The hypothalamic–pituitary–adrenal axis in critical illness

Hypothalamic-pituitary-adrenal (HPA) axis function is crucial to maintain and restore homeostasis. The HPA axis does not function in isolation. Rather, the HPA axis modulates and reacts to signals from endocrine, neural, and immune systems. Cortisol is the major glucocorticoid secreted by the human adrenal cortex. Its actions are largely mediated by the glucocorticoid receptor. The potent anti-inflammatory actions of glucocorticoids led to their use in critically ill patients. Metaanalyses of these early studies (before 1985) concluded that large glucocorticoid doses had no effect and were potentially detrimental. More recently, the pendulum has swung in the opposite direction based on the concept that critically ill patients may have relative adrenal insufficiency and/or acquired glucocorticoid resistance. However, inconsistent diagnostic criteria, heterogeneity of subjects, variable nutritional status, and pre-existing conditions preclude formulating definitive conclusions regarding glucocorticoid use among critically patients. Diagnosing adrenal insufficiency in the critically ill patient remains challenging. To resolve the issue, our challenge is to develop physiologically relevant tools to assess glucocorticoid action and GR function at the cellular level.     

The pituitary–adrenal axis and body composition

The activity of the pituitary–adrenal axis can profoundly impact on body composition. This is dramatically seen in Cushing’s syndrome (CS) but changes in body composition are also implicated in depression and alcoholic pseudocushing’s. The pathophysiological mechanisms underlying these changes remain poorly understood. Changes to body composition in CS include increased fat mass, decreased bone mass, thinning of the skin and reduced lean mass. Why these tissues are affected so dramatically is unclear. Additionally, the change in body composition between individuals varies considerably for reasons which are only now becoming evident. This paper reviews the phenotypic changes with altered pituitary–adrenal axis activity and discusses the mechanisms involved. The primary focus is on adipose, bone, muscle and skin since the most dramatic changes are seen in these tissues.     

Female hypogonadism: evaluation of the hypothalamic–pituitary–ovarian axis

Female hypogonadism refers to deficient or abnormal function of the hypothalamic–pituitary–ovarian axis that clinically presents with menstrual cycle disturbances. Female hypogonadism can be due to a congenital or acquired cause, and the defect can be at the level of the hypothalamus, pituitary or ovary. A careful history, physical exam and selected laboratory testing can often determine the locus of the defect and whether it results from a structural or hormonal problem. Laboratory testing generally relies on basal hormone levels; however, timing of blood sampling in relation to menses is important to interpretation of the data.     

Revised GH and cortisol cut-points for the glucagon stimulation test in the evaluation of GH and hypothalamic–pituitary–adrenal axes in adults: results from a prospective randomized multicenter study

Context

Recent studies suggest using lower GH cut-points for the glucagon stimulation test (GST) in diagnosing adult GH deficiency (GHD), especially in obese patients. There are limited data on evaluating GH and hypothalamic–pituitary–adrenal (HPA) axes using weight-based dosing for the GST.

Objective

To define GH and cortisol cut-points to diagnose adult GHD and secondary adrenal insufficiency (SAI) using the GST, and to compare fixed-dose (FD: 1 or 1.5 mg in patients >90 kg) with weight-based dosing (WB: 0.03 mg/kg). Response to the insulin tolerance test (ITT) was considered the gold standard, using GH and cortisol cut-points of ≥3 ng/ml and ≥18 µg/dL, respectively.

Design

28 Patients with hypothalamic-pituitary disease and 1–2 (n = 14) or ≥3 (n = 14) pituitary hormone deficiencies, and 14 control subjects matched for age, sex, estrogen status and body mass index (BMI) underwent the ITT, FD- and WB-GST in random order.

Results

Age, sex ratio and BMI were comparable between the three groups. The best GH cut-point for diagnosis of GHD was 1.0 (92 % sensitivity, 100 % specificity) and 2.0 ng/mL (96 % sensitivity and 100 % specificity) for FD- and WB-GST, respectively. Age negatively correlated with peak GH during FD-GST (r = ?0.32, P = 0.04), but not WB-GST. The best cortisol cut-point for diagnosis of SAI was 8.8 µg/dL (92 % sensitivity, 100 % specificity) and 11.2 µg/dL (92 % sensitivity and 100 % specificity) for FD-GST and WB-GST, respectively. Nausea was the most common side effect, and one patient had a seizure during the FD-GST.

