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BACKGROUND/OBJECTIVE: Extreme hypercortisolemia in an otherwise healthy patient can be due to familial dysalbuminemia, generalized glucocorticoid resistance, and estrogen-containing medications. I report a woman who appeared to have an exaggerated increase in the serum cortisol level following oral contraceptive treatment. CASE REPORT: A 50-year-old woman presented with extreme morning hypercortisolemia-cortisol levels of 61 and 55 mcg/dL (4 and 3 months before presentation, respectively; normal range, 8-25 mcg/dL)-found during workup of mildly increased white cell counts. The morning cortisol level had been 10 mcg/dL after administration of 1-mg dexamethasone. The 24-hour urine free cortisol level had been normal and only slightly increased after correction by creatinine. The patient was anxious about the extremely high cortisol levels but otherwise felt well. She took norgestimate-ethinyl estradiol contraceptive (0.18/0.215/0.25 mg - 35 mcg). Physical examination showed a well-appearing, lean female. The thyroid-stimulating hormone, total thyroxine, free thyroxine, total triiodothyronine, free triiodothyronine, androstenedione, dehydroepiandrosterone sulfate, aldosterone, and renin levels were normal. Morning total cortisol and cortisol-binding globulin (CBG) were tested before and after she held the oral contraceptive for 2 months. The total cortisol and CBG levels decreased from 50 to 26 mcg/dL and from 6.4 to 3.8 mg/dL (normal range, 1.7-3.1 mg/dL), respectively. DISCUSSION: Increases in the serum cortisol-binding proteins are a well-recognized cause for increases in the serum cortisol levels. CONCLUSION: This case suggests that modern oral contraceptives with low to moderate estrogen activity can cause extreme increases in the serum cortisol levels due to marked increases in the CBG levels.

Background/Objective: Extreme hypercortisolemia in an otherwise healthy patient can be due to familial dysalbuminemia, generalized glucocorticoid resistance, and estrogen-containing medications. I report a woman who appeared to have an exaggerated increase in the serum cortisol level following oral contraceptive treatment. Case Report: A 50-year-old woman presented with extreme morning hypercortisolemia—cortisol levels of 61 and 55 mcg/dL (4 and 3 months before presentation, respectively; normal range, 8-25 mcg/dL)—found during workup of mildly increased white cell counts. The morning cortisol level had been 10 mcg/dL after administration of 1-mg dexamethasone. The 24-hour urine free cortisol level had been normal and only slightly increased after correction by creatinine. The patient was anxious about the extremely high cortisol levels but otherwise felt well. She took norgestimate-ethinyl estradiol contraceptive (0.18/0.215/0.25 mg - 35 mcg). Physical examination showed a well-appearing, lean female. The thyroid-stimulating hormone, total thyroxine, free thyroxine, total triiodothyronine, free triiodothyronine, androstenedione, dehydroepiandrosterone sulfate, aldosterone, and renin levels were normal. Morning total cortisol and cortisol-binding globulin (CBG) were tested before and after she held the oral contraceptive for 2 months. The total cortisol and CBG levels decreased from 50 to 26 mcg/dL and from 6.4 to 3.8 mg/dL (normal range, 1.7-3.1 mg/dL), respectively. Discussion: Increases in the serum cortisol-binding proteins are a well-recognized cause for increases in the serum cortisol levels. Conclusion: This case suggests that modern oral contraceptives with low to moderate estrogen activity can cause extreme increases in the serum cortisol levels due to marked increases in the CBG levels.

Intensive care unit (ICU) admissions in the United States exceed 5.7 million annually, often leading to complications such as post-intensive care syndrome and high mortality rates. Among these challenges, critical illness-related corticosteroid insufficiency (CIRCI) requires emphasis due to its complex, multiple-cause pathophysiology and varied presentations. CIRCI, characterized by adrenal insufficiency during critical illness, presents in up to 30% of ICU patients and may manifest as an exaggerated inflammatory response. Factors such as dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, altered cortisol metabolism, tissue corticosteroid resistance, and drug-induced suppression contribute to CIRCI. Diagnosis is a complex process, relying on a comprehensive assessment including clinical presentation, laboratory findings, and dynamic stimulatory testing. Treatment involves intensive medical care and exacting glucocorticoid therapy. Recent guidelines advocate for individualized approaches tailored to patient presentation and etiology. Understanding the pathophysiology and treatment of CIRCI is vital for clinicians managing critically ill patients and striving to improve outcomes. This research paper aims to explore the latest developments in the pathophysiology and management of CIRCI.

