observed. In conclusion, treatment with enzalutamide or apalutamide increases systemic exposure to active glucocorticoids. These findings have potential consequences for immune suppression and the efficacy of treatment combinations using next-generation AR antagonists. On-treatment, glucocorticoid changes might serve as a pharmacodynamic biomarker.

The effect of deep AR suppression with enzalutamide or apalutamide on endogenous glucocorticoids: Implications for adverse effects and development of combination therapies.

17 Background: Metabolic consequences of potent AR suppression with enzalutamide and apalutamide are unresolved. Endocrine perturbations induced by potent AR antagonists may promote adverse effects and impinge on the potential efficacy of combination therapies, including for example, immunotherapies. We hypothesized that enzalutamide and apalutamide will block 11β-HSD2, the major enzyme that inactivates cortisol in peripheral tissues and results in increased systemic exposure to endogenous active glucocorticoids. We further hypothesized that AR is co-expressed with 11β-HSD2, suggesting a mechanism of suppression. Methods: Cortisol and cortisol/cortisone ratio (substrate/product of 11β-HSD2) were measured in serum using mass spectrometry before and on-treatment in 3 clinical trials: 1) neoadjuvant apalutamide + leuprolide 2) enzalutamide +/- PROSTVAC for metastatic castration-resistant prostate cancer 3) enzalutamide +/- PROSTVAC for non-metastatic castration-sensitive prostate cancer. AR and 11β-HSD2 expression were assessed in kidneys of 13 men and 9 women. Results: A rise in cortisol concentration and cortisol/cortisone ratio occurs uniformly across all 3 trials of potent AR antagonists. For example, a rise in cortisol/cortisone ratio occurred in 23/25 (92%) patients (p&lt;0.001), 30/38 (79%) patients (p=0.051), and 36/64 (67%) patients (p&lt;0.001), in the 3 respective trials. AR is only expressed alongside 11β-HSD2 in the kidneys of men but not women. Conclusions: Treatment with enzalutamide or apalutamide increases systemic exposure to active glucocorticoids. This effect is likely mediated by AR suppression of 11β-HSD2 in the kidney. These findings have potential consequences for immune suppression, the efficacy of treatment combinations using next-generation AR antagonists, and adverse effects of these drugs.

Deep androgen receptor suppression in prostate cancer exploits sexually dimorphic renal expression for systemic glucocorticoid exposure

Enzalutamide and apalutamide are potent next-generation androgen receptor (AR) antagonists used in metastatic and non-metastatic prostate cancer. Metabolic, hormonal and immunologic effects of deep AR suppression are unknown. We hypothesized that enzalutamide and apalutamide suppress 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2), which normally converts cortisol to cortisone, leading to elevated cortisol concentrations, increased ratio of active to inactive glucocorticoids and possibly suboptimal response to immunotherapy. On-treatment glucocorticoid changes might serve as an indicator of active glucocorticoid exposure and resultant adverse consequences. Human kidney tissues were stained for AR and 11β-HSD2 expression. Patients in three trials [neoadjuvant apalutamide plus leuprolide, enzalutamide ± PROSTVAC (recombinant poxvirus prostate-specific antigen vaccine) for metastatic castration-resistant prostate cancer (CRPC) and enzalutamide ± PROSTVAC for non-metastatic castration-sensitive prostate cancer] were analyzed for cortisol and its metabolites using liquid chromatography-mass spectrometry (LC-MS/MS). Progression-free survival was determined in the metastatic CRPC study of enzalutamide ± PROSTVAC for those with glucocorticoid changes above and below the median. Concurrent AR and 11β-HSD2 expression occurs only in the kidneys of men. A statistically significant rise in cortisol concentration, cortisol/cortisone ratio and tetrahydrocortisol/tetrahydrocortisone ratio with AR antagonist treatment occurred uniformly across all three trials. In the trial of enzalutamide ± PROSTVAC for metastatic CRPC, high cortisol/cortisone ratio in the enzalutamide arm was associated with significantly improved progression-free survival. However, in the enzalutamide+ PROSTVAC arm, the opposite trend was observed. Enzalutamide and apalutamide treatment toggles renal 11β-HSD2 and significantly increases indicators of and exposure to biologically active glucocorticoids, which is associated with clinical outcomes.

