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.     

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.     

Immediate postoperative cortisol levels accurately predict postoperative hypothalamic–pituitary–adrenal axis function after transsphenoidal surgery for pituitary tumors

Accurate assessment of the hypothalamic–pituitary–adrenal (HPA) axis is critical for the appropriate management of patients with pituitary adenoma after transsphenoidal surgery. We examine the role of immediate postoperative cortisol levels to assess hypothalamic–pituitary–adrenal axis (HPA) axis function post-operatively. We performed preoperative cortrosyn stimulation test (CST) and measured immediate postoperative serum cortisol levels in 100 patients undergoing 104 transsphenoidal surgeries. These results were compared to those of the CST at 4–6 weeks postoperatively, which served as a measure of HPA axis function. The ability of immediate postoperative, day of surgery (DOS) cortisol levels to predict normal HPA axis function was determined using standard predictive analytic methods and confusion matrix calculations. We found that postoperative, DOS cortisol level ≥15 μg/dL is a sensitive and accurate predictors of normal postoperative HPA axis function, with a sensitivity of 98%, an accuracy of 97%, and a positive predictive value of 99%. Our data suggest that an immediate, postoperative, DOS cortisol level ≥15 μg/dL predicts distant, normal, post-operative HPA axis function following transsphenoidal surgery.     

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.     

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.     

Intra-articular methylprednisolone acetate injection at the knee joint and the hypothalamic–pituitary–adrenal axis: a randomized controlled study

The objective of this study was to evaluate the effect of intra-articular corticosteroid injection (IACI) of methylprednisolone acetate (MPA) on the hypothalamic–pituitary–adrenal (HPA) axis in patients with osteoarthritis of the knee. Patients with symptomatic osteoarthritis of the knee who failed to respond to nonsteroidal anti-inflammatory medications and physical therapy were randomized between group 1 and group 2. Group 1 patients had an IACI of 80 mg of MPA at the knee joint and group 2 patients had an intra-articular injection (IAI) of 6 ml (60 mg) of sodium hyaluronate (control group). Immediately prior to the IAI and on weeks 1, 2, 3, 4, and 8 following IAI, patients from both groups underwent a low-dose (1 μg) adrenocorticotropin hormone (ACTH) stimulation test. Demographic, clinical, laboratory, and radiologic variables were documented in all patients. Both criteria of <7 μg/dl increase in the serum cortisol level and absolute levels of <18 μg/dl 30 min following the ACTH stimulation test were used to define secondary adrenal insufficiency (SAI). Twenty patients were randomized in each group. In group 1, 25 % of patients had SAI vs. none in group 2 (p?=?0.0471). The earliest SAI was observed at week 2, and latest SAI was observed at week 4. SAI was observed at one time point, two consecutive time points, or two separate time points in the same patient. There was no correlation between SAI and any of the demographic, clinical, or laboratory variables. An IACI of 80 mg MPA at the knee joint induced a transient SAI in 25 % of the patients, an effect that was observed between week 2 and week 4 following the IACI.     

Hypothalamic–pituitary–gonadal axis homeostasis predicts longevity

The reproductive-cell cycle theory of aging posits that reproductive hormone changes associated with menopause and andropause drive senescence via altered cell cycle signaling. Using data from the Wisconsin Longitudinal Study (n?=?5,034), we analyzed the relationship between longevity and menopause, including other factors that impact “ovarian lifespan” such as births, oophorectomy, and hormone replacement therapy. We found that later onset of menopause was associated with lower mortality, with and without adjusting for additional factors (years of education, smoking status, body mass index, and marital status). Each year of delayed menopause resulted in a 2.9% reduction in mortality; after including a number of additional controls, the effect was attenuated modestly but remained statistically significant (2.6% reduction in mortality). We also found that no other reproductive parameters assessed added to the prediction of longevity, suggesting that reproductive factors shown to affect longevity elsewhere may be mediated by age of menopause. Thus, surgical and natural menopause at age 40, for example, resulted in identical survival probabilities. These results support the maintenance of the hypothalamic–pituitary–gonadal axis in homeostasis in prolonging human longevity, which provides a coherent framework for understanding the relationship between reproduction and longevity.     

