Dynamic Pituitary–Adrenal Interactions in the Critically Ill after Cardiac Surgery

Abstract Context Patients with critical illness are thought to be at risk of adrenal insufficiency. There are no models of dynamic hypothalamic–pituitary–adrenal (HPA) axis function in this group of patients and thus current methods of diagnosis are based on aggregated, static models. Objective To characterize the secretory dynamics of the HPA axis in the critically ill (CI) after cardiac surgery. Design Mathematical modeling of cohorts. Setting Cardiac critical care unit. Patients 20 male patients CI at least 48 hours after cardiac surgery and 19 healthy (H) male volunteers. Interventions None. Main Outcome Measures Measures of hormone secretory dynamics were generated from serum adrenocorticotrophic hormone (ACTH) sampled every hour and total cortisol every 10 min for 24 h. Results All CI patients had pulsatile ACTH and cortisol profiles. CI patients had similar ACTH secretion (1036.4 [737.6] pg/mL/24 h) compared to the H volunteers (1502.3 [1152.2] pg/mL/24 h; P = .20), but increased cortisol secretion (CI: 14 447.0 [5709.3] vs H: 5915.5 [1686.7)] nmol/L/24 h; P < .0001). This increase in cortisol was due to nonpulsatile (CI: 9253.4 [3348.8] vs H: 960 [589.0] nmol/L/24 h, P < .0001), rather than pulsatile cortisol secretion (CI: 5193.1 [3018.5] vs H: 4955.1 [1753.6] nmol/L/24 h; P = .43). Seven (35%) of the 20 CI patients had cortisol pulse nadirs below the current international guideline threshold for critical illness-related corticosteroid insufficiency, but an overall secretion that would not be considered deficient. Conclusions This study supports the premise that current tests of HPA axis function are unhelpful in the diagnosis of adrenal insufficiency in the CI. The reduced ACTH and increase in nonpulsatile cortisol secretion imply that the secretion of cortisol is driven by factors outside the HPA axis in critical illness.

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A Paradoxical Gender Dissociation within the Growth Hormone/Insulin-Like Growth Factor I Axis during Protracted Critical Illness1

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.85.1.6316 ◽

2000 ◽

Vol 85 (1) ◽

pp. 183-192

Author(s):

G. Van den Berghe ◽

R. C. Baxter ◽

F. Weekers ◽

P. Wouters ◽

C. Y. Bowers ◽

...

Keyword(s):