Tomorrow’s gonna suck: Today’s stress anticipation predicts tomorrow’s post-awakening cortisol increase

The cortisol awakening response (a rapid rise in cortisol concentration shortly after awakening) is hypothesized to prepare the organism to cope with upcoming demands, suggesting a key role for anticipatory stress in its regulation. Yet, no thorough test of this hypothesis incorporating temporal dynamics of the underlying processes has been conducted so far. To address this gap in the literature, the present study investigated the effects of anticipated stress for the next day (assessed in the evening) on an estimate of the cortisol awakening response (assessed in the following morning). In an ambulatory assessment paradigm, 42 participants (69% female; mean age = 22.8, range = 18–30 years) completed 5 consecutive days of assessments in their daily lives, collecting saliva samples at awakening and 30 min later. Using hierarchical linear modeling, associations with anticipatory stress were examined separately on the within- and between-person level. In line with our expectations, anticipatory stress predicted the post-awakening cortisol increase on the within-person level, implying an elevated cortisol rise on days for which more stress than usual had been anticipated. In contrast, on the between-person level higher average anticipatory stress did not predict an increased cortisol rise. Taken together, the findings confirm a key role of anticipatory stress in the regulation of the cortisol awakening response on the within-person level.

Glucocorticoid overexposure in neonatal life alters pancreatic beta-cell function in newborn foals1

Studies in humans and animals have linked abnormal programming of adult tissue function to excess glucocorticoids during perinatal development. The current study investigated the hypothesis that physiological variations in glucocorticoid concentrations during early neonatal life of the foal alter the secretory responses of the pancreatic β cells 2 and 12 wk after treatment. Spontaneously delivered foals received either saline or long-acting ACTH for 5 d from 1 d after birth to maintain an endogenous rise in cortisol concentrations. Starting at d 10, pancreatic β cell function was studied using an intravenous (i.v.) glucose tolerance test, an i.v. arginine challenge, and an i.v. tolbutamide challenge. The maximum increment in plasma insulin achieved in response to exogenous glucose was less in ACTH-treated foals at both 2 and 12 wk of age (P<0.05). By 12 wk of age, developmental changes also occurred in the magnitude and biphasic pattern of glucose-stimulated insulin release. The area under the insulin curve during the early phase of insulin secretion (0 to 30 min) was not different between the 2- and 12-wk-old animals but was significantly greater during the later phase (30 to 120 min) at 12 wk than at 2 wk (P<0.05). Arginine infusion induced a brief 5 to 15 min increase in plasma concentrations of insulin that was not different in saline- and ACTH-treated foals. The β-cell response to tolbutamide infusion was rapid and monophasic, and there was no difference (P>0.05) in the area under the insulin curve with treatment at 2 or at 12 wk. However, after tolbutamide, plasma insulin concentrations remained increased for a longer period in the ACTH-treated than in the saline-treated foals at 12 wk of age (P<0.05). Hence, this is the first study to show altered pancreatic β-cell function after ACTH-induced glucocorticoid overexposure during early postnatal life in foals.

Impact of citalopram on the HPA system. A study of the combined DEX/CRH test in 30 unipolar depressed patients

BackgroundDysregulation of the hypothalamic-pituitary-adrenocortical (HPA) system is one of the best replicated pathophysiological findings in depression. However, studies on the influence of treatment on the HPA system have partly yielded inconsistent results. ObjectiveTo assess the effects of citalopram monotherapy on the HPA system of mainly drug naïve patients with major depression by means of the combined DEX/CRH test. MethodsThe DEX/CRH test was conducted twice in 30 patients (25 drug naïve for the index episode) with major depression (single episode or unipolar recurrent; SCID I- and II-confirmed): directly before the start of a citalopram monotherapy (day 0) and four weeks thereafter (day 28). ResultsTwenty-three patients responded (≥50% reduction in the HDRS21-score), and 17 of them also reached criteria of remission (HDRS ≤ 7). Baseline (dexamethasone-suppressed) and CRH-stimulated ACTH concentrations significantly decreased from day 0 to day 28. CRH-stimulated cortisol concentrations also fell, although not significantly, but baseline cortisol concentrations exhibited a significant increase from day 0 to day 28. ConclusionsThe blunting of the ACTH response in the DEX/CRH test under citalopram is in line with what has been observed in most studies with antidepressants. However, the partial rise in cortisol concentrations indicates an increase in the sensitivity of the adrenal cortex to ACTH. State-dependent alterations in the volume and the ACTH responsiveness of the adrenal gland have repeatedly been reported in depressed subjects, which indicates the possibility that SSRIs such as citalopram might exhibit a direct or indirect effect on the adrenal cortex.

