Hypothalamic-pituitary-adrenal Axis In Patients Research Articles

SAT272 Insulin Signaling In Hyperactivation Of The HPA Axis In Metabolic Diseases

Abstract Disclosure: D. Cozma: None. P. Siatra: None. I. Oikonomakos: None. D. Kalra: None. U.A. Friedrich: None. A. Dahl: None. S.R. Bornstein: None. S. Zeissig: None. C.L. Andoniadou: None. C. Steenblock: None. Stress can lead to an increase in body fat and obesity as main clinical conditions preceding the metabolic syndrome [1]. In metabolic stress, hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis has been observed, resulting in increased steroidogenesis and alteration of cortisol secretion [1]. This increased sensitivity of the HPA axis may be related to the development of comorbidities or severe illness in patients with metabolic diseases and vice versa. Disorders of the HPA axis, e.g., Cushing’s disease, resulting from overproduction of ACTH, share similar clinical symptoms with metabolic diseases [1]. The molecular signaling mechanisms that cause such changes in the HPA axis under metabolic stress remain elusive. Previous studies indicate a role of insulin in the regulation of adrenal steroidogenesis by upregulating the transcriptional activity of NR5A1 [2]. Here, we study the molecular mechanisms to insulin-induced hyperactivation of the HPA axis and characterize the molecular changes that lead to altered cortisol secretion. We generated non-adherent spheroids from primary adrenocortical cells in vitro and treated these with insulin. This resulted in an increase of spheroid diameter over time [Slope: 5.163 ± 0.994; P=0.0139; n=11], compared to control [Slope: -4.058 ± 0.987; P=0.0261; n=10], indicating greater cell expansion following insulin treatment. Similarly, repeating this experiment with adherent primary anterior pituitary stem cell colonies showed an increase in colony size when treated with insulin compared to control [Diameter: 1221.0 ± 290.9 µm vs. 914.5 ± 256.2 µm; P=0.0079; n=3]. This indicates that the stem cell populations of the adrenal and pituitary gland are responsive to insulin stimulation, likely leading to increased proliferation. This is complementary to our previous studies where we revealed increased secretion of aldosterone in insulin-stimulated adrenocortical cultures [3]. To identify signaling pathways related to insulin stimulation, we performed bulk RNA sequencing of in vitro primary cultures of adrenocortical and pituitary cells with and without insulin treatment. Analysis of these data sets reveals specific signaling pathways that are candidates in regulation of metabolic stress in vivo. Using mouse models of obesity and diabetes along with genetic lineage-tracing studies, we aim to decipher the role of these pathways on HPA axis stem/progenitor cells during metabolic stress. The outcomes will pave the way for a better understanding of HPA axis activity during metabolic stress adaption, and the role of the HPA axis in patients suffering from metabolic diseases.

Hypothalamic-pituitary-adrenal axis activity in patients with primary polydipsia compared to healthy controls.

Primary polydipsia is characterized by excessive fluid intake which may suppress vasopressin levels. It is speculated that suppressed vasopressin levels lead to a dysregulated hypothalamic-pituitary-adrenal (HPA) axis as vasopressin co-modulates the HPA axis. However, data are contradictory. The aim of this study was to investigate markers of the HPA axis in patients with primary polydipsia compared to healthy controls. Exploratory analysis combining data from two different prospective observational studies. We included 34 patients with primary polydipsia (68% females, median aged 29.5 years (interquartile range, IQR: 26.0, 38.8) and 20 healthy controls (55% females, median age 24.0 years [IQR: 22.0, 27.2]). The main outcome was difference in HPA axis activity assessed using circadian serum and salivary cortisol, 24-hurinary free cortisoland cortisol levels before and after adrenocorticotropic hormone (ACTH) stimulation; vasopressin suppression was assessed measuring fasting copeptin levels between patients with primary polydipsia and healthy controls using Wilcoxon rank-sum test. No difference was seen in circadian serum cortisol levels (p = .9), urinary free cortisol levels (p = .17)and serum cortisol in response to ACTH stimulation (p = .77) between groups. Circadian salivary cortisol levels were significantly lower in patients with primary polydipsia compared to healthy controls with an estimated difference of -3.7 nmol/L (95%CI: -5.5, -1.8 nmol/L, p < .001). Fasting copeptin levels were significantly lower in patients with primary polydipsia compared to healthy volunteers (p < 0.01). Our results suggest no difference in HPA axis activity between patients with primary polydipsia and healthy controls. The observed difference in salivary cortisol levels may be linked to a dilution effect in saliva rather than an altered stress axis considering the other findings.

