Impaired Hypothalamic-pituitary-adrenal Axis Research Articles

Targeting the Arginine Vasopressin V1b Receptor System and Stress Response in Depression and Other Neuropsychiatric Disorders.

A healthy stress response is critical for good mental and overall health and promotes neuronal growth and adaptation, but the intricately balanced biological mechanisms that facilitate a stress response can also result in predisposition to disease when that equilibrium is disrupted. The hypothalamic-pituitary-adrenal (HPA) axis neuroendocrine system plays a critical role in the body's response and adaptation to stress, and vasopressinergic regulation of the HPA axis is critical to maintaining system responsiveness during chronic stress. However, exposure to repeated or excessive physical or emotional stress or trauma can shift the body's stress response equilibrium to a "new normal" underpinned by enduring changes in HPA axis function. Exposure to early life stress due to adverse childhood experiences can also lead to lasting neurobiological changes, including in HPA axis function. HPA axis impairment in patients with depression is considered among the most reliable findings in biological psychiatry, and chronic stress has been shown to play a major role in the pathogenesis and onset of depression and other neuropsychiatric disorders. Modulating HPA axis activity, for example via targeted antagonism of the vasopressin V1b receptor, is a promising approach for patients with depression and other neuropsychiatric disorders associated with HPA axis impairment. Despite favorable preclinical indications in animal models, demonstration of clinical efficacy for the treatment of depressive disorders by targeting HPA axis dysfunction has been challenging, possibly due to the heterogeneity and syndromal nature of depressive disorders. Measures of HPA axis function, such as elevated cortisol levels, may be useful biomarkers for identifying patients who may benefit from treatments that modulate HPA axis activity. Utilizing clinical biomarkers to identify subsets of patients with impaired HPA axis function who may benefit is a promising next step in fine-tuning HPA axis activity via targeted antagonism of the V1b receptor.

Understanding the relationships between physiological and psychosocial stress, cortisol and cognition.

Stress is viewed as a state of real or perceived threat to homeostasis, the management of which involves the endocrine, nervous, and immune systems. These systems work independently and interactively as part of the stress response. The scientific stress literature, which spans both animal and human studies, contains heterogeneous findings about the effects of stress on the brain and the body. This review seeks to summarise and integrate literature on the relationships between these systems, examining particularly the roles of physiological and psychosocial stress, the stress hormone cortisol, as controlled by the hypothalamic-pituitary-adrenal (HPA) axis, and the effects of stress on cognitive functioning. Health conditions related to impaired HPA axis functioning and their associated neuropsychiatric symptoms will also be considered. Lastly, this review will provide suggestions of clinical applicability for endocrinologists who are uniquely placed to measure outcomes related to endocrine, nervous and immune system functioning and identify areas of intervention.

Methylation and expression of glucocorticoid receptor exon-1 variants and FKBP5 in teenage suicide-completers

A dysregulated hypothalamic-pituitary-adrenal (HPA) axis has repeatedly been demonstrated to play a fundamental role in psychiatric disorders and suicide, yet the mechanisms underlying this dysregulation are not clear. Decreased expression of the glucocorticoid receptor (GR) gene, which is also susceptible to epigenetic modulation, is a strong indicator of impaired HPA axis control. In the context of teenage suicide-completers, we have systematically analyzed the 5’UTR of the GR gene to determine the expression levels of all GR exon-1 transcript variants and their epigenetic state. We also measured the expression and the epigenetic state of the FK506-binding protein 51 (FKBP5/FKBP51), an important modulator of GR activity. Furthermore, steady-state DNA methylation levels depend upon the interplay between enzymes that promote DNA methylation and demethylation activities, thus we analyzed DNA methyltransferases (DNMTs), ten-eleven translocation enzymes (TETs), and growth arrest- and DNA-damage-inducible proteins (GADD45). Focusing on both the prefrontal cortex (PFC) and hippocampus, our results show decreased expression in specific GR exon-1 variants and a strong correlation of DNA methylation changes with gene expression in the PFC. FKBP5 expression is also increased in both areas suggesting a decreased GR sensitivity to cortisol binding. We also identified aberrant expression of DNA methylating and demethylating enzymes in both brain regions. These findings enhance our understanding of the complex transcriptional regulation of GR, providing evidence of epigenetically mediated reprogramming of the GR gene, which could lead to possible epigenetic influences that result in lasting modifications underlying an individual’s overall HPA axis response and resilience to stress.