Conclusion

The GST correctly classified GHD using GH cut-points of 1 ng/ml for FD-GST and 2 ng/ml for WB-GST, hence using 3 ng/ml as the GH cut-point will misclassify some GH-sufficient adults. The GST may also be an acceptable alternative to the ITT for evaluating the HPA axis utilizing cortisol cut-points of 9 µg/dL for FD-GST and 11 µg/dL for WB-GST.

     

The acute effect of fludrocortisone on basal and hCRH-stimulated hypothalamic–pituitary–adrenal (HPA) axis in humans

Mineralocorticoid receptors (MR) in the hippocampus display an important role in the control of hypothalamic–pituitary–adrenal (HPA)-axis, mediating the “proactive”-feedback of glucocorticoids. Fludrocortisone (FC), a potent MR agonist, has been shown to decrease HPA activity through a mechanism placed at hippocampal level. In order to clarify the effects of MR agonism on HPA function in humans, we studied the effects of FC, in a dose-related manner, on both basal and CRH-stimulated HPA axis during the quiescent phase. 8 young women were studied. ACTH, cortisol and aldosterone levels were evaluated every 15′, from 1600 to 2000 hours, in randomized sessions: (1) placebo p.o. + placebo i.v., (2) 0.3 mg FC p.o. + placebo, (3) 0.1 mg FC. + placebo, (4) 0.075 mg FC + placebo, (5) 0.05 mg FC + placebo, (6) placebo + hCRH (2.0 μg/kg iv-bolus), (7) 0.3 mg FC + hCRH, (8) 0.1 mg FC + hCRH, (9) 0.075 mg FC + hCRH, (10) 0.05 mg FC + hCRH. FC induced a dose-related trend toward a further decrease of the ACTH and cortisol levels, while it showed a significant and dose-dependent inhibition of the hormonal response to hCRH (p < 0.05 for the doses of 0.3, 0.1 and 0.075 mg). Conversely, 0.05 mg FC did not modify the CRH-stimulatory effect on both ACTH and cortisol secretion. Aldosterone levels were not modified by FC administration. Fludrocortisone inhibits corticotrope and adrenal response to hCRH in humans, in a dose-dependent manner. The 0.075 mg FC seems the lowest active while 0.05 mg the first neutral dose on HPA activity. These data suggest a possible hypophysial MR-mediated inhibiting effect of FC, although its pituitary glucocorticoid-mediated effect cannot be excluded. The interplay between fludrocortisone and hypophysial glucocorticoid receptors needs to be clarified in order to define better the clinical consequences of the hormonal replacement therapy of patients with primary adrenal insufficiency.     

Effects of experimentally induced hyperthyroidism on central hypothalamic–pituitary–adrenal axis function in rats: in vitro and in situ studies

Hyperthyroidism is associated with hypercorticosteronemia, although the locus that is principally responsible for the hypercorticosteronism remains unclear. The purpose of this study was to assess the effects of hyperthyroidism on the functional integrity of the hypothalamic–pituitary–adrenal (HPA) axis, to identify the locus in the HPA axis that is principally affected, and address the time-dependent effects of alterations in thyroid status. The functional integrity of each component of the HPA axis was examined in vitro and in situ in sham-thyroidectomized male Sprague–Dawley rats given placebo or in thyroidectomized rats given pharmacological dose (50 μg) of thyroxin for 7 or 60 days. Basal plasma corticosterone and corticosterone binding globulin (CBG) concentrations were significantly increased in short- and long-term hyperthyroid rats, and by 60 days. Basal plasma ACTH levels were similar to controls. Both hypothalamic CRH content and the magnitude of KCL- and arginine vasopressin (AVP)-induced CRH release from hypothalamic culture were increased in long-term hyperthyroid rats. There was a significant increase in the content of both ACTH and β-endorphin in the anterior pituitaries of both short- and long-term hyperthyroid animals. Short-term hyperthyroid rats showed a significant increase in basal POMC mRNA expression in the anterior pituitary, and chronically hyperthyroid animals showed increased stress-induced POMC mRNA expression. Adrenal cultures taken from short-term hyperthyroid rats responded to exogenous ACTH with an exaggerated corticosterone response, while those taken from 60-day hyperthyroid animals showed responses similar to controls. The findings show that hyperthyroidism is associated with hypercorticosteronemia and HPA axis dysfunction that becomes more pronounced as the duration of hyperthyroidism increases. The evidence suggests that experimentally induced hyperthyroidism is associated with central hyperactivity of the HPA axis.     