Intensive care unit (ICU) admissions in the United States exceed 5.7 million annually, often leading to complications such as post-intensive care syndrome and high mortality rates. Among these challenges, critical illness-related corticosteroid insufficiency (CIRCI) requires emphasis due to its complex, multiple-cause pathophysiology and varied presentations. CIRCI, characterized by adrenal insufficiency during critical illness, presents in up to 30% of ICU patients and may manifest as an exaggerated inflammatory response. Factors such as dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, altered cortisol metabolism, tissue corticosteroid resistance, and drug-induced suppression contribute to CIRCI. Diagnosis is a complex process, relying on a comprehensive assessment including clinical presentation, laboratory findings, and dynamic stimulatory testing. Treatment involves intensive medical care and exacting glucocorticoid therapy. Recent guidelines advocate for individualized approaches tailored to patient presentation and etiology. Understanding the pathophysiology and treatment of CIRCI is vital for clinicians managing critically ill patients and striving to improve outcomes. This research paper aims to explore the latest developments in the pathophysiology and management of CIRCI. [ABSTRACT FROM AUTHOR]

Introduction: Adrenocortical carcinoma (ACC) is a rare malignancy of the adrenal cortex. Whilst surgery is the preferred treatment, adjunctive therapy with mitotane may be offered post-surgically to minimise the risk of recurrence or, in the absence of surgery, to attenuate progression. Aim: The objective was to evaluate the effects of mitotane treatment on serum protein concentrations in patients treated for ACC with mitotane therapy and compare this to patients with other adrenal neoplasms and a normal pregnant cohort. Methods: Serum cortisol, thyroid function tests, adrenocorticotrophic hormone (ACTH), cortisol-binding globulin (CBG), thyroxine-binding globulin (TBG), gonadotrophins and androgens were measured on plasma and serum samples. Thirty-five patients with ACC were included, and mitotane levels were noted to be sub-/supra-therapeutic. Data were tested for normality, reported as mean ± s.d., and compared to other two cohorts using paired-sample t-test with a 5% P-value for significance and a 95% CI. Results: Patients on mitotane therapy had a higher mean serum CBG concentration compared to the adrenal neoplasm group (sub-therapeutic: 79.5 (95% CI: 33.6, 125.4 nmol/L), therapeutic: 85.3 (95% CI: 37.1–133.6 nmol/L), supra-therapeutic: 75.7 (95% CI: −19.3, 170.6 nmol/L) and adrenal neoplasm: 25.5 (95% CI: 17.5, 33.5 nmol/L). Negative correlations between serum cortisol and CBG concentration were demonstrated within the supra-therapeutic plasma mitotane and adrenal neoplasm groups. Conclusion: Patients with ACC and therapeutic plasma mitotane concentrations had higher serum CBG concentrations compared to those with adrenal neoplasms or pregnant women, and higher serum cortisol. Whilst there was no direct correlation with cortisol and mitotane level, the negative correlation of cortisol with CBG may suggest that the direct effect of mitotane in increasing cortisol may also reflect that mitotane has a direct adrenolytic effect.

Background: Gluconeogenesis is stimulated by low blood glucose to maintain the glucose level; it involves lipolysis (breaking down of triglycerides), release of cortisol, and production of glycerol which can be converted into glucose. Hypoglycemia is associated with Plasmodium infection in children. Glucose homeostasis also involves glycogenolysis. This work was designed to determine the possible evidence of gluconeogenesis in Plasmodium-infected children in relationship with the parasite density to provide the information for useful direction in the management of Plasmodium infection in children. Methods: Thirty-five (2–5 years; female – 14, male – 11) Plasmodium-infected children were recruited as test patients, while fifty (n = 50; female – 25, male – 23) age-matched children (Plasmodium-noninfected children) were recruited from the same environment as controls. Plasma cortisol and cortisol-binding globulin were measured by the ELISA; total bile acid, glycerol by spectrophotometry, glucose, and total triglycerides were measured using Cobas C111, while Plasmodium identification and density were carried out by Leishman's thin blood film technique. Results: The results obtained showed a significant increase in plasma cortisol, cortisol-binding globulin, total bile acid, and glycerol with increase in parasite density and in children with the parasite densities of 512 ± 4.0 and 1014 ± 6.0 than the control children (P < 0.05). There was also a significant decrease in plasma glucose and total triglycerides with decrease in parasite density and in children with the parasite densities of 512 ± 4.0 and 1014 ± 6.0 than the control children (P < 0.05). Conclusion: There was evidence of gluconeogenesis in Plasmodium-infected children in relationship with the parasite density, as the results showed increase in cortisol, cortisol-binding globulin, total bile acid, and glycerol and a decrease in plasma glucose and total triglycerides.