Association of MRI-based adrenal gland volume and impaired glucose metabolism in a population-based cohort study.

The aim of this study was to assess adrenal gland volume by using magnetic resonance imaging (MRI) and to study its role as an indirect marker of impaired glucose metabolism and hypothalamic-pituitary-adrenal (HPA) axis activation in a population-based cohort. Asymptomatic participants were enrolled in a nested case-control study and underwent a 3-T MRI, including T1w-VIBE-Dixon sequences. For the assessment of adrenal gland volume, adrenal glands were manually segmented in a blinded fashion. Impaired glucose metabolism was determined using fasting glucose and oral glucose tolerance test. Cardiometabolic risk factors were also obtained. Inter- and intrareader reliability as well as univariate and multivariate associations were derived. Among 375 subjects included in the analysis (58.5% male, 56.1±9.1years), 25.3% participants had prediabetes and 13.6% had type 2 diabetes (T2DM). Total adrenal gland volume was 11.2±4.2ml and differed significantly between impaired glucose metabolism and healthy controls with largest total adrenal gland volume in T2DM (healthy controls: 10.0±3.9ml, prediabetes: 12.5±3.8ml, T2DM: 13.9±4.6ml; p<0.001). In the multivariate analysis, association of T2DM and increased adrenal gland volume was independent of age, sex, hypertension, triglycerides and body mass index (BMI), but was attenuated in subjects with prediabetes after adjustment for BMI. T2DM is significantly associated with increased adrenal gland volume by MRI in an asymptomatic cohort, independent of age, sex, dyslipidaemia, hypertension and BMI. Adrenal gland volume may represent an indirect marker of impaired glucose metabolism and HPA axis dysfunction.

The dysregulation of the hypothalamic\u2013pituitary\u2013adrenal axis in diet-induced prediabetic male Sprague Dawley rats

BackgroundAltered function of the hypothalamic–pituitary–adrenal (HPA) axis in type 2 diabetic patients, a condition preceded by pre-diabetes, has been shown to increase the risk of depression as well as cause downstream effects resulting in upregulation of gluconeogenesis and dyslipidemia. In addition, stress, either psychological from managing diabetes or lifestyle related, further activates the HPA axis causing an exaggerated stress response. This study investigated the activity of the HPA axis in selected markers of glucose handling, and the stress response relative to components of the HPA axis in a diet-induced pre-diabetic rat model.MethodsSprague Dawley Rats were randomly divided into non-pre-diabetic group (NPD) and pre-diabetic group (PD) (n = 6, per group) over a 20-week induction period and a further 12-week experimental period to get 32 weeks. At the end of the 20 and 32-week periods, glucose handling using the Homeostasis Model Assessment indices, adrenocorticotropic (ACTH) and corticosterone (CORT) concentrations were measured. Stress was induced and the forced swim test were performed in the 12-week experimental week. At the end of 32 weeks glucocorticoid and mineralocorticoid hippocampal receptors were also measured.ResultsImpaired glucose handling in the PD group as well as increase in corticosterone was observed at the end of both 20 and 32-week periods by comparison to NPD groups. No changes were observed in ACTH concentration at week 20 while, at week 32, a decrease in plasma ACTH concentration was observed in the PD group by comparison to the NPD group. The stressed-induced animals were stressed using the forced swim test: the behaviour observed showed an increase in immobility time in the PD stressed group by comparison to the NPD group. This was followed by the observation of a decrease in ACTH and CORT concentration in the PD stressed group by comparison to the NPD stressed group. Mineralocorticoid and glucocorticoid receptors gene expression were elevated in the stressed PD group relative to the stressed NPD group.ConclusionThese observations, together, suggest that diet-induced pre-diabetes is associated with impaired HPA axis activity and deteriorating response to stress.