Loss of the pregnancy-induced rise in cortisol concentrations in the ewe impairs the fetal insulin-like growth factor axis

Maternal cortisol levels increase during pregnancy. Although this change is important for optimal fetal growth, the mechanisms of the changes in growth remain unclear. The hypothesis examined was that alterations in maternal plasma cortisol concentrations are associated with changes in the fetal insulin-like growth factor (IGF) axis. Pregnant ewes in late gestation (115 ± 0.4 days) were studied: six control animals, five ewes given 1 mg kg(-1) day(-1) cortisol (high cortisol) and five adrenalectomised ewes given 0.5-0.6 mg kg(-1) day(-1) cortisol (low cortisol). Blood samples were taken throughout the experiment and at necropsy (130 ± 0.2 days) and fetal liver was frozen for mRNA analysis. Fetal IGF-I and insulin plasma concentrations were lower and insulin-like growth factor-binding protein-1 (IGFBP-1) concentrations were higher in the low cortisol group compared with those in the control group (P < 0.05). Fetal liver IGF-II and IGFBP-3 mRNA were decreased in low cortisol animals compared with controls (P < 0.05). There were no significant changes in these parameters in the high cortisol group, and there were no changes in fetal liver IGF-I, growth hormone receptor, IGF-I receptor, IGF-II receptor, IGFBP-1 or IGFBP-2 mRNA levels between the groups. These data suggest that reduced fetal IGF availability contributes to reduced fetal growth when maternal cortisol secretion is impaired, but not during exposure to moderate increases in cortisol.

Sex differences in hypothalamic–pituitary–adrenal axis function in patients with chronic pain syndrome

Chronic pain is often equated with chronic stress yet the relationship between chronic pain and hypothalamic–pituitary–adrenal (HPA) axis activity is poorly understood. The objective of this study was to examine diurnal functioning of the HPA axis in patients with clinically defined non-inflammatory chronic pain syndrome (CPS) compared to controls. The sample consisted of 37 adults with CPS and 47 healthy controls. All participants provided saliva samples at awakening, 12:00, 18:00 and 21:00 h on two consecutive days, as well as completing self-report questionnaires relating to anxiety and depression. The CPS group had a significantly lower overall mean diurnal salivary cortisol concentration compared to the control group (p < 0.01) but no significant differences were found between the two groups for repeated cortisol sampling across the day. However, a three-way interaction of time of day by patient status by sex was found (p < 0.032), with lower cortisol concentration in male patients compared to female patients in the afternoon period. No significant group effect was found for the rate of decline in the circadian rise in cortisol concentration. These data demonstrate that CPS is associated with a degree of hypocortisolemia, particularly in male patients. The altered dynamics of cortisol secretion in CPS in relation to the onset and duration of pain in patients remains to be determined.

Plasma vasopressin and oxytocin concentrations increase simultaneously during suckling in goats

Goats are often kept on small farms where they suckle kids and are hand milked for human consumption. Our first objective was to investigate whether vasopressin secretion increases together with oxytocin during hand milking and suckling in seven goats 6-8 weeks after parturition. Four goats suckled and three were hand milked on the first day and the treatments were reversed on the next day. Blood samples were taken via a semi-permanent catheter. Plasma concentrations of vasopressin and oxytocin increased during suckling, but not during hand milking. Plasma cortisol concentration was elevated for 10 min after both treatments. These results initiated a second series in which the objectives were to measure vasopressin and oxytocin concentrations during hand milking in a larger number of goats and to investigate whether the rise in cortisol concentration was due to the experimental conditions or to milking, by adding a no-milking treatment. Nine goats in lactation weeks 4-10 were studied. Heart rate and arterial blood pressure were registered in eight of the goats. Oxytocin concentration did not change during hand milking and the vasopressin concentration was below the detection limit. Heart rate and blood pressure were elevated during milking and for about 10 min thereafter. Cortisol concentration increased after milking, as above. None of the variables changed in the no-milking treatment. This suggests that the rise in cortisol concentration was due to milk excretion and was not a stress reaction. In conclusion, suckling increased plasma concentrations of vasopressin and oxytocin, but hand milking did not. In a mixed system, presence of the kids may be necessary to stimulate release of the peptides and thereby contraction of the myoepithelial cells. However, milk stored in the udder cisterns can be obtained by hand milking without presence of oxytocin or vasopressin.