Purpose: Beta-thalassemia major is a severe, congenital hematological disorder and, if untreated, leads to early mortality. Progress in therapeutical strategies improved clinical outcomes and life expectancy; however, increased survival led to the development of new disorders, including endocrinopathies. Little is known on the possible impairment of adrenocortical function, a potentially life-threatening condition, in long-term thalassaemic survivors. We therefore decided to assess adrenal reserve and the value of salivary cortisol during ACTH stimulation in the diagnosis of adrenocortical insufficiency in adult patients with β-thalassemia major.Methods: Cross-sectional study including 72 adults with β-thalassemia major. Patients were tested with 1 µg ACTH for serum and salivary cortisol.Results: Subnormal serum cortisol responses to ACTH stimulation (i.e., <500 nmol/l) were registered in 15 out of 72 patients. Salivary cortisol increased in parallel with serum cortisol and a clear-cut positive correlation was detected at each timepoint. Moreover, peak salivary cortisol values after ACTH stimulation were significantly lower in patients with impaired adrenal reserve (513.6 ± 52.33 vs. 914.1 ± 44.04 nmol/l p < 0.0001).Conclusions: Our results attest to the need for testing for adrenal insufficiency among adult thalassaemic patients, as up to 20% presented impaired adrenal reserve. Salivary and serum cortisol levels during stimulation with ACTH were closely correlated and the use of salivary cortisol sampling during ACTH testing may represent a surrogate to serum cortisol in these patients. [ABSTRACT FROM AUTHOR]

Background Cortisol levels rise with the physiological stress of surgery. Previous studies have used older, less-specific assays, have not differentiated by severity or only studied procedures of a defined type. The aim of this study was to examine this phenomenon in surgeries of varying severity using a widely used cortisol immunoassay. Methods Euadrenal patients undergoing elective surgery were enrolled prospectively. Serum samples were taken at 8 am on surgical day, induction and 1 hour, 2 hour, 4 hour and 8 hour after. Subsequent samples were taken daily at 8 am until postoperative day 5 or hospital discharge. Total cortisol was measured using an Abbott Architect immunoassay, and cortisol-binding globulin ( CBG) using a radioimmunoassay. Surgical severity was classified by POSSUM operative severity score. Results Ninety-three patients underwent surgery: Major/Major+ (n = 37), Moderate (n = 33) and Minor (n = 23). Peak cortisol positively correlated to severity: Major/Major+ median 680 [range 375-1452], Moderate 581 [270-1009] and Minor 574 [272-1066] nmol/L (Kruskal-Wallis test, P = .0031). CBG fell by 23%; the magnitude of the drop positively correlated to severity. Conclusions The range in baseline and peak cortisol response to surgery is wide, and peak cortisol levels are lower than previously appreciated. Improvements in surgery, anaesthetic techniques and cortisol assays might explain our observed lower peak cortisols. The criteria for the dynamic testing of cortisol response may need to be reduced to take account of these factors. Our data also support a lower-dose, stratified approach to dosing of steroid replacement in hypoadrenal patients, to minimize the deleterious effects of over-replacement. [ABSTRACT FROM AUTHOR]