Negative correlation between IL-1β, IL-12 and TNF-γ, and cortisol levels in patients with panic disorder.

IntroductionChronic exposure to stress is a major risk factor in anxiety disorders (ADs) and can be accompanied by an altered microbiome–gut–brain axis and a compromised immune system. In recent years, the study of inflammatory processes in AD has gained special attention. Continued stress causes the reactivity of the hypothalamic–pituitary–adrenal (HPA) axis, the alteration of the intestinal microbiota and the consequent release of pro‐inflammatory cytokines, affecting the sensitivity to stress and the similar behavior of anxiety.MethodThe aim of the present study was to evaluate the interrelationships between measures of proinflammatory cytokines and cortisol in patients with panic disorder (PD).ResultsThe main results of the correlation analysis revealed that the levels of pro‐inflammatory cytokines interleukin (IL)‐1β, IL‐12, and tumor necrosis factor gamma were negatively correlated with cortisol scores (area under the curve with respect to the ground).ConclusionsThese results suggest that the inflammatory response is associated with the reactivity of the HPA axis in patients with PD and may influence the maintenance of anxiety behavior.

Low-dose short synacthen test with salivary cortisol in patients with suspected central adrenal insufficiency.

ContextThe low-dose short synacthen test (LDSST) is recommended for patients with suspected central adrenal insufficiency (AI) if their basal serum cortisol (F) levels are not indicative of an intact hypothalamic–pituitary–adrenal (HPA) axis.ObjectiveTo evaluate diagnostic threshold for salivary F before and 30 min after administering 1 μg of synacthen, performed before 09:30 h.DesignA cross-sectional study from 2014 to 2020.SettingA tertiary referral university hospital.PatientsIn this study, 174 patients with suspected AI, 37 with central AI and 137 adrenal sufficient (AS), were included.Main outcome measureThe diagnostic accuracy (sensitivity (SE), specificity (SP)) of serum and salivary F levels measured, respectively, by chemiluminescence immunoassay and liquid chromatography-tandem mass spectrometry.ResultsLow basal serum or salivary F levels could predict AI. For the LDSST, the best ROC-calculated threshold for serum F to differentiate AI from AS was 427 nmol/L (SE 79%, SP 89%), serum F > 500 nmol/L reached SP 100%. A salivary F peak > 12.1 nmol/L after administering synacthen reached SE 95% and SP 84% for diagnosing central AI, indicating a conclusive reduction in the likelihood of AI. This ROC-calculated threshold for salivary F was similar to the 2.5th percentile of patients with a normal HPA axis, so it was considered sufficient to exclude AI. Considering AS those patients with salivary F > 12.1 nmol/L after LDSST, we could avoid unnecessary glucocorticoid treatment: 99/150 subjects (66%) had an inadequate serum F peak after synacthen, but salivary F was >12.1 nmol/L in 79 cases, who could, therefore, be considered AS.ConclusionsSalivary F levels > 12.1 nmol/L after synacthen administration can indicate an intact HPA axis in patients with an incomplete serum F response, avoiding the need to start glucocorticoid replacement treatment.

Does aerobic exercise affect the hypothalamic-pituitary-adrenal hormonal response in patients with fibromyalgia syndrome?

[Purpose] The hypothalamic-pituitary-adrenal (HPA) axis in the etiopathogenesis of fibromyalgia is not clear. This study aimed to analyze the effects of a 6-week aerobic exercise program on the HPA axis in patients with fibromyalgia and to investigate the effects of this program on the disease symptoms, patients’ fitness, disability, and quality of life. [Subjects and Methods] Fifty fibromyalgia patients were randomized to Group 1 (stretching and flexibility exercises at home for 6 weeks) and Group 2 (aerobic exercise three times a week and the same at-home exercises as Group 1 for 6 weeks). Serum levels of cortisol, adrenocorticotropic hormone, insulin-like growth factor-1, and growth hormone were analyzed at baseline and at the end of, and 1 hr after an exercise stress test. [Results] Group 2 showed better improvement in morning stiffness duration and pain. Growth hormone levels significantly increased after intervention and cortisol levels significantly decreased at time-time interaction in both groups. No significant differences in adrenocorticotropic hormone and insulin-like growth factor-1 were found. [Conclusion] The results of this study seem to support the hypothesis that there is a dysregulation of the HPA axis in patients with FM, and that a six-week exercise program can influence symptoms and affect the HPA axis hormones.