The gut–brain axis in obesity

Currently the only effective treatment for morbid obesity with a proven mortality benefit is surgical intervention. The underlying mechanisms of these surgical techniques are unclear, but alterations in circulating gut hormone levels have been demonstrated to be at least one contributing factor. Gut hormones seem to communicate information from the gastrointestinal tract to the regulatory appetite centres within the central nervous system (CNS) via the so-called 'Gut-Brain-Axis'. Such information may be transferred to the CNS either via vagal or non-vagal afferent nerve signalling or directly via blood circulation. Complex neural networks, distributed throughout the forebrain and brainstem, are in control of feeding and energy homoeostasis.This article aims to review how appetite is potentially regulated by these gastrointestinal hormones. Identification of the underlying mechanisms of appetite and weight control may pave the way to develop better surgical techniques and new therapies in the future.     

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.     

The stomach–brain axis

The stomach has distinct functions in relation to the ingestion and handling of solids and liquids. These functions include storage of the food before it is gradually emptied into the duodenum, mechanical crushing of larger food particles to increase the surface area, secretion of an acidic enzyme rich gastric juice and mixing the ingested food with the gastric juice. In addition, the stomach ‘senses’ the composition of the gastric content and this information is passed via the vagal nerve to the lateral hypothalamus and the limbic system, most likely as palatability signals that influence eating behaviour. Other sensory qualities related to the stimulation of gastric tension receptors are satiety and fullness. Receptors that respond to macronutrient content or gastric wall tension influence appetite and meal related hormone responses.The ingestion of food – in contrast to an infusion of nutrients into the stomach – has distinct effects on the activation of specific brain regions. Brain areas such as thalamus, amygdala, putamen and praecuneus are activated by the ingestion of food. Gastric nutrient infusion evokes greater activation in the hippocampus and anterior cingulate. The brain integrates these interrelated neural and hormonal signals arising from the stomach as well as visual, olfactory and anticipatory stimuli that ultimately influence eating and other behavioural patterns. Furthermore, there is now good evidence from experimental studies that gastric afferents influence mood, and animal studies point towards the possibility that gastric dysfunction may be a risk factor for mood disorders such as anxiety and depression. The stomach is also not only colonised by Helicobacter pylori but a large array of bacteria. While there is sufficient evidence to suggest that H. pylori may alter caloric intake and mood, the role of other gastric microbiome for the brain function is unknown. To address this appropriate targeted gastric microbiome studies would be required instead of widely utilised opportunistic stool microbiome studies.In summary, it is now well established that there are important links between the brain and the stomach that have significant effects on gastric function. However, the stomach also influences the brain. Disturbances in the crosstalk between the stomach and the brain may manifest as functional GI disorders while disturbances in the stomach–brain communication may also result in an altered regulation of satiety and as a consequence may affect eating behaviour and mood. These observations may enable the identification of novel therapies targeted at the gastroduodenum that positively alter brain function and treat or prevent conditions such as obesity or functional gastrointestinal disorders.     

The joint–gut axis in inflammatory bowel diseases

Inflammatory bowel diseases, Crohn's disease and ulcerative colitis, are associated with a variety of extraintestinal manifestations. The most common extraintestinal manifestation, articular involvement, occurs in 16% to 33% of inflammatory bowel disease patients. These arthropathies may increase morbidity, resulting in a worse quality of life compared with inflammatory bowel disease patients without arthropathies. Thus, arthropathies in inflammatory bowel diseases represent a major medical problem in these patients. Arthritis associated with inflammatory bowel diseases is one of the diseases captured under the umbrella of spondyloarthritis. Spondyloarthritis is a group of inflammatory diseases with overlapping features and is linked to Human Leukocyte Antigen-B27. Arthropathy in inflammatory bowel diseases is clinically divided into peripheral and axial involvement. Peripheral arthritis often flares with relapses of bowel disease resulting in a different treatment approach than axial arthritis in which the course is independent of inflammatory bowel disease activity. Definitions, prevalence, pathophysiology and treatment of the arthropathies commonly seen in inflammatory bowel diseases such as peripheral arthritis, dactylitis, enthesitis, arthralgia, sacroiliitis, inflammatory back pain and ankylosing spondylitis are summarized.     

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.