Objectives To investigate the agreement between the calculated free cortisol levels according to widely applied Coolens and adjusted Södergård equations with measured levels in the critically ill. Design and methods A prospective study in a mixed intensive care unit. We consecutively included 103 patients with treatment-insensitive hypotension in whom an adrenocorticotropic hormone (ACTH) test (250 μg) was performed. Serum total and free cortisol (equilibrium dialysis), corticosteroid-binding globulin and albumin were assessed. Free cortisol was estimated by the Coolens method (C) and two adjusted Södergård (S1 and S2) equations. Bland Altman plots were made. Results The bias for absolute (t = 0, 30 and 60 min after ACTH injection) cortisol levels was 38, − 24, 41 nmol/L when the C, S1 and S2 equations were used, with 95% limits of agreement between − 65–142, − 182–135, and − 57–139 nmol/L and percentage errors of 66, 85, and 64%, respectively. Bias for delta (peak-baseline) cortisol was 14, − 31 and 16 nmol/L, with 95% limits of agreement between − 80–108, − 157–95, and − 74–105 nmol/L, and percentage errors of 107, 114, and 100% for C, S1 and S2 equations, respectively. Conclusions Calculated free cortisol levels have too high bias and imprecision to allow for acceptable use in the critically ill. [ABSTRACT FROM AUTHOR]

Objectives: To characterize the dynamics of the pituitary-adrenal interaction during the course of coronary artery bypass grafting both on and off pump. Since our data pointed to a major change in adrenal responsiveness to adrenocorticotropic hormone, we used a reverse translation approach to investigate the molecular mechanisms underlying this change in a rat model of critical illness. Design: Clinical studies: Prospective observational study. Animal studies: Controlled experimental study. Setting: Clinical studies: Cardiac surgery operating rooms and critical care units. Animal studies: University research laboratory. Subjects: Clinical studies: Twenty, male patients. Animal studies: Adult, male Sprague-Dawley rats. Interventions: Clinical studies: Coronary artery bypass graft-both on and off pump. Animal studies: Injection of either lipopolysaccharide or saline (controls) via a jugular vein cannula. Measurements and Main Results: Clinical studies: Blood samples were taken for 24 hours from placement of the first venous access. Cortisol and adrenocorticotropic hormone were measured every 10 and 60 minutes, respectively, and corticosteroid-binding globulin 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 adrenocorticotropic hormone and cortisol to supranormal values at around the end of surgery. Adrenocorticotropic hormone levels then returned toward preoperative values. Ultradian pulsatility of both adrenocorticotropic hormone and cortisol was maintained throughout the perioperative period in all individuals. The sensitivity of the adrenal gland to adrenocorticotropic hormone increased markedly at around 8 hours after surgery maintaining very high levels of cortisol in the face of "basal" levels of adrenocorticotropic hormone. This sensitivity began to return toward preoperative values at the end of the 24-hour sampling period. Animal studies: Adult, male Sprague-Dawley rats were given either lipopolysaccharide or sterile saline via a jugular vein cannula. Hourly blood samples were subsequently collected for adrenocorticotropic hormone and corticosterone measurement. Rats were killed 6 hours after the injection, and the adrenal glands were collected for measurement of steroidogenic acute regulatory protein, steroidogenic factor 1, and dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 messenger RNAs and protein using real-time quantitative polymerase chain reaction and Western immunoblotting, respectively. Adrenal levels of the adrenocorticotropic hormone receptor (melanocortin type 2 receptor) messenger RNA and its accessory protein (melanocortin type 2 receptor accessory protein) were also measured by real-time quantitative polymerase chain reaction. In response to lipopolysaccharide, rats showed a pattern of adrenocorticotropic hormone and corticosterone that was similar to patients undergoing coronary artery bypass grafting. We were also able to demonstrate increased intra-adrenal corticosterone levels and an increase in steroidogenic acute regulatory protein, steroidogenic factor 1, and melanocortin type 2 receptor accessory protein messenger RNAs and steroidogenic acute regulatory protein, and a reduction in dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 and melanocortin type 2 receptor messenger RNAs, 6 hours after lipopolysaccharide injection. Conclusions: Severe inflammatory stimuli activate the hypothalamic- pituitary-adrenal axis resulting in increased steroidogenic activity in the adrenal cortex and an elevation of cortisol levels in the blood. Following coronary artery bypass grafting, there is a massive increase in both adrenocorticotropic hormone and cortisol secretion. Despite a subsequent fall of adrenocorticotropic hormone to basal levels, cortisol remains elevated and coordinated adrenocorticotropic hormone-cortisol pulsatility is maintained. This suggested that there is an increase in adrenal sensitivity to adrenocorticotropic hormone, which we confirmed in our animal model of immune activation of the hypothalamic-pituitary- adrenal 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 hypothalamicpituitary- adrenal responses to major surgery will provide us with a more rational approach to glucocorticoid therapy in critically ill patients. [ABSTRACT FROM AUTHOR]