Body Mass Index ◽

Critical Illness ◽

Critically Ill ◽

Approximate Entropy ◽

Female Patients ◽

Gh Secretion ◽

Factor I ◽

Igf I ◽

Male Patients ◽

Secretory Pattern

Female gender appears to protect against adverse outcome from prolonged critical illness, a condition characterized by blunted and disorderly GH secretion and impaired anabolism. As a sexual dimorphism in the GH secretory pattern of healthy humans and rodents determines gender differences in metabolism, we here compared GH secretion and responsiveness to GH secretagogues in male and female protracted critically ill patients. GH secretion was quantified by deconvolution analysis and approximate entropy estimates of 9-h nocturnal time series in 9 male and 9 female patients matched for age (mean ± sd, 67 ± 11 and 67 ± 15 yr), body mass index, severity and duration of illness, feeding, and medication. Serum concentrations of PRL, TSH, cortisol, and sex steroids were measured concomitantly. Serum levels of GH-binding protein, insulin-like growth factor I (IGF-I), IGF-binding proteins (IGFBPs), and PRL were compared with those of 50 male and 50 female community-living control subjects matched for age and body mass index. In a second study, GH responses to GHRH (1 μg/kg), GH-releasing peptide-2 (GHRP-2; 1 μg/kg) and GHRH plus GHRP-2 (1 and 1 μg/kg) were examined in comparable, carefully matched male (n = 15) and female (n = 15) patients. Despite identical mean serum GH concentrations, total GH output, GH half-life, and number of GH pulses, critically ill men paradoxically presented with less pulsatile (mean ± sd pulsatile GH fraction, 39 ± 14% vs. 67 ± 20%; P = 0.002) and more disorderly (approximate entropy, 0.946 ± 0.113 vs. 0.805 ± 0.147; P = 0.02) GH secretion than women. Serum IGF-I, IGFBP-3, and acid-labile subunit (ALS) levels were low in patients compared with controls, with male patients revealing lower IGF-I (P = 0.01) and ALS (P = 0.005) concentrations than female patients. Correspondingly, circulating IGF-I and ALS levels correlated positively with pulsatile (but not with nonpulsatile) GH secretion. Circulating levels of GH-binding protein and IGFBP-1, -2, and -6 were higher in patients than controls, without a detectable gender difference. In female patients, PRL levels were 3-fold higher, and TSH and cortisol tended to be higher than levels in males. In both genders, estrogen levels were more than 3-fold higher than normal, and testosterone (2.25 ± 1.94 vs. 0.97 ± 0.39 nmol/L; P = 0.03) and dehydroepiandrosterone sulfate concentrations were low. In male patients, low testosterone levels were related to reduced GH pulse amplitude (r = 0.91; P = 0.0008). GH responses to GHRH were relatively low and equal in critically ill men and women (7.3 ± 9.4 vs. 7.8 ± 4.1 μg/L; P = 0.99). GH responses to GHRP-2 in women (93 ± 38 μg/L) were supranormal and higher (P < 0.0001) than those in men (28 ± 16 μg/L). Combining GHRH with GHRP-2 nullified this gender difference (77 ± 58 in men vs. 120 ± 69 μg/L in women; P = 0.4). In conclusion, a paradoxical gender dissociation within the GH/IGF-I axis is evident in protracted critical illness, with men showing greater loss of pulsatility and regularity within the GH secretory pattern than women (despite indistinguishable total GH output) and concomitantly lower IGF-I and ALS levels. Less endogenous GHRH action in severely ill men compared with women, possibly due to profound hypoandrogenism, accompanying loss of the putative endogenous GHRP-like ligand action with prolonged stress in both genders may explain these novel findings.

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Enhanced circadian ACTH release in obese premenopausal women: reversal by short-term acipimox treatment

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00254.2004 ◽

2004 ◽

Vol 287 (5) ◽

pp. E848-E856 ◽

Cited By ~ 17

Author(s):

Petra Kok ◽

Simon W. Kok ◽

Madelon M. Buijs ◽

Jos J. M. Westenberg ◽

Ferdinand Roelfsema ◽

...

Keyword(s):

Hpa Axis ◽

Experimental Studies ◽

Premenopausal Women ◽

Secretory Activity ◽

Cortisol Secretion ◽

Obese Women ◽

Acth Secretion ◽

Double Blind ◽

Deconvolution Analysis ◽

Acth Release

Several studies suggest that the hypothalamo-pituitary-adrenal (HPA) axis is exceedingly active in obese individuals. Experimental studies show that circulating free fatty acids (FFAs) promote the secretory activity of the HPA axis and that human obesity is associated with high circulating FFAs. We hypothesized that HPA axis activity is enhanced and that lowering of circulating FFAs by acipimox would reduce spontaneous secretion of the HPA hormonal ensemble in obese humans. To evaluate these hypotheses, diurnal ACTH and cortisol secretion was studied in 11 obese and 9 lean premenopausal women (body mass index: obese 33.5 ± 0.9 vs. lean 21.2 ± 0.6 kg/m2, P < 0.001) in the early follicular stage of their menstrual cycle. Obese women were randomly assigned to treatment with either acipimox (inhibitor of lipolysis, 250 mg orally four times daily) or placebo in a double-blind crossover design, starting one day before admission until the end of the blood-sampling period. Blood samples were taken during 24 h with a sampling interval of 10 min for assessment of plasma ACTH and cortisol concentrations. ACTH and cortisol secretion rates were estimated by multiparameter deconvolution analysis. Daily ACTH secretion was substantially higher in obese than in lean women (7,950 ± 1,212 vs. 2,808 ± 329 ng/24 h, P = 0.002), whereas cortisol was not altered (obese 36,362 ± 5,639 vs. lean 37,187 ± 4,239 nmol/24 h, P = 0.912). Acipimox significantly reduced ACTH secretion in the obese subjects (acipimox 5,850 ± 769 ng/24 h, P = 0.039 vs. placebo), whereas cortisol release did not change (acipimox 33,542 ± 3,436 nmol/24 h, P = 0.484 vs. placebo). In conclusion, spontaneous ACTH secretion is enhanced in obese premenopausal women, whereas cortisol production is normal. Reduction of circulating FFA concentrations by acipimox blunts ACTH release in obese women, which suggests that FFAs are involved in the pathophysiology of this neuroendocrine anomaly.