“Warming-promotion acupuncture ” on knee osteoarthritis:a randomized controlled trial

<正>Objective To observe the clinical efficacy differences between warming-promotion acupuncture,mild reinforcing-reducing acupuncture and acupoint injection for knee osteoarthritis(KOA).Methods Ninety cases of KOA were randomly assigned into a warming-promotion acupuncture group(group A),a mild reinforcing-edu-     

The effects of ultrasound-guided corticosteroid injection compared to oxygen–ozone (O2–O3) injection in patients with knee osteoarthritis: a randomized controlled trial

Clinical Rheumatology - Osteoarthritis (OA) is a chronic multifactorial disease characterized by progressive joint degeneration. The purpose of this study was to compare the effects of...     

Effects of prenatal stress on hypothalamic–pituitary–adrenal (HPA) axis function over two generations of guinea pigs (Cavia aperea f. porcellus)

Prenatal stress can alter hypothalamic-pituitary-adrenal axis function with potential consequences for later life. The aim of our study was to examine in guinea pigs (Cavia aperea f. porcellus) the effects of stress experienced during F0 pregnancy on glucocorticoid levels in plasma and feces, as well as challenge performance, in F1 offspring (n=44) and fecal glucocorticoid levels in F2 offspring (n=67). F1 animals were either born to F0 dams that had been stressed with strobe light during early to mid pregnancy, resulting in a short term increase but long-term down-regulation of maternal glucocorticoid levels, or to undisturbed F0 dams. The same stressor was used as a challenge for F1 offspring at age 26 days and around 100 days. Basal plasma cortisol concentrations during early F1 development, as well as overall glucocorticoid levels at challenge tests, were lower in F1 animals that were prenatally stressed than in control animals. Fecal cortisol metabolites were initially at lower levels in prenatally stressed F1 animals, relative to control animals, but shifted to higher levels around day 68, with an additional sex difference. Effects were also seen in the F2 generation, as male but not female offspring of prenatally stressed F1 animals had significantly higher levels of cortisol metabolites in feces after weaning. We conclude that stress exposure of F0 dams resulted in lower basal glucocorticoid levels in F1 offspring during the pre-pubertal phase and during stress exposure, but higher glucocorticoid levels in post-adolescent F1 animals. Also in males of F2 generation effects of stress exposure of F0 dams were detected.     

Effects of an educational–behavioral joint protection program on people with moderate to severe rheumatoid arthritis: a randomized controlled trial

The aim of this study was to asses the effects on pain, disability, and health status of an educational–behavioral joint protection program in a group of moderate–severe rheumatoid arthritis (RA) patients. Eighty-five subjects with RA in treatment with anti-tumor necrosis factor alpha (TNFα) drugs (infliximab) were enrolled into the study and randomized into either an experimental group (46, EG) or a control group (39, CG). We organized four EG meetings, which included information on pathophysiology and evolution of RA, joint protection during normal activities of daily living, suggestions on how to adapt the surrounding environment, and self-learning exercises to perform at home. Sociodemographic characteristics and degree of knowledge of the disease, measured by the Health Service Interview (HSI), were recorded at baseline. The outcome measures included the Visual Analogue Scale (VAS), the Arthritis Impact Measurement Scale 2 (AIMS2), and the Health Assessment Questionnaire (HAQ), which were administered at the beginning and end of the trial. Thirty-six patients from the EG (7 men and 29 women; mean age 54.2 years) and 34 from the CG (6 men and 28 women; mean age 52.2 years) completed the trial. No statistical differences in baseline evaluations were found between the two groups. According to the answers given on the HSI, the majority of our patients had poor knowledge of RA and its consequences. After a mean time of 8 months, the patients receiving educational training displayed a significant decrease, compared to the CG, in the VAS (p = 0.001), HAQ (p = 0.000), and physical (p =0.000), symptoms (p = 0.049), and social interaction (p = 0.045) scores on the AIMS2, but not in other items. Our study showed that 8 months after attending an educational–behavioral joint protection program, subjects with moderate–severe RA presented less pain and disability and thus an enhanced health status. This approach may efficiently complement drug therapy in these patients.     