EPA-0427 – Specific cortisol response to stress in patients with eating disorders: a sign of disturbed hypothalamic-pituitary-adrenal axis activity?

Introduction There are some data that suggest the existence of a dysfunction of the Hypothalamic-Pituitary-Adrenal (HPA) Axis in patients with eating disorders (anorexia nervosa –AN- and bulimia nervosa -BN-). If such a dysfunction exists, it would result in an altered cortisol response to stress. Objectives To compare the cortisol response to stress in a group of patients with AN, BN and a control group. Methods Seventeen female AN patients, 17 female BN patients and 26 healthy female controls were compared. The Trier Social Stress Test (TSST) was used to induce stress. Throughout the test, seven samples of saliva were collected from each subject, and cortisol was investigated in each of the samples using radioimmunoassay (RIA). Results Each group had a specific profile of cortisol release. Upon arrival at the laboratory, the AN patients had higher cortisol levels, but they quickly returned to normal values, becoming similar to those of controls. In contrast, in the BN patients the cortisol levels were at any time significantly lower than those of the AN patients and the controls, displaying a globally blunted response. Conclusions The results support the hypothesis of a dysfunctional functioning of HPA axis in patients with eatings disorders, althoug suggest that it might be particularly important in BN patients. Supported by grants PI060974 (Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica [I+D+I]. FIS. Instituto Salud Carlos III. Ministerio de Sanidad, Servicios Sociales e Igualdad) and GRU09173 (Plan de Investigacion Regional de Extremadura. Gobierno de Extremadura y European Social Fund).

1426 HYPOTHALAMIC-PITUITARY-ADRENAL AXIS ACTIVITY AND AUTONOMIC NERVOUS SYSTEM CHANGES IN PATIENTS WITH CHRONIC PROSTATITIS/CHRONIC PELVIC PAIN SYNDROME COMPLICATED BY ERECTILE DYSFUNCTION

You have accessJournal of UrologyInfections/Inflammation of the Genitourinary Tract: Prostate & Genitalia1 Apr 20111426 HYPOTHALAMIC-PITUITARY-ADRENAL AXIS ACTIVITY AND AUTONOMIC NERVOUS SYSTEM CHANGES IN PATIENTS WITH CHRONIC PROSTATITIS/CHRONIC PELVIC PAIN SYNDROME COMPLICATED BY ERECTILE DYSFUNCTION Jian Bai, Jihong Liu, Shaogang Wang, Li Zhuan, Deng He, Min Ni, and Zhangqun Ye Jian BaiJian Bai Wuhan, China, People's Republic of More articles by this author , Jihong LiuJihong Liu Wuhan, China, People's Republic of More articles by this author , Shaogang WangShaogang Wang Wuhan, China, People's Republic of More articles by this author , Li ZhuanLi Zhuan Wuhan, China, People's Republic of More articles by this author , Deng HeDeng He Wuhan, China, People's Republic of More articles by this author , Min NiMin Ni Wuhan, China, People's Republic of More articles by this author , and Zhangqun YeZhangqun Ye Wuhan, China, People's Republic of More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.1338AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS) have been known to be reactive to psychological factors such as stress. Growing data suggest that stress conditions could be associated with the development or aggravation of prostatic disease. The present study aims to investigate the characteristics of ANS and HPA axis in Patients with Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) concomitant with and erectile dysfunction (ED). METHODS We recruited 25 CP/CPPS men with ED (group 1), 25 CP/CPPS men with voiding symptom only (group 2), 25 men with ED no CP/CPPS (group 3) and 25 age-matched, asymptomatic controls (group 4). Saliva samples were collected on 2 consecutive days at 9 specific times with strict reference to time of morning awakening for evaluation of free cortisol, reflecting secretory activity of the HPA axis. We quantified cortisol variations as the 2-day average slope of the awakening cortisol response and the subsequent diurnal levels. Heart rate variability (HRV) analysis was performed using the 24 hour Holter monitorisation. RESULTS One-way ANOVA showed that HRV values in patients from the four groups are similar. Mean ratio of LF/HF in groups 1 was 2.28¡À1.96, more higher compared with group 4 (1.24¡À0.62, P=0.015). However, HPA axis measures were not changed significantly. CONCLUSIONS The HRV changes suggest altered autonomic nervous system responses in men with CP/CPPS and ED. Predominance of sympathetic nervous system activity is possibly associated with comitant CP/CPPS and ED, whereas HPA axis activity is not. Observations suggest opportunities for neurophysiological study of relationships of stress, ED and CP/CPPS. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e571 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jian Bai Wuhan, China, People's Republic of More articles by this author Jihong Liu Wuhan, China, People's Republic of More articles by this author Shaogang Wang Wuhan, China, People's Republic of More articles by this author Li Zhuan Wuhan, China, People's Republic of More articles by this author Deng He Wuhan, China, People's Republic of More articles by this author Min Ni Wuhan, China, People's Republic of More articles by this author Zhangqun Ye Wuhan, China, People's Republic of More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Evaluation of the hypothalamic-pituitary-adrenal axis in patients with antiphospholipid syndrome