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Assessing adrenal insufficiency of corticosteroid secretion using free versus total cortisol levels in critical illness

Intensive Care Medicine ◽

10.1007/s00134-011-2342-x ◽

2011 ◽

Vol 37 (12) ◽

pp. 1986-1993 ◽

Cited By ~ 30

Author(s):

Nienke Molenaar ◽

A. B. Johan Groeneveld ◽

Hilde M. Dijstelbloem ◽

Margriet F. C. de Jong ◽

Armand R. J. Girbes ◽

...

Keyword(s):

Critical Illness ◽

Adrenal Insufficiency ◽

Total Cortisol ◽

Cortisol Levels ◽

Corticosteroid Secretion

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Pituitary–Adrenal Responses and Glucocorticoid Receptor Expression in Critically Ill Patients with COVID-19

International Journal of Molecular Sciences ◽

10.3390/ijms222111473 ◽

2021 ◽

Vol 22 (21) ◽

pp. 11473

Author(s):

Dimitra A. Vassiliadi ◽

Alice G. Vassiliou ◽

Ioannis Ilias ◽

Stylianos Tsagarakis ◽

Anastasia Kotanidou ◽

...

Keyword(s):

Stress Response ◽

Critical Illness ◽

Glucocorticoid Receptor ◽

Critically Ill ◽

Hpa Axis ◽

Systemic Inflammation ◽

Critically Ill Patients ◽

Tissue Damage ◽

Receptor Expression ◽

Metabolic Effects

The hypothalamus–pituitary–adrenal (HPA) axis was described as the principal component of the stress response 85 years ago, along with the acute-phase reaction, and the defense response at the tissue level. The orchestration of these processes is essential since systemic inflammation is a double-edged sword; whereas inflammation that is timely and of appropriate magnitude is beneficial, exuberant systemic inflammation incites tissue damage with potentially devastating consequences. Apart from its beneficial cardiovascular and metabolic effects, cortisol exerts a significant immunoregulatory role, a major attribute being that it restrains the excessive inflammatory reaction, thereby preventing unwanted tissue damage. In this review, we will discuss the role of the HPA axis in the normal stress response and in critical illness, especially in critically ill patients with coronavirus disease 2019 (COVID-19). Finally, a chapter will be dedicated to the findings from clinical studies in critical illness and COVID-19 on the expression of the mediator of glucocorticoid actions, the glucocorticoid receptor (GCR).

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Hypothalamic Pituitary Adrenal Function during Critical Illness: Limitations of Current Assessment Methods

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2006-0674 ◽

2006 ◽

Vol 91 (10) ◽

pp. 3725-3745 ◽

Cited By ~ 218

Author(s):

Baha M. Arafah

Keyword(s):