NOD‐like Receptors: Novel Regulators of the Microbiota‐Gut‐Brain Axis in Mice

BackgroundThe crosstalk between the gut and the brain has revealed a complex communication system responsible for maintaining a proper gastrointestinal (GI) homeostasis as well as affect emotional mood and cognitive functions. The immune system, which is recognized to maintain the symbiotic relationship between the host and the microbiota, plays a pivotal role in the regulation of the microbiota‐gut‐brain (MGB) axis. Specifically, nucleotide binding oligomerization domain (Nod)‐like receptors (NLR), which sense bacterial pathogens and initiate the innate immune response, are essential in maintaining GI homeostasis. Moreover, their expression in the brain implicates them as potential prime mediators of the MGB axis. The hypothalamic‐pituitary adrenal (HPA) axis is a critical component of the stress response, and has been shown to be closely correlated to the MGB axis.HypothesisWe hypothesized that deficiency in NLRs, (i.e. Nod1/Nod2), will dysregulate the MGB axis, including mood, cognitive behavior, and GI physiology.MethodsAdult (6–8 weeks of age) male and female Nod1/Nod2 double knockout (NodDKO) and wild type (WT; C57Bl/6) mice were utilized. Mice were subjected to behavioral tests (novel object recognition [NOR] task, light/dark box, open field test) following exposure to an acute stress (water avoidance stress [WAS]) to assess recognition memory, anxiety‐like behavior, and general health, respectively.ResultsDeletion of Nod1 and Nod2 receptors reduced cognitive performance in both male and female mice following WAS compared to WT controls. In contrast, only male NodDKO mice exhibited anxiety‐like behavior vs. WT controls. These changes in behavior were accompanied by altered mRNA expression levels of genes for stress (↓corticotropin releasing factor receptor [CRFR]1; ↑CRFR2), cognition (↑brain‐derived neurotropic factor [BDNF]) and inflammation (↑tumor necrosis factor [TNF]α; ↓interleukin [IL]10) in the hippocampus and prefrontal cortex of NodDKO mice in a sexually dimorphic manner. Stress‐induced impairment in colonic physiology (↑short circuit current [Isc] and ↑conductance [G]) were also observed in NodDKO mice in addition to altered mRNA expression for pro‐inflammatory cytokines (↑IL6) and antimicrobial peptides (↓RegIIIγ).ConclusionOur study suggests that innate immune NLRs are important for the regulation of mood, cognitive memory and GI physiology in response to acute stress in part via an impaired HPA axis, demonstrating a critical role in the maintenance of the MGB axis and homeostasis.Support or Funding InformationThis work was funded by NIH 1R01AT009365‐01 (MGG), 5R21MH108154‐01 (MGG).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Perioperative Management of Patients on Steroids Requiring Surgery

Patients with chronic lung disease, inflammatory bowel disease, rheumatoid arthritis, and solid-organ transplantations are often on steroid supplementation either intermittently or chronically. Endogenous steroid use results in decreased adrenocorticotropic hormone secretion by the pituitary gland through negative feedback mechanisms. Over several weeks, this can result in adrenal gland atrophy, eventually leading to secondary adrenal insufficiency. Appropriate management of perioperative glucocorticoid replacement therapy can be challenging, but appropriate replacement is essential to optimize patient outcomes. Insufficient dosing of glucocorticoids during the perioperative period can result in hypotension and even death. Excessive treatment with glucocorticoids decreases wound healing, increases the risk of hyperglycemia, and increases susceptibility to infection. This review covers the historical perspective, the hypothalamic-pituitary-adrenal (HPA) axis, when to suspect an impaired HPA axis, an argument against supraphysiologic glucocorticoid treatment in the perioperative period, the rationale for treating patients with impaired renal function, guidelines for dosing glucocorticoids in the perioperative period, and consulting a specialist. Figures show a clinical algorithm for evaluation and treatment of adrenal insufficiency in the perioperative period and the HPA axis. Tables list steroid conversions and perioperative glucocorticoid treatment recommendations. This review contains 2 highly rendered figures, 2 tables, and 22 references.

Perioperative Management of Patients on Steroids Requiring Surgery

Patients with chronic lung disease, inflammatory bowel disease, rheumatoid arthritis, and solid-organ transplantations are often on steroid supplementation either intermittently or chronically. Endogenous steroid use results in decreased adrenocorticotropic hormone secretion by the pituitary gland through negative feedback mechanisms. Over several weeks, this can result in adrenal gland atrophy, eventually leading to secondary adrenal insufficiency. Appropriate management of perioperative glucocorticoid replacement therapy can be challenging, but appropriate replacement is essential to optimize patient outcomes. Insufficient dosing of glucocorticoids during the perioperative period can result in hypotension and even death. Excessive treatment with glucocorticoids decreases wound healing, increases the risk of hyperglycemia, and increases susceptibility to infection. This review covers the historical perspective, the hypothalamic-pituitary-adrenal (HPA) axis, when to suspect an impaired HPA axis, an argument against supraphysiologic glucocorticoid treatment in the perioperative period, the rationale for treating patients with impaired renal function, guidelines for dosing glucocorticoids in the perioperative period, and consulting a specialist. Figures show a clinical algorithm for evaluation and treatment of adrenal insufficiency in the perioperative period and the HPA axis. Tables list steroid conversions and perioperative glucocorticoid treatment recommendations. This review contains 2 highly rendered figures, 2 tables, and 22 references.