Hypothalamic-pituitary-adrenal (HPA) axis insufficiency is the most common endocrine disorder in patients with antiphospholipid syndrome (APS). Primary adrenal failure because of venous thrombosis and/or adrenal haemorrhage is the leading diagnosis, while another possible mechanism is autoimmune adrenal failure. Prospective evaluation of the HPA axis in patients with APS has not been previously performed. To evaluate the HPA axis in patients with APS. Ambulatory patients (age 18 years and older) with APS were given a symptom questionnaire. Baseline aldosterone, corticotropin (ACTH) and adrenal cortex autoantibodies (ACA) were measured. Cortisol was measured at baseline and after 1-mcg ACTH stimulation. In all, 24 patients (18 women/6 men; mean age 44.6 +/- 16.1 years) participated in the study. Of these, 21 had primary APS with disease duration of 5.8 +/- 6.2 years. Baseline cortisol level was 12.6 +/- 4.2 mg/dl (normal 7-25). After ACTH stimulation, it was 24.7 +/- 4.1 mg/dl and 22.8 +/- 7.4 mg/dl at 30 and 60 min respectively. All patients had a stimulated cortisol level of at least 18 mg/dl, although three patients had stimulated cortisol between 18 and 20 mg/dl, one of which reported previous inhaled steroid treatment. Weakness, dizziness and nausea were reported at baseline by 50%, 38% and 25% of the patients respectively. ACA were negative in all patients examined. In our cohort, patients with APS did not have HPA axis insufficiency. Partial adrenal insufficiency could not be excluded in two patients. Further longitudinal studies are needed to determine the significance of periodic evaluation of the HPA axis in patients with APS.

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.

Role of the hypothalamic-pituitary-adrenal axis in rheumatoid arthritis

Objective A subnormal response of the hypothalamic-pituitary-adrenal (HPA) axis to inflammatory stimuli was found to be associated with the occurrence of chronic arthritis in Lewis rats. This study was carried out to determine the role of the HPA axis in patients with rheumatoid arthritis (RA). Methods Thirty patients with RA of less than 2 years duration were studied. Laboratory tests including ESR, RF and X-ray hands were performed in all patients. All patients were subjected to the standard insulin-induced hypoglycemia test to determine the integrity of the HPA axis. Serum cortisol was estimated at 11 PM on the day prior to the test in eight of these patients. Results Twelve out of 30 patients had subnormal cortisol response to insulin-induced hypoglycemia. (normal: cortisol >20 μg/dl and 7 μg > basal cortisol). Two patients had a maximal cortisol response 7 μg > basal but less than 20 μg/dl, i.e. a partial response. Seven patients had a supranormal basal cortisol with no further stimulation with hypoglycemia. Nine patients had an adequate response. Conclusion 21/30 (70%) of patients showed some abnormality of HPA axis response. We propose that a primary abnormality of the HPA axis may play a significant role in the pathogenesis of RA.