Critical Illness ◽

Critically Ill ◽

Critically Ill Patients ◽

Serum Cortisol ◽

Adrenal Function ◽

Serum Free ◽

Total Cortisol ◽

Free Cortisol ◽

Alternative Approaches ◽

Hpa Function

Abstract Context: Activation of the hypothalamic-pituitary-adrenal (HPA) axis represents one of several important responses to stressful events and critical illnesses. Despite a large volume of published data, several controversies continue to be debated, such as the definition of normal adrenal response, the concept of relative adrenal insufficiency, and the use of glucocorticoids in the setting of critical illness. Objectives: The primary objective was to review some of the modulating factors and limitations of currently used methods of assessing HPA function during critical illness and provide alternative approaches in that setting. Design: This was a critical review of relevant data from the literature with inclusion of previously published as well as unpublished observations by the author. Data on HPA function during three different forms of critical illnesses were reviewed: experimental endotoxemia in healthy volunteers, the response to major surgical procedures in patients with normal HPA, and the spontaneous acute to subacute critical illnesses observed in patients treated in intensive care units. Setting: The study was conducted at an academic medical center. Patients/Participants: Participants were critically ill subjects. Intervention: There was no intervention. Main Outcome Measure: The main measure was to provide data on the superiority of measuring serum free cortisol during critical illness as contrasted to those of total cortisol measurements. Results: Serum free cortisol measurement is the most reliable method to assess adrenal function in critically ill, hypoproteinemic patients. A random serum free cortisol is expected to be 1.8 μg/dl or more in most critically ill patients, irrespective of their serum binding proteins. Because the free cortisol assay is not currently available for routine clinical use, alternative approaches to estimate serum free cortisol can be used. These include calculated free cortisol (Coolens’ method) and determining the free cortisol index (ratio of serum cortisol to transcortin concentrations). Preliminary data suggest that salivary cortisol measurements might be another alternative approach to estimating the free cortisol in the circulation. When serum binding proteins (albumin, transcortin) are near normal, measurements of total serum cortisol continue to provide reliable assessment of adrenal function in critically ill patients, in whom a random serum total cortisol would be expected to be 15 μg/dl or more in most patients. In hypoproteinemic critically ill subjects, a random serum total cortisol level is expected to be 9.5 μg/dl or more in most patients. Data on Cosyntropin-stimulated serum total and free cortisol levels should be interpreted with the understanding that the responses in critically ill subjects are higher than those of healthy ambulatory volunteers. The Cosyntropin-induced increment in serum total cortisol should not be used as a criterion for defining adrenal function, especially in critically ill patients. Conclusions: The routine use of glucocorticoids during critical illness is not justified except in patients in whom adrenal insufficiency was properly diagnosed or others who are hypotensive, septic, and unresponsive to standard therapy. When glucocorticoids are used, hydrocortisone should be the drug of choice and should be given at the lowest dose and for the shortest duration possible. The hydrocortisone dose (50 mg every 6 h) that is mistakenly labeled as low-dose hydrocortisone leads to excessive elevation in serum cortisol to values severalfold greater than those achieved in patients with documented normal adrenal function. The latter data should call into question the current practice of using such doses of hydrocortisone even in the adrenally insufficient subjects.

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Increased Hypothalamic-Pituitary-Adrenal Axis Activity in Huntington’s Disease

Endocrinology ◽

10.1210/endo.150.3.9999 ◽

2009 ◽

Vol 150 (3) ◽

pp. 1558-1558

Author(s):

N. Ahmad Aziz ◽

Hanno Pijl ◽

Marijke Frölich ◽

A. W. Maurits van der Graaf ◽

Ferdinand Roelfsema ◽

...

Keyword(s):

Body Mass Index ◽

Huntington's Disease ◽

Body Mass ◽

Hpa Axis ◽

Signs And Symptoms ◽

Diurnal Variations ◽

Cortisol Secretion ◽

Hypothalamic Pituitary Adrenal ◽

Total Cortisol ◽

Cortisol Levels

Abstract Context: Huntington’s disease (HD) is a fatal hereditary neurodegenerative disorder characterized by motor, cognitive, and behavioral disturbances. Hypothalamic-pituitary-adrenal (HPA) axis dysfunction could contribute to a number of HD signs and symptoms; however, no data are available on cortisol diurnal variations and secretory dynamics in HD patients. Objective: The aim of the study was to perform a detailed analysis of HPA axis function in HD patients in relation to clinical signs and symptoms. Design, Setting, and Participants: Twenty-four-hour cortisol secretion was studied in eight early-stage, medication-free HD patients and eight age-, sex-, and body mass index-matched controls in a clinical research laboratory. Cortisol levels were measured every 10 min. Main Outcome Measures: Multiparameter autodeconvolution and cosinor regression were applied to quantify basal, pulsatile, and total cortisol secretion rates as well as diurnal variations in cortisol levels. Results: Total cortisol secretion rate and the amplitude of the diurnal cortisol profile were both significantly higher in HD patients compared with controls (3490 ± 320 vs. 2500 ± 220 nmol/liter/24 h, P = 0.023; and 111 ± 14 vs. 64 ± 8 nmol/liter, P = 0.012, respectively). Cortisol concentrations in patients were particularly increased in the morning and early afternoon period. In HD patients, mean 24-h cortisol levels significantly correlated with total motor score, total functional capacity, as well as body mass index. Conclusions: HPA axis hyperactivity is an early feature of HD and is likely to result from a disturbed central glucocorticoid feedback due to hypothalamic pathology. HPA axis dysfunction may contribute to some signs and symptoms in HD patients.