Does knee malalignment mediate the effects of quadriceps strengthening on knee adduction moment, pain, and function in medial knee osteoarthritis? A randomized controlled trial

OBJECTIVE: To examine whether the effects of 12 weeks of quadriceps strengthening on the knee adduction moment, pain, and function in people with medial knee osteoarthritis (OA) differ in those with and without varus malalignment. METHODS: A single-blind, randomized controlled trial of 107 community volunteers with medial knee OA was conducted. Participants were stratified according to knee malalignment (more varus or more neutral) and then randomized into either a 12-week supervised home-based quadriceps strengthening group or a control group with no intervention. The primary outcome was the knee adduction moment, measured using 3-dimensional gait analysis. Secondary outcomes included the Western Ontario and McMaster Universities Osteoarthritis Index scores (measuring pain and physical function), step test score, stair climb test score, and maximum quadriceps isometric strength. Analyses of covariance were carried out based on intent-to-treat principles. RESULTS: Quadriceps strengthening did not significantly alter the knee adduction moment in either the more malaligned or the more neutral group (unadjusted knee adduction moment 0.12 and 0.05% Nm/BWxHT, respectively). Function did not improve significantly following quadriceps strengthening in either alignment group, but there was a significant improvement in knee pain in the more neutrally aligned group (P < 0.001). CONCLUSION: Quadriceps strengthening did not have any significant effect on the knee adduction moment in participants with either more varus or more neutral alignment. The benefits of quadriceps strengthening on pain were more evident in those with more neutral alignment. Knee alignment thus represents a local mechanical factor that can mediate symptomatic outcome from exercise interventions in knee OA.     

Oral enzyme combination versus diclofenac in the treatment of osteoarthritis of the knee – a double-blind prospective randomized study

The aim of this study was to compare the efficacy and safety of an oral enzyme–rutosid combination (ERC) containing rutosid and the enzymes bromelain and trypsin, with that of diclofenac in patients with osteoarthritis (OA) of the knee. A total of 103 patients presenting with painful episodes of OA of the knee were treated for 6 weeks in two study centers in a randomized, double-blind, parallel group trial. Altogether, 52 patients were treated in the ERC group and 51 patients were treated in the diclofenac group. Primary efficacy criteria were Lequesnes Algofunctional Index (LFI) and a complaint index, including pain at rest, pain on motion and restricted function. The efficacy criteria were analyzed by applying the Wilcoxon–Mann–Whitney test that provides the Mann–Whitney estimator (MW) as a measure of relevance. Non-inferiority was considered to be proven if the lower bound of the 97.5% one-sided confidence interval (CI-LB) was higher than MW=0.36 (benchmark of not yet relevant inferiority). Both treatments resulted in clear improvements. Within the 6-week observation period, the mean value of the LFI decreased from 13.0 to 9.4 in the ERC group and from 12.5 to 9.4 in the diclofenac group. Non-inferiority of ERC was demonstrated by both primary criteria, LFI (MW=0.5305; CI-LB=0.4171) and complaint index (MW=0.5434; CI-LB=0.4296). Considerable improvements were also seen in secondary efficacy criteria, with a slight tendency towards superiority of ERC. The global judgment of efficacy by physician resulted in at least good ratings for 51.4% of the ERC patients, and for 37.2% of the diclofenac patients. In the majority of patients tolerability was judged in both drug groups as very good or good. The current study indicates that ERC can be considered as an effective and safe alternative to NSAIDs such as diclofenac in the treatment of painful episodes of OA of the knee. Placebo-controlled studies are now needed to confirm these results.Abbreviations ERC Enzyme–rutosid combination - LFI Lequesnes Algofunctional Index Dr. Mehnaz Rashid was the Clinical Trials monitor on behalf of Pacific Pharmaceuticals (Lahore, Pakistan) and Dr. W. Schiess played the same role on behalf of Mucos Pharma (Germany)     