Stress responsiveness in patients with psoriasis

Conflicts of interest: none declared. Sir, We read with great interest the article by Richards et al.1 regarding an attenuated psychological stressor response in the hypothalamic–pituitary–adrenal (HPA) axis in patients with psoriasis, especially in those with an apparent stress‐sensitive disease. In 1985, we reported a similar attenuation in the HPA axis in patients with psoriasis compared with healthy controls following stressor exposure similar to that used in the eloquent laboratory set‐up by Richards et al.2 Moreover, despite standardized stressor exposures, the psoriatic group in our study reported higher mental strain levels during stress, which was also reflected in higher blood glucose and urinary adrenaline levels during stressor exposures vs. controls. Thus, the greater cortisol attenuation might be due to changes in the HPA and other stress‐responsive systems and/or how patients with psoriasis interpret challenges, that is, differences in the stress appraisal process. In recent years, there has been an increasing focus on the importance of suboptimal stressor activation of the HPA axis during acute stressor exposures and its implications to health.3 Studies of patients with psoriasis indicate that heightened stress responsiveness of the sympathetic nervous system is accompanied by an inability to activate the HPA axis. This might have important implications for the dermatological health of patients and be of special interest in light of the fact that for many years cortisone has been the mainstay in psoriasis treatment.

Increased nocturnal secretion of ACTH and cortisol in obsessive compulsive disorder

Information on the function of the hypothalamic-pituitary-adrenal (HPA) axis, the main mammalian system of stress response, in obsessive compulsive disorder (OCD) is inconsistent. In this study, nine inpatients with a DSM-IV diagnosis of OCD without comorbid major depression (Yale-Brown Obsessive Compulsive Scale [Y-BOCS] score >15; HAMD-21 total score ⩽16) and nine healthy matched controls were included. Blood of patients (seven males; 31.8 ± 9.3 years, Y-BOCS: 27.3 ± 4.3, HAMD-21: 13.3 ± 1.9) and controls (seven males, 31.6 ± 9.1 years) was drawn every 20 min between 23:00 and 7:00 h during sleep using a long catheter for later ACTH and cortisol analysis. Secretion patterns of cortisol and ACTH were similar in both groups, in OCD, however, at a higher level. Area under the curve plasma concentrations of both ACTH ( p < 0.05) and cortisol ( p < 0.005) were significantly greater in patients with OCD (ACTH: 674.3 ± 57.4; cortisol: 2148.4 ± 271.7) than in controls (ACTH: 460.2 ± 61.0; cortisol: 1191.2 ± 124.1). In conclusion, our findings suggest that the activity of the HPA axis in patients with OCD is increased compared to healthy controls.

Assessing the HPA axis in patients with pituitary disease: a UK survey

Assessing the integrity of the hypothalamic-pituitary-adrenal (HPA) axis following pituitary surgery is necessary to determine the requirement for glucocorticoid replacement therapy, but there remains controversy about the optimum way to measure this. Postal questionnaire survey among UK endocrinologists to evaluate the current methods used. The response rate was low (81 out of 598 questionnaires mailed), although 85% were consultants. Fifty-five percent measured 9:00 h plasma cortisol in the immediate postoperative phase. Most carried out definitive testing between 4 and 12 weeks: 36% routinely used the insulin tolerance test (ITT), 59% used the short synacthen test (SST). The 30-min cortisol value was used by 67% as a 'pass' when interpreting the results. Others included cortisol measurement at 60 min (17%) or incremental value (7%). For long-term follow-up of patients not rendered ACTH-deficient by surgery, 64% used the SST for patients who had received radiotherapy. If patients had not had radiotherapy, 42% used the SST, whereas 33% did no routine testing unless the patient was symptomatic or there was evidence of tumour recurrence on imaging. If patients were symptomless but 'failed' the chosen test, 28% still treated the patient with glucocorticoid replacement, 38% retested before treatment and 24% recommended glucocorticoid cover for when unwell or 'stressed'. Fifty-six percent used hydrocortisone at doses of 20 mg/day as replacement therapy. Thus, assessment of the HPA axis remains controversial. Although the SST is becoming more popular, there is still considerable variation in the interpretation of results and, in particular, the decision of whether or not to treat with lifelong glucocorticoid replacement therapy.