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Reduced nocturnal ACTH-driven cortisol secretion during critical illness

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00009.2014 ◽

2014 ◽

Vol 306 (8) ◽

pp. E883-E892 ◽

Cited By ~ 35

Author(s):

Eva Boonen ◽

Philippe Meersseman ◽

Hilke Vervenne ◽

Geert Meyfroidt ◽

Fabian Guïza ◽

...

Keyword(s):

Time Series ◽

Critical Illness ◽

Dose Response ◽

Approximate Entropy ◽

Pulse Frequency ◽

Cortisol Secretion ◽

Acth Secretion ◽

Deconvolution Analysis ◽

Cortisol Metabolism ◽

Free Cortisol

Recently, during critical illness, cortisol metabolism was found to be reduced. We hypothesize that such reduced cortisol breakdown may suppress pulsatile ACTH and cortisol secretion via feedback inhibition. To test this hypothesis, nocturnal ACTH and cortisol secretory profiles were constructed by deconvolution analysis from plasma concentration time series in 40 matched critically ill patients and eight healthy controls, excluding diseases or drugs that affect the hypothalamic-pituitary-adrenal axis. Blood was sampled every 10 min between 2100 and 0600 to quantify plasma concentrations of ACTH and (free) cortisol. Approximate entropy, an estimation of process irregularity, cross-approximate entropy, a measure of ACTH-cortisol asynchrony, and ACTH-cortisol dose-response relationships were calculated. Total and free plasma cortisol concentrations were higher at all times in patients than in controls (all P < 0.04). Pulsatile cortisol secretion was 54% lower in patients than in controls ( P = 0.005), explained by reduced cortisol burst mass ( P = 0.03), whereas cortisol pulse frequency ( P = 0.35) and nonpulsatile cortisol secretion ( P = 0.80) were unaltered. Pulsatile ACTH secretion was 31% lower in patients than in controls ( P = 0.03), again explained by a lower ACTH burst mass ( P = 0.02), whereas ACTH pulse frequency ( P = 0.50) and nonpulsatile ACTH secretion ( P = 0.80) were unchanged. ACTH-cortisol dose response estimates were similar in patients and controls. ACTH and cortisol approximate entropy were higher in patients ( P ≤ 0.03), as was ACTH-cortisol cross-approximate entropy ( P ≤ 0.001). We conclude that hypercortisolism during critical illness coincided with suppressed pulsatile ACTH and cortisol secretion and a normal ACTH-cortisol dose response. Increased irregularity and asynchrony of the ACTH and cortisol time series supported non-ACTH-dependent mechanisms driving hypercortisolism during critical illness.

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Critical Care Implications of Adrenal Disease States

10.2310/7ccsp.8015 ◽

2020 ◽

Author(s):

Shaun Thompson ◽

Erin Etoll

Keyword(s):