S-Citalopram in neuroendocrine challenge-tests: Serotonergic responsivity in healthy male and female human participants

The aim of the present study was to assess the usefulness of the selective serotonin-reuptake-inhibitor S-Citalopram as a serotonergic challenge probe in 24 healthy male and 24 healthy female participants. The participants received a single oral dose of 10 and 20mg of S-Citalopram in a placebo-controlled double blind crossover design. In female subjects phases of the menstrual cycle were controlled. Changes in concentrations of cortisol in saliva were used to indicate serotonergic reactivity. S-Citalopram induced a reliable dose dependent rise in cortisol concentrations. Results reveal a clear dose-response relationship in both sexes. However, in contrast to the 10mg condition the dosage of 20mg led to significantly higher cortisol levels in females, whereas no differences could be observed with respect to different phases of the menstrual cycle (follicular vs. luteal). Adverse side effects were reported only after 20mg. The results clearly indicate that the dosage of 10mg should be preferred when challenging males and females. Results will be discussed with regard to the further use of S-Citalopram in neuroendocrine challenge tests.

Gut Protein Uptake and Mechanisms of Meal-Induced Cortisol Release

The enhanced cortisol release after protein-rich meals might represent a neuroendocrine response to food allergens. We tested whether the antigenicity of proteins contributes to this effect. Twelve healthy men nasogastrically received casein, its less allergenic hydrolysate, and placebo. Contrary to expectations, secretion of cortisol (area under the curve, 742.70 +/- 73.48 vs. 542.95 +/- 70.31 micromol/liter.min, P < 0.03) and ACTH (2020.21 +/- 251.10 vs. 1649.82 +/- 241.23 micromol/liter.min, P < 0.05) was stronger on casein-hydrolysate than casein. Systemic immune activity remained unaffected as indicated by unchanged IL-6 plasma concentrations. This finding indicates that the grade of hydrolysis of a protein and the presence of particular amino acids, rather than its antigenicity, are crucial for the pituitary-adrenal response to nutrients. To further examine whether this response is triggered at the gastrointestinal mucosa or after the substance has reached the circulation, in a supplementary experiment, amino acids were given either nasogastrically or iv to healthy men (n = 4). Only the nasogastric infusion of amino acids induced a significant rise in cortisol concentrations. Serum concentrations of tryptophan, which is known to directly excite the hypothalamo-pituitary-adrenal axis, were comparable for both conditions. We conclude that the meal-related hypothalamo-pituitary-adrenal axis response to amino acids results from a signal that rather acts at the gastrointestinal mucosa than directly via the circulating blood.

Effects of periconceptional undernutrition on the initiation of parturition in sheep.

In sheep, parturition is initiated by increased fetal hypothalamic-pituitary-adrenal axis (HPAA) activity leading to PGE(2) and PGF(2alpha) production and a rise in the 17beta-estradiol-progesterone (E(2)/P(4)) ratio. Uteroplacental PG production can also increase fetal HPAA activity. Periconceptional maternal undernutrition accelerates fetal HPAA maturation resulting in preterm labor. We determined whether preterm labor was preceded by an increase in PG concentrations and E(2)/P(4) ratio and whether these increases preceded or followed the corresponding rise in cortisol concentrations. Singleton-bearing ewes were nourished ad libitum (N, n = 9) or undernourished (UN, n = 10) to reduce maternal weight by 15% from -61 days (d) to +30 d after mating with ad libitum intake thereafter. Paired maternal and fetal blood samples were collected from 126 d until delivery. Half the UN group delivered prematurely (>2 SD below mean gestation for the flock). PG and cortisol concentrations and E(2)/P(4) ratio increased before delivery in the same way in both groups. However, the increases occurred 7-10 d earlier in UN than in N animals. In both UN and N fetuses cortisol concentrations rose before fetal and maternal PG concentrations and maternal E(2)/P(4) ratio. Periconceptional maternal undernutrition induces preterm delivery in sheep by advancing the expected prepartum rise in cortisol and PG concentrations and E(2)/P(4) ratio. The rise in fetal cortisol concentration precedes the rise in fetal and maternal PG concentrations and maternal E(2)/P(4) ratio, suggesting that the underlying mechanism is likely to be acceleration of fetal HPAA maturation, resulting in initiation of the normal process of parturition.

Serum cortisol and 17-hydroxyprogesterone interrelation in classic 21-hydroxylase deficiency: is current replacement therapy satisfactory?