Sulphonylureas and cancer: a case–control study

This study was aimed at the assessment of incidence of malignancies in type 2 diabetic patients treated with different sulphonylureas. A matched case–control study was performed. Cases were 195 diabetic patients aged 69.0 ± 9.2 years who had an incident malignancy. Controls were 195 diabetic patients, unaffected by cancer, who were matched with the corresponding case for age, sex, duration of diabetes, BMI, HbA1_c, comorbidity, smoking and alcohol abuse. Exposure to hypoglycaemic drugs during the 10 years preceding the event (or matching index date) was assessed. After adjusting for concomitant therapies, exposure to metformin and gliclazide for more than 36 months was associated with a significant reduction in the risk of cancer (adj. ORs with 95% CI: 0.28 (0.13–0.57), p < 0.001, and 0.40 (0.21–0.57), p = 0.004, respectively). Conversely, use of glibenclamide for at least 36 months was associated with increased incidence of malignancies (adj. OR 2.62 (1.26–5.42); p = 0.009). Treatment with insulin, thiazolidinediones, or acarbose, was not associated with significant differences in the incidence of cancer. Long-term treatments with individual sulphonylureas could have differential effects on the risk of cancer. In particular, the possible protective effect of gliclazide, as well as the risk associated with glibenclamide, deserves further investigation.     

Physician education and report cards: do they make the grade? results from a randomized controlled trial

PURPOSE: We sought to determine whether tailored educational interventions call improve the quality of care, as measured by the provision of preventive care services recommended by the US Preventive Services Task Force, as well as lead to better patient satisfaction. SUBJECT AND METHODS: We performed a randomized controlled study among 41 primary care physicians who cared for 1,810 randomly selected patients aged 65 to 75 years old at Kaiser Permanente Woodland Hills, a group-model health maintenance organization in southern California. All physicians received ongoing education. Physicians randomly assigned to the comprehensive intervention group also received peer-comparison feedback and academic detailing. Baseline and postintervention (2 to 2.5 years later) surveys examining the provision of preventive care and patient satisfaction were performed and medical records were reviewed. RESULTS: Based on the results of patient surveys, there were significant improvements over time in the provision of preventive care in both the education and the comprehensive intervention groups for influenza immunization (79% versus 89%, P <0.01, and 80% versus 91%, P <0.01), pneumococcal immunization (42% versus 73%, P < 0.01 and 34% versus 73%, P < 0.01), and tetanus immunization (64% versus 72%, P <0.01, and 59% versus 79%, P <0.01). Mammography (90% versus 80%, P <0.01) and clinical breast examination (85% versus 79%, P <0.05) scores worsened in the education only group but not in the comprehensive intervention group. However, there were few differences in rates of preventive services between the groups at the end of the study, and the improvements in preventive care were not confirmed by medical record review. Patient satisfaction scores improved significantly in the comprehensive intervention group (by 0.06 points on a 1 to 5 scale, P = 0.02) but not in the education only group (by 0.02 points, P = 0.42); however, the improvement was not significantly greater in the comprehensive intervention group (P = 0.20). CONCLUSION: A physician-targeted approach of education, peer-comparison feedback, and academic detailing has modest effects on patient satisfaction and possibly on the offering of selected preventive care services. The lack of agreement between patient reports and medical records review raises concerns about current methods of ascertaining compliance with guidelines for preventive care.     

Symptomatic knee osteonecrosis in patients with systemic lupus erythematosus: a case–control study

To explore the associated risk factors of symptomatic knee osteonecrosis (KON) in patients with systemic lupus erythematosus (SLE), we conducted a retrospective case–control study to compare the clinical and laboratory features between SLE patients with and without symptomatic KON matched by age and gender. Univariate and multivariate regression analyses were used to evaluate possible associated risk factors. Twenty (one male, nineteen females) out of 3941 lupus patients were identified as symptomatic KON, which was confirmed by magnetic resonance imaging. The mean age at KON onset was 34.4 (range 12–67) years, and the median course of lupus at KON onset was 72.5 (range 8–123) months. Univariate and multivariate analyses identified that the prevalence of cutaneous vasculitis (OR 5.23; 95 % CI 1.11–24.70), hyperfibrinogenemia (OR 4.75; 95 % CI 1.08–20.85), and elevated IgG levels (OR 6.05; 95 % CI 1.58–23.16) were statistically higher in KON group, and hydroxychloroquine (HCQ) usage was statistically lower in KON group (OR 0.27; 95 % CI 0.07–0.97). Glucocorticoid usage, in terms of maximal dose, duration of treatment, and the percentage of receiving methylprednisolone pulse therapy, did not show statistical difference between the two groups (p > 0.05). Symptomatic KON is a relatively rare complication of SLE. Cutaneous vasculitis, hyperfibrinogenemia, and elevated IgG levels are possible risk factors, whereas HCQ may provide a protective effect. Our results suggest that lupus activity as well as hypercoagulation status may play a role in the pathogenesis of KON in lupus.