Critical Care ◽

Critical Illness ◽

Adrenal Insufficiency ◽

Critically Ill ◽

Critically Ill Patients ◽

Morbidity And Mortality ◽

Critically Ill Patient ◽

Disease States ◽

Adrenal Disease ◽

Corticosteroid Insufficiency

Adrenal disease in the critically ill patient can present many challenges for the intensivist. Besides primary, secondary, and tertiary adrenal insufficiency, a state known as critical care–related corticosteroid insufficiency (CIRCI) has been described. Adrenal insufficiency can pose many issues to the critically ill patient as it can decrease the patient’s ability to respond to the stress that critical illness presents to the human body. Proper recognition and diagnosis of adrenal insufficiency in the critically ill patient can be extremely important in the treatment of these patients and could be a lifesaving intervention if CIRCI is discovered. A less commonly encountered issue of adrenal disease lies in the area of adrenal hormone excess caused by a pheochromocytoma or extra-adrenal paragangliomas. These tumors can release large amounts of endogenous catecholamines that cause significant patient morbidity and mortality if not recognized early and treated appropriately. Although adrenal insufficiency and adrenal excess are less commonly encountered problems in critically ill patients, the recognition and treatment of these disease states can prevent the morbidity and mortality of critically ill patients that suffer from these disease states. This review contains 5 figures, 5 tables, and 89 references. Key words: adrenal insufficiency, hypothalamic-pituitary axis, critical illness–related corticosteroid insufficiency, pheochromocytoma, steroid replacement therapy

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Adrenal Insufficiency In Critically Ill Patients

Bangladesh Critical Care Journal ◽

10.3329/bccj.v3i1.24101 ◽

2015 ◽

Vol 3 (1) ◽

pp. 27-30

Author(s):

SM Ashrafuzzaman

Keyword(s):

Septic Shock ◽

Critical Illness ◽

Adrenal Insufficiency ◽

Critically Ill ◽

Critically Ill Patients ◽

High Index ◽

Acth Level ◽

Short Term ◽

High Index Of Suspicion ◽

Low Cortisol

Adrenal insufficiency means hypo function of the adrenal cortex, usually resulting in low glucocorticoid level and it may be associated with low mineralocorticoid, rarely low adrenal androgen level. It can be categorized into two types: primary and secondary. Primary adrenal insufficiency or Addison's disease is associated with low cortisol and high ACTH level. Secondary/tertiary adrenal insufficiency is due to pituitary or hypothalamic disorders and is associated with both low cortisol and ACTH level. Among critically ill patients (CIP) adrenal insufficiency is not uncommon. The reported incidence of adrenal insufficiency varies greatly depending on the population of critically ill patients studied, the type of test, cut off levels used, and the severity of illness. Several studies have shown increased mortality in patients with very low or very high baseline cortisol levels. Manifestations of adrenal insufficiency in the critically ill patient are numerous and nonspecific, so clinicians are urged to have a high index of suspicion while taking history and doing physical examination and be alert to important diagnostic clues, such as hyponatremia, hyperkalemia, and hypotension, that are refractory to fluids and vasopressor without any clear causation. In current literature there is no consensus level of cortisol (basal/random/stimulated) in critically ill subjects. But it is shown that both high and low cortisol level is associated with increased mortality. In one study Basal Serum Cortisol <414 nmol/L and > 696 nmol/L is shown as indicative of higher risk among critically ill patients. Even with Septicemia or ARDS all subjects dont suffer from adrenal insufficiency often termed relative adrenal insufficiency or critical illness associated adrenal insufficiency. It has been observed that short term low dose IV hydrocortisone may be beneficial in selective group of patients in intensive care unit (ICU) with critical illness. Diagnosis of adrenal insufficiency associated with critical illness is still challenging for physicians working in ICU. Treatment should be started without delay in emergency situation with Injection Hydrocortisone intravenously or even intramuscularly. Since the condition appears to be common in patients with septic shock, clinicians should have a high index of suspicion for its occurrence in critically ill patients with persistent hypotension despite adequate fluid resuscitation and/or poor hemodynamic response to vasopressor. Adrenal insufficiency associated with other illnesses in ICU are attributed to previous primary or secondary adrenal insufficiency. Treatment with physiologic doses of corticosteroids should be started as soon as possible since short-term treatment carries very few risks and has been shown to decrease both morbidity and mortality. Only suspected cases should be evaluated and could be treated with 100-200 mg Hydrocortisone in divided doses for 5-7 days. Glucocorticoid cannot be recommended as a routine adjuvant therapy in all cases of septic shock or ARDS. But glucocorticoid earned its position among other rescue strategies in subgroups of ICU patients with the highest mortality risk. Steroid use is an art and needs to be used by experienced physician. Otherwise it may do more harm than benefit.Bangladesh Crit Care J March 2015; 3 (1): 27-30

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