Glucocorticoid Hormones Research Articles

Endocrine hormone imbalance in heart failure with reduced ejection fraction: A cross-sectional study.

Sustained neurohormonal activation plays a central role in the progression of heart failure (HF). Other endocrine axes may also be affected. It was the aim of this study to examine the endocrine profile (thyroid, parathyroid, glucocorticoid, and sex hormones