Impaired Neuroendocrine and Immune Response to Acute Stress in Medication-Naive Patients With a First Episode of Psychosis

Little is known about how the biological stress response systems--the autonomic nervous system (ANS), the hypothalamic-pituitary-adrenal (HPA) axis, and the immune system--function during psychosis. Results of studies on the effect of stress on the immune and autonomic system in patients with schizophrenia are inconsistent. The present study investigates whether the stress response is impaired in medication-naive patients with a first episode of psychosis. Ten male patients with a first episode of psychosis and 15 controls were exposed to the stress of public speaking. Parameters of the ANS (heart rate and catecholamines), the HPA axis (plasma adrenocorticotropic hormone [ACTH] and cortisol), and the immune system (number and activity of natural killer [NK] cells) were measured. Peak responses were calculated to examine the relationship between stress-induced activation of the different systems. Subjective stress and anxiety before and during the task were assessed. Patients and controls displayed similar autonomic responses to acute stress. However, there was an impaired HPA axis response, slow onset and return of ACTH, and flattened cortisol response and a reduced increase in number NK cells and NK cell activity in patients with a first episode of psychosis. Furthermore, in patients, the relationship between the different stress response systems was weaker or absent compared with controls. These findings indicate that impairments in stress processing are associated with the endophenotype of psychosis and are not a result of illness progression or antipsychotic medication.

Chronic Administration of Monosodium Glutamate under Chronic Variable Stress Impaired Hypothalamic-Pituitary-Adrenal Axis Function in Rats

The hypothalamic-pituitary-adrenal (HPA) axis is the primary endocrine system to respond to stress. The HPA axis may be affected by increased level of corticotrophin-releasing factors under chronic stress and by chronic administration of monosodium glutamate (MSG). The purpose of this study was to investigate whether chronic MSG administration aggravates chronic variable stress (CVS)-induced behavioral and hormonal changes. Twenty-four adult male Sprague-Dawley rats, weighing 200~220 g, were divided into 4 groups as follows: water administration (CON), MSG (3 g/kg) administration (MSG), CVS, and CVS with MSG (3 g/kg) administration (CVS+MSG). In addition, for the purpose of comparing the effect on plasma corticosterone levels between chronic stress and daily care or acute stress, 2 groups were added at the end of the experiment; the 2 new groups were as follows: naïve mice (n=7) and mice exposed to restraint stress for 2 h just before decapitation (A-Str, n=7). In an open field test performed after the experiment, the CVS+MSG group significant decrease in activity. The increase in relative adrenal weights in the CVS and CVS+MSG group was significantly greater than those in the CON and/or MSG groups. In spite of the increase in the relative adrenal weight, there was a significant decrease in the plasma corticosterone levels in the CVS+MSG group as compared to all other groups, except the naïve group. These results suggest that impaired HPA axis function as well as the decrease in the behavioral activity in adult rats can be induced by chronic MSG administration under CVS rather than CVS alone.

Neuroendocrine and Immunological Correlates of Chronic Stress in ‘Strictly Healthy’ Populations

Background: Chronic stress has been associated with detrimental or maladaptive neuroendocrine and immunological changes. Objectives: We assessed the neuroendocrine and immunological correlates of a realistic chronic stress experienced by strictly healthy caregivers of Alzheimer’s disease patients and age-matched controls. Methods: We screened 330 caregivers and 206 non-caregivers according to the ‘strictly healthy’ conditions established by the SENIEUR protocol. Forty-one strictly healthy caregivers (60.56 ± 16.56 years) and 33 non-stressed controls (60.27 ± 14.11 years) were selected for this study. Salivary cortisol and dehydroepiandrosterone sulfate (DHEAS) were assessed at multiple points by radioimmunoassay. Peripheral T cell proliferation and cellular sensitivity to glucocorticoids (corticosterone and dexamethasone, DEX) were evaluated by colorimetric assays. We also examined the hypothalamic-pituitary-adrenal (HPA) axis response to the administration of a low-dose DEX in vivo. Results: The caregivers were significantly more stressed, anxious and depressed than non-caregivers (all p < 0.0001), in contrast to similar cortisol levels. Caregivers had reduced DHEAS levels (–32%, p < 0.0001), an increased cortisol/DHEAS ratio (39.7%, p < 0.0001) and impaired HPA axis response to DEX intake. Caregivers had a higher T cell proliferation (p < 0.0001) and increased sensitivity to glucocorticoids in vitro (p < 0.01) as compared to non-stressed controls. Conclusions: Our results suggest that the maintenance of health in chronically stressed populations may be associated with both protective and detrimental neuroendocrine and immunological changes.