In this study we examined the relationship between cortisol and inflammatory status in early lactating dairy cows after a stimulation test of the adrenal cortex. Twenty-four cows were grouped into quartiles (6 cows per each quartile) in accordance with the liver activity index (based on plasma concentration of negative acute phase proteins in early lactation); the quartiles were lower (LO; cows with the lowest liver functionality), intermediate lower, intermediate upper, and upper (UP; cows with the highest liver functionality). Each cow was injected i.v. with 20 µg of a synthetic analog of ACTH at 35 d in milk (DIM). Blood samples were taken to assess inflammatory status, and at 0, 30, and 60 min after ACTH challenge to measure total cortisol. The free cortisol fraction was analyzed in the LO and UP quartiles and the bound cortisol fraction was estimated as the difference between total and free cortisol. The LO, in comparison with the other quartiles, suffered a more severe inflammatory status, with the highest values of haptoglobin, reactive oxygen metabolites, and total nitric oxide metabolites and the lowest concentration of direct or indirect markers of negative acute phase proteins. The cows in the LO quartile had the highest values of plasma nonesterified fatty acids and β-hydroxybutyrate at 7 DIM, suggesting a more severe body lipid mobilization. The LO quartile cows showed the highest frequency of health problems and the lowest milk yield in the first 35 DIM. Thirty minutes after the ACTH treatment, the concentration of total cortisol was lower in LO in comparison to other groups. Similarly, the bound cortisol fraction was lower in LO versus UP. The adrenal response appeared inversely related with health status after calving (e.g., lower in LO cows, experiencing the most severe inflammatory status). The lower increase in cortisol after the ACTH challenge in cows with greater inflammation (LO quartile) seems a consequence of the lower availability of cortisol-binding globulin synthetized by the liver, but other mechanisms can be involved (e.g., rate of cortisol production, secretion, and metabolic clearance). Our data provide evidence that inflammation and metabolic changes reduce the concentration of circulating plasma cortisol during an acute stress. Hence, the acute phase response in dairy cows should be taken into account to interpret the results obtained from stimulation tests of the adrenal cortex. [ABSTRACT FROM AUTHOR]

The gene (Cbg) encoding cortisol-binding globulin (CBG) has been proposed as a candidate gene to explain genetic variation in cortisol secretion and carcass composition in pigs. The objective of this study was to evaluate the association between CBG and pork quality in 5 European breeding lines, Piétrain, Large White (LW), and Landrace purebred lines, a Duroc synthetic line, and a Meishan (MS) × LW advanced intercros s. Cortisol-binding globulin maximum binding capacity (CBG-Bmax) was twice as high (P < 0.05) in MS × LW pigs compared with the other lines. There was no (P ≥ 0.364) association between CBG-Bmax and carcass quality traits in Piétrain gilts, but CBG-Bmax was associated with increased loin yields in LW (P = 0.010) and Landrace (P = 0.103) gilts, decreased ham yields (P = 0.082) in Duroc guts, and increased fat depth (P = 0.064) and leaf fat (P = 0.001) in MS × LW guts. There was no association between CBG-Bmax and pork quality traits in Piétrain (P ≥ 0.269) and Duroc (P ≥ 0.114) gilts. Conversely, CBG-Bmax was associated with lighter (higher L* values; P < 0.05) pork in Land-race guts, as well as lower (P ≤ 0.055) ultimate pH in the LM and semimembranosus, and a tendency for lower (P = 0.095) L* values of pork from LW gilts. Within MS × LW pigs, CBG-Bmax was associated with increased drip loss (P = 0.001) and decreased i.m. fat in the semimembranosus (P = 0.005). Because drip loss is an economically important pork quality trait, results of this study could be used in the selection of improved water-holding capacity of pork from synthetic lines involving the MS breed. [ABSTRACT FROM AUTHOR]