Long-term citalopram administration reduces responsiveness of HPA axis in patients with major depression: relationship with S-citalopram concentrations in plasma and cerebrospinal fluid (CSF) and clinical response

A dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a well-documented neurobiological finding in major depression. Moreover, clinically effective therapy with antidepressant drugs may normalize the HPA axis activity. The aim of this study was to test whether citalopram (R/S-CIT) affects the function of the HPA axis in patients with major depression (DSM IV). Twenty depressed patients (11 women and 9 men) were challenged with a combined dexamethasone (DEX) suppression and corticotropin-releasing hormone (CRH) stimulation test (DEX/CRH test) following a placebo week and after 2, 4, and 16 weeks of 40 mg/day R/S-CIT treatment. The results show a time-dependent reduction of adrenocorticotrophic hormone (ACTH) and cortisol response during the DEX/CRH test both in treatment responders and nonresponders within 16 weeks. There was a significant relationship between post-DEX baseline cortisol levels (measured before administration of CRH) and severity of depression at pretreatment baseline. Multiple linear regression analyses were performed to identify the impact of psychopathology and hormonal stress responsiveness and R/S-CIT concentrations in plasma and cerebrospinal fluid (CSF). The magnitude of decrease in cortisol responsivity from pretreatment baseline to week 4 on drug [delta-area under the curve (AUC) cortisol] was a significant predictor (p<0.0001) of the degree of symptom improvement following 16 weeks on drug (i.e., decrease in HAM-D21 total score). The model demonstrated that the interaction of CSF S-CIT concentrations and clinical improvement was the most powerful predictor of AUC cortisol responsiveness. The present study shows that decreased AUC cortisol was highly associated with S-CIT concentrations in plasma and CSF. Therefore, our data suggest that the CSF or plasma S-CIT concentrations rather than the R/S-CIT dose should be considered as an indicator of the selective serotonergic reuptake inhibitors (SSRIs) effect on HPA axis responsiveness as measured by AUC cortisol response.

Stimulation of the Hypothalamic-Pituitary-Adrenal Axis with the Opioid Antagonist Nalmefene

Nalmefene Stimulation of the HPA Axis. The Hypothalamic-pituitary-adrenal (HPA) axis plays a vital role in the body's response to stress. The traditional gold standard for evaluating the HPA axis, the insulin hypoglycemia test (IHT), has several known limitations, and a second test, the standard ACTH stimulation test, can detect severe deficiencies of cortisol, but often misses mild or early cases. Therefore, a better test for the evaluation of the HPA axis is needed. This study evaluated the opiate antagonist nalmefene as a stimulation test of the HPA axis. 25 healthy subjects were studied, 9 women and 16 men, mean age 30.4 yr. (range 21-55), and mean BMI 24.1 kg/m2 (range 18.6-34.2). Subjects received one of 3 doses of intravenously administered nalmefene: 2 mg (n = 6), 6 mg (n = 12), or 10 mg (n = 7). Serum cortisol and plasma ACTH were measured before and serially over two hours after the administration of nalmefene. ACTH and cortisol levels rose significantly and similarly after the 10 mg dose and the 6 mg dose. After the 10 mg dose, mean peak ACTH was 82.4 +/- 22.6 pg/ml and mean peak cortisol was 25.2 +/- 1.8 microg/dl. After the 6 mg dose, mean peak ACTH was 70.3 +/- 7.7 pg/ml and mean peak cortisol was 24.7 +/- 1.7 microg/dl. Cortisol levels rose above 18 microg/dl in all subjects receiving 10 mg of nalmefene, and in all but two of the subjects receiving 6 mg of nalmefene. Side effects to nalmefene were of greater duration and intensity in the subjects receiving 10 mg of nalmefene vs. those receiving 6 or 2 mg. These included most notably fatigue, lightheadedness, nausea and vomiting. Of the nalmefene doses we studied, 6 mg achieved the best combination of stimulation of ACTH and cortisol and fewest side effects. If further studies show a concordance between nalmefene and IHT, nalmefene testing could be used to assess the HPA axis in patients at risk for dysfunction of this axis.

The midnight-to-morning urinary cortisol increment method is not reliable for the assessment of hypothalamic-pituitary-adrenal insufficiency in patients with end-stage kidney disease.