Peri-operative glucocorticoid replacement therapy in transsphenoidal pituitary adenoma surgery: a prospective controlled study

We set out to prospectively study the peri-operative changes of the hypothalamic-pituitary-adrenal axis (HPA), and to test the hypothesis that the peri-operative corticoid replacement regimen used at the authors' institution in patients with impaired HPA undergoing transsphenoidal pituitary adenoma surgery is adequate. Thirty seven patients (21 females, 16 males, mean age 50.6 years) underwent transsphenoidal pituitary adenoma surgery (mean tumour diameter 20.6 mm, 13 tumours hormone-secreting). The HPA functions of these patients were classified as impaired (group A, n = 15) or preserved (group B, n = 22) according to the results of a pre-operative corticotrophin releasing-hormone test (CRHT). Eleven patients (9 female, 2 male, mean age 53.6 years) without pituitary adenomas and with a preserved HPA (as assessed by medical history and morning serum cortisol (MSC) measurements), undergoing decompressive surgery for degenerative lumbar disc disease, were also studied (group C). On the day of surgery, the patients of group A received 100 mg hydrocortisone (HC) replacement therapy, which was thereafter gradually tapered off in a standardised fashion. The patients of groups B and C were not treated with corticoids. Pre-operative, intra-operative and post-operative variables of these three patient groups were compared. The urinary free cortisol excretion (UFC) in group A declined from 6732 +/- 7683 microg/d on the day of surgery to 305 +/- 358 microg/d on the 10(th) post-operative day. In group B, the respective UFC values were 12,851 +/- 16,278 microg/d and 223 +/- 235 microg/d. In both of these groups, the mean UFC did not fall into the normal range during the first ten post-operative days. On none of the post-operative days, was there a significant difference between the UFC of groups A and B. The UFC values of group C dropped from 177 +/- 157 microg/d on the day of surgery to 87 +/- 61 microg/d on post-operative day six, reaching the normal range from the 2(nd) post-operative day onwards. All UFC values of group C were significantly lower than those of group A and B. None of the evaluated clinical, laboratory and MRI parameters, as disclosed by uni- and multivariate analysis, showed any significant influence on the peri-operative UFC values. The peri-operative UFC of pituitary adenoma patients with preserved HPA was very high, as compared to patients with degenerative lumbar disc disease. The present study showed for the first time, that the proposed regimen of peri-operative corticoid replacement therapy used in patients with pituitary adenomas and impaired HPA raised cortisol levels to match the physiological increase of UFC in patients with pituitary adenoma surgery and preserved HPA. However, although statistically not significant, the UFC of patients with pituitary adenomas and preserved HPA seemed considerably higher on the day of surgery than in patients with pituitary adenomas and HPA impairment. Although there is no evidence to make it mandatory, administration of 150 mg instead of 100 mg HC substitution on the day of pituitary adenoma surgery in patients with HPA impairment may be prudent.

Impaired HPA axis and their feedback regulation in SERT knockout mice

A polymorphism in 5-HT transporter linked promoter region (5-HTTLPR) is related to the personality and affective disorders. To understand the mechanisms underlying this phenomenon, we used mice with reduced or deficient serotonin transporter (SERT+/− or −/− mice) as a model to investigate the mechanisms mediating their hypersensitivity to stress that is also observed in the humans with short alleles of 5-HTTLPR. We hypothesized that the hypothalamic-pituitary-adrenal (HPA) axis and their feedback regulation are impaired in these mice. The functional, cellular and molecular alterations in the components of HPA axis and the glucocorticoid receptor (GR)-related feedback regulation were characterized during basal and stressed conditions in SERT +/− and −/− mice relative to SERT+/+ mice. Our results revealed that the hypothalamic CRF neurons were suppressed in the basal condition, but was hyper-activated during stress in SERT+/− and −/− mice relative to SERT+/+ mice. The pituitary CRF 1 receptors were up-regulated and sensitized in SERT−/− mice. The basal levels of GR were reduced in the hypothalamus, pituitary and adrenal cortex of SERT+/− and −/− mice. Consistently, dexamethasome-induced attenuation of corticosterone was blunted in SERT−/− mice. These data suggest that the stress-induced hyperactivity of the HPA axis in SERT+/− and −/− mice may be due to the reduction of GR-mediated feedback regulation.