One of the main aims in the management of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency is to achieve adequate suppression of the adrenal cortex with the smallest possible dose of glucocorticoid substitution. To evaluate the administration schedule of current replacement therapy regimens, we investigated the cortisol-17-hydroxyprogesterone interrelation in 36 patients (13 males and 23 females; median age, 12.3 yr; range, 6.1-18.8 yr) with salt-wasting congenital adrenal hyperplasia. As sufficient variation in 17-hydroxyprogesterone concentrations was required to allow analysis of the cortisol-17-hydroxyprogesterone interrelation, patients were divided into 2 groups depending on the adequacy of hypothalamic-pituitary-adrenal axis suppression. The first group consisted of 17 patients with suppressed 17-hydroxyprogesterone concentrations (group 1), and the second group consisted of 19 patients with nonsuppressed 17-hydroxyprogesterone concentrations (group 2). We determined serum cortisol and 17-hydroxyprogesterone concentrations at 20-min intervals for a total of 24 h while patients were receiving their usual replacement treatment with hydrocortisone and 9alpha-fludrocortisone. We also determined the lowest dose of dexamethasone required to suppress the 0800 h serum ACTH concentrations when administered as a single dose (0.3 or 0.5 mg/m(2)) the night before. Mean 24-h cortisol and 17-hydroxyprogesterone concentrations were 3.9 microg/dl (SD = 2.1) and 66.2 ng/dl (SD = 92.7), respectively, in group 1 and 4.1 microg/dl (SD = 2.5) and 4865.7 ng/dl (SD = 6951) in group 2. The 24-h 17-hydroxyprogesterone concentrations demonstrated circadian variation, with peak values observed between 0400-0900 h. In group 2, 17-hydroxyprogesterone concentrations decreased gradually in response to the rise in cortisol concentrations during the day, but remained low during the night despite the almost undetectable cortisol concentrations between 1600-2000 h. Mean 0800 h androstenedione concentrations correlated strongly with integrated 17-hydroxyprogesterone concentrations (r = 0.81; P < 0.0001), but not with integrated cortisol concentrations. There was a significant negative correlation between cortisol and 17-hydroxyprogesterone at lag time 0 min (r = -0.187; P < 0.0001), peaking at lag time 60 min (r = -0.302; P < 0.0001), with cortisol leading 17-hydroxyprogesterone by these time intervals. Finally, 0800 h serum ACTH concentrations were sufficiently suppressed after a dexamethasone dose of 0.3 mg/m(2) in all but three patients. These findings indicate that in classic 21-hydroxylase deficiency, hydrocortisone should be administered during the period of increased hypothalamic-pituitary-adrenal axis activity, between 0400-1600 h, with the biggest dose given in the morning. Blood investigations performed as part of monitoring of congenital adrenal hyperplasia patients should include androstenedione and 17-hydroxyprogesterone concentrations determined in the morning before the administration of hydrocortisone. It should also be emphasized that blood investigations are only complementary to the overall assessment of these patients, which is primarily based on the evaluation of growth and pubertal progress.

Cortisol in fetal fluids and the fetal adrenal at parturition in the tammar wallaby (Macropus eugenii).

Glucocorticoid hormones may play a critical role in initiating parturition in tammar wallabies. In this study, we investigated the concentration of cortisol in fetal fluids and cortisol production by fetal adrenals over the last 3 days of the 26-day pregnancy and within 24 h postpartum. The fetal adrenals almost doubled in size between Days 24 and 26 of pregnancy, and their cortisol content increased over 10-fold during this period, from 10 pg to over 100 pg per adrenal pair. After birth, neonatal adrenals continued to grow, but cortisol content fell dramatically to 20 pg. The prepartum increase in adrenal cortisol was reflected by a substantial rise in cortisol concentrations in yolk sac fluid, allantoic fluid, and fetal blood, which were below 10 ng/ml on Day 24 and rose to over 40 ng/ml by Day 26. Cortisol concentrations in neonatal blood decreased postpartum, mirroring decreased cortisol content in neonatal adrenals. Cortisol production by the fetal adrenal was stimulated in vitro by ACTH and prostaglandin E2, suggesting that the in vivo increase may be stimulated by release of ACTH from the fetal hypothalamic-pituitary axis and prostaglandin E2 from the placenta. These results indicate that increasing cortisol production by the fetal adrenal is a characteristic of late pregnancy in the tammar wallaby and support the suggestion that fetal cortisol may trigger the initiation of parturition in this marsupial species.