A previous study reported that the midnight-to-morning urinary cortisol increment method could be used to reliably assess the insufficiency of the hypothalamic-pituitary-adrenal (HPA) axis. The principal aim of the present study is to verify whether the midnight-to-morning urinary cortisol increment is a reliable method for the assessment of the HPA axis in patients with various degrees of impaired kidney function. Fifty-six clinically stable patients with chronic kidney disease (CKD) and 14 healthy subjects were enrolled in the present study. Patients with CKD were divided on the basis of glomerular filtration rate (GFR) into the following arbitrary groups: mild (GFR: 60-89 ml/min/1.73 m2, no.=15), moderate (GFR: 30-59 ml/min/1.73 m2, no.=12) and severe kidney insufficiency (GFR: 15-29 ml/min/1.73 m2, no.=13), and hemodialysis patients. Plasma cortisol and ACTH levels were measured. The HPA axis was assessed by short Synacthen test and overnight dexamethasone suppression test. Double voided urine samples were collected at midnight and waking in the patients and the controls. Urinary free cortisol (UFC) and creatinine levels were measured and the UFC/creatinine ratio (Cort/Cr) was calculated. Then, the Cort/Cr increment was calculated as the morning Cort/Cr minus the midnight Cort/Cr. Baseline plasma cortisol levels were not significantly different between two groups. However, we found that CKD patients had significantly greater plasma ACTH levels than controls. The patients with CKD had also significantly lower morning UFC levels than controls and there was a progressive fall in morning UFC levels with decreasing GFR. The assessment of the HPA axis in patients with GFR lower than 29 ml/min was hampered by falsely abnormal responses to the midnight-to-morning urinary cortisol increment method. Plasma cortisol responded normally to exogenously administered ACTH, while plasma cortisol was suppressed by overnight dexamethasone administration in all patients with CKD. In conclusion, this method is not a reliable test for assessment of the HPA insufficiency in patients with GFR lower than 29 ml/min.

The Hypothalamic-Pituitary-Adrenal Axis in Major Depressive Disorder: A Brief Primer for Primary Care Physicians.

BACKGROUND: One of the most enduring and replicated findings in biological psychiatry is activation of the hypothalamic-pituitary-adrenal (HPA) axis in a subset of patients with major depressive disorder. This review will discuss some of these findings and their pertinence to the assessment and treatment of depressed patients. METHOD: MEDLINE, PsychINFO, and Current Contents databases were searched for pertinent articles on the HPA axis in patients with depression. In addition, hand searches were conducted of references from these sources and abstracts from meetings and books on this topic. Articles that would provide an overview of major or interesting studies in the field were selected for inclusion. RESULTS: The data support that HPA axis activation is common in depressed patients. Frequently reported findings include elevated cortisol and corticotropin-releasing hormone (CRH), nonsuppression on the dexamethasone suppression test, a blunted adrenocorticotropic hormone (ACTH) response to CRH, and hippocampal volume reduction. Evidence of HPA axis activation appears to have prognostic value and is associated with increased risk of depression relapse and even suicide. CONCLUSION: Future research in this area will focus on a better understanding of the etiology and long-term consequences of HPA axis activation in depressed patients. In addition, medications that act on the HPA axis are currently in development and may be part of the psychiatrist's and primary care physician's pharmacopoeia in the near future.

The hypothalamic-pituitary-adrenal axis of patients with severe sepsis: Altered response to corticotropin-releasing hormone

To investigate the functional integrity of the hypothalamic-pituitary-adrenal (HPA) axis in patients with severe sepsis by stimulating with corticotropin-releasing hormone (CRH). Prospective observational study in consecutive intensive care unit patients with severe sepsis. Surgical intensive care unit and outpatient department of endocrinology in a university hospital. The study included 20 patients with the diagnosis of severe sepsis; six critically ill, nonseptic patients after major surgery; ten patients with primary adrenal insufficiency; ten patients with anterior pituitary insufficiency; and ten individuals without clinical signs of HPA axis disturbance. CRH tests were performed with an intravenous bolus injection of 100 microg of human CRH. We studied the functional integrity of the HPA axis in patients with severe sepsis by performing the CRH test. In addition, during the period of severe sepsis, we repeatedly measured basal plasma concentrations of adrenocorticotropin hormone (ACTH) and cortisol. The mean basal plasma cortisol concentration was decreased significantly in nonsurvivors with severe sepsis (288.8 +/- 29.1 [sem] nmol/L) compared with survivors (468.1+/- 18.6 nmol/L; p <.01). By calculating the ACTH/cortisol indices, we found no evidence for adrenal insufficiency in patients with severe sepsis. The mean ACTH/cortisol indices of nonsurvivors with severe sepsis (0.02 +/- 0.008) and survivors (0.01 +/- 0.002) were significantly lower compared with the index of patients with primary adrenal insufficiency (6.8 +/- 1.0; p <.001). In contrast, in nonsurvivors with severe sepsis, the plasma cortisol response to CRH stimulation was impaired compared with survivors: The mean basal cortisol concentration within the CRH test was 269.4 +/- 39.8 nmol/L in nonsurvivors compared with 470.8 +/- 48.4 nmol/L in survivors and increased to a peak value of 421.6 +/- 72.6 nmol/L in nonsurvivors and 680.7 +/- 43.8 nmol/L in survivors (p <.02). However, the change in plasma cortisol, expressed as mean +/- sem and calculated by subtracting the basal cortisol from the peak cortisol after CRH stimulation, was not significantly different in survivors with severe sepsis (243.5 +/- 36.1, range 111.0-524.0 nmol/L, n = 15) compared with nonsurvivors (161.0 +/- 38.9, range 42.0-245.0 nmol/L, n = 5; p >.05). We found lower basal plasma cortisol concentrations in nonsurvivors compared with survivors of severe sepsis. In addition, the plasma cortisol response to a single CRH stimulation was impaired in nonsurvivors compared with survivors. Reduced responses to CRH stimulation may reflect a state of endocrinologic organ dysfunction in severe sepsis.