Salivary cortisol response to awakening in chronic fatigue syndrome.

There is accumulating evidence of hypothalamic-pituitary-adrenal (HPA) axis disturbances in chronic fatigue syndrome (CFS). The salivary cortisol response to awakening has been described recently as a non-invasive test of the capacity of the HPA axis to respond to stress. The results of this test correlate closely with those of more invasive dynamic tests reported in the literature; furthermore, it can be undertaken in a naturalistic setting. To assess the HPA axis using the salivary cortisol response to awakening in CFS. We measured salivary cortisol upon awakening and 10, 20, 30 and 60 min afterwards in 56 patients with CFS and 35 healthy volunteers. Patients had a lower cortisol response to awakening, measured by the area under the curve. This naturalistic test of the HPA axis response to stress showed impaired HPA axis function in CFS.

Early sexual abuse and low cortisol.

Post-traumatic stress disorder (PTSD) is a mental health disorder precipitated by a stressful event that produces fear or terror in the individual. Post-traumatic stress disorder studies, particularly in early sexual abuse, have been associated with neuroendocrine dysfunction, most notably the hypothalamic-pituitary-adrenal (HPA) axis. Since the literature on PTSD and neuroendocrine factors in young subjects has been sparse, the present studies were designed to look at the basal functioning of the HPA axis in response to early sexual abuse in girls aged 5 to 7 years. Morning salivary samples were collected for cortisol determination from subjects and controls who were scheduled for a physical exam by their pediatrician. The present study shows that subjects who had been abused within the last couple of months had significantly lower cortisol in comparison to control subjects (age, social economic status and race matched). The data suggest that children may have an impaired HPA axis after early trauma.

Evaluation of the integrity of the hypothalamic-pituitary-adrenal axis by insulin hypoglycemia test.

We retrospectively reviewed dynamic ACTH and cortisol responses to insulin hypoglycemia in 193 subjects with suspected ACTH deficiency to ascertain the predictive values of various diagnostic criteria. Based on the achievement of a peak cortisol level of 18 micrograms/dL or above, 133 subjects were classified as having an intact hypothalamic-pituitary-adrenal (HPA) axis, and 60 subjects were determined to have ACTH deficiency. Baseline and peak cortisol concentrations were strongly correlated (r = 0.63; P < 0.0001). Peak cortisol increased in parallel to ACTH increments, but plateaued at approximately 22 micrograms/dL at peak ACTH levels above approximately 75 pg/mL (r = 0.61; P < 0.0001). Basal cortisol values above 17 micrograms/dL or below 4 micrograms/dL were highly predictive of an intact or impaired HPA axis, respectively, but intermediate values had only limited sensitivity and specificity. The criteria of HPA axis integrity, defined as an increment in plasma cortisol of more than 7 micrograms/dL above the baseline or as a doubling of the baseline cortisol value, were associated with high false positive and false negative rates. We conclude that 1) the baseline morning serum cortisol concentration has very limited predictive power in differentiating between normal and impaired HPA function; 2) the use of criteria based on incremental changes in serum cortisol from baseline leads to unacceptably high false positive and false negative rates; and 3) insulin hypoglycemia is still the best indicator of the integrity of the response of the HPA axis to stress.

The effect of percutaneously absorbed steroids on hypothalamic--pituitary--adrenal function after intensive use in in-patients.

Hypothalamic-pituitary-adrenal (HPA) axis function has been monitored in adults and children who required intensive treatment of their skin disease with topical corticosteroid preparations while in hospital. Evidence of mild suppression of the HPA axis was seen in adults when the more potent topical steroids were used, but recovery of function was rapid when the intensive treatment ceased. In children suppression was still present in twelve of sixteen cases on the 2nd day after treatment with 0-1% betamethasone 17-valerate ointment had stopped, yet in nine cases treated in a comparable manner with 1% hydrocortisone acetate ointment, there was no evidence of impaired HPA axis function.