Changes in plasma cortisol concentrations in bitches in response to different combinations of halothane and butorphanol, with or without ovariohysterectomy

Changes in plasma cortisol concentrations were assessed in bitches in response to nine treatments: control, anaesthesia, analgesia, analgesia followed by anaesthesia, anaesthesia followed by analgesia at intubation, anaesthesia followed by analgesia at extubation, anaesthesia plus surgery, analgesia followed by anaesthesia plus surgery, and anaesthesia plus surgery followed by analgesia. The anaesthetic was halothane, the analgesic was butorphanol (0·4 mg kg −1) and the surgery was ovariohysterectomy. Blood samples, for plasma cortisol assays, were taken regularly from before treatment for five hours and then again after 24 hours. A small transient rise in plasma cortisol concentration in the control group was attributed to mild distress associated with novel experiences. A more pronounced and protracted rise in cortisol concentration in the analgesia group was ascribed to a dysphoric state of bitches under the influence of the agonist-antagonist butorphanol. Halothane anaesthesia alone resulted in no change in plasma cortisol concentration. When butorphanol was given after anaesthesia was induced or while the animal was still under the influence of anaesthesia (immediately after tracheal extubation), there was no immediate rise in plasma cortisol concentration and low concentrations were maintained for up to 60 minutes after halothane withdrawal. A marked rise in plasma cortisol concentration, which was sustained above pretreatment values for at least five hours, occurred in all surgery groups. Giving intravenous butorphanol 30 minutes prior to surgery had no effect on the surgically-induced rise in plasma cortisol concentration and no effect on the postsurgical plasma cortisol concentration. In contrast, butorphanol given at extubation did reduce plasma cortisol concentrations during the postsurgical period. These observations did not support the hypothesis that preoperative use of butorphanol would reduce the cortisol response after surgery under halothane anaesthesia.

Angiotensin II infusion in vivo does not modulate cortisol secretion in the late-gestation ovine fetus.

Maturation of the fetal adrenal gland is critical for the onset of ovine parturition. It has long been proposed that the fetal adrenal gland may be under inhibitory influences during late gestation. In vitro evidence has suggested that angiotensin II may be such an inhibitory factor and may help to prevent a premature increase in cortisol concentrations. The aim of this study was to test the effect of angiotensin II infusion in vivo on basal cortisol concentrations and fetal adrenal responsiveness to an ACTH-(1-24) challenge. Fetuses received a continuous infusion of either angiotensin II (100 ng . min-1 . kg-1; n = 7) or saline (2 ml/h; n = 4), which commenced at 140 days of gestation (GA) and continued for a total of 50 h. Adrenal responsiveness to the administration of ACTH-(1-24) (5 microg/kg) was determined during angiotensin II or saline infusions at both 2 and 48 h after infusion onset. Angiotensin II had no significant effect on adrenal responsiveness after acute (2 h) or chronic (48 h) infusion. There was no effect of saline or angiotensin II infusion on basal immunoreactive ACTH or cortisol concentrations after 2 h, but there was a significant increase in basal cortisol concentrations in both treatment groups by 48 h, probably reflecting the normal rise in cortisol concentrations at this GA. Mean arterial blood pressure was significantly increased in angiotensin II-infused fetuses only. This study has therefore found no evidence to suggest that angiotensin II infusion in vivo modulates fetal basal cortisol concentrations or adrenal responsiveness in the last week of gestation, in contrast with previous in vitro studies. These results throw into question the proposed role of angiotensin II as a negative modulator of adrenal function in the ovine fetus.

Effects of morning rise in cortisol concentration on regulation of lipolysis in subcutaneous adipose tissue.

Cortisol has a well-defined circadian rhythm. The aim of the study was to examine the effect of the morning rise in cortisol concentration on lipolysis in adipose tissue. Ten healthy subjects were studied on two occasions, and six of these were studied on three occasions. During the first two occasions, either a control or cortisol suppression study was performed by using metyrapone, and on the third occasion exogenous cortisol replacement was given in addition to metyrapone. Lipolysis in the subcutaneous adipose tissue of the anterior abdominal wall was studied by measurement of arteriovenous differences. Reduction in the early morning rise in cortisol led to significantly decreased venoarterialized differences for nonesterified fatty acids (P < 0.05) and glycerol (P < 0.01), attributable in part to decreased hormone-sensitive lipase (EC 3.1.1.3) action (P < 0.05) in adipose tissue. At the same time the arterialized plasma triacylglycerol concentration increased (P < 0.005) with a significant reduction in the adipose lipoprotein lipase (EC 3.1.1.34) rate of action (P < 0.05). In the replacement study, values were identical to those of the control study, showing that metyrapone had no nonspecific effects on lipolysis. We conclude that the morning rise in plasma cortisol concentration plays an important role in the regulation of lipolysis in adipose tissue in normal healthy adults.