Comparable effects of inhaled fluticasone propionate and budesonide on the HPA-axis in adult asthmatic patients

This randomized, double-blind, double-dummy, multicentre cross-over study compared the effects on the hypothalamic-pituitary-adrenal (HPA) axis of fluticasone propionate (750 μ g twice daily given via the DiskusTMand budesonide (800 μ g twice daily given via the TurbuhalerTM. Two treatment periods of 2 weeks each were preceded by a 2-week run-in period and separated by a 2-week washout period. During run-in and washout, patients received beclomethasone dipropionate (BDP) or budesonide at a constant dose of 1500–1600 μ g day−1. Sixty patients aged 18–75 years with moderate to severe asthma not fully controlled by treatment with 1500–1600 μ g day−1budesonide or BDP entered run-in and 45 completed the study. HPA axis suppression was assessed by morning serum cortisol (area under the curve from 08·00 to 10·30 hours) and 12-h nocturnal urinary cortisol excretion, measured at the end of run-in (baseline 1), at the end of washout (baseline 2), and at the end of each treatment period.Neither budesonide nor fluticasone produced significant suppression of either parameter compared to baselines. Only a few patients had serum-cortisol and urinary cortisol values below the normal range, before and after treatment. This shows that the patients did not have adrenal suppression before entering the study. The ratio between the AUC serum cortisol measured after fluticasone treatment and after budesonide treatment was 0·99 (95% CI 0·92–1·06), indicating equivalent effects on the HPA axis. This result was achieved after having omitted two patients' results, due to their very sensitive reaction to budesonide, but not to fluticasone. Two exacerbations of acute asthma occurred during budesonide treatment and none during fluticasone treatment. Both treatments were well tolerated. In conclusion, budesonide 1600 μ g day−1via TurbuhalerTMand fluticasone propionate 1500μ g day−1via DiskusTMhad no clinical effects on the HPA axis in patients with moderate to severe asthma.

Recombinant interleukin-6 activates the hypothalamic-pituitary-adrenal axis in humans.

The inflammatory cytokines, tumor necrosis factor-alpha, interleukin-1 alpha and -beta (IL-1 alpha and -beta), and IL-6 can activate the hypothalamic-pituitary-adrenal (HPA) axis. Tumor necrosis factor-alpha and IL-1 have been tested in both experimental animals and humans, but their administration has been limited by significant toxicity, mainly severe hypotension. IL-6, on the other hand, has demonstrated modest toxicity in animals. We evaluated the ability of recombinant IL-6 to stimulate the human HPA axis in patients with cancer and a good performance status, who received daily morning sc injections of 30 micrograms/kg IL-6 for 7 consecutive days, during the course of a phase I trial. IL-6 caused impressively marked and prolonged elevations of plasma ACTH and cortisol on the first day and blunted ACTH responses on the seventh day of treatment, perhaps as a result of increased baseline cortisol levels. The overall cortisol response, however, on the seventh day was of similar magnitude, suggesting that a new equilibrium in the feedback regulation of the HPA axis occurs with chronic IL-6 administration. The toxic effects of IL-6 were modest, suggesting that it might be useful for clinical testing of the HPA axis, as an alternative to the insulin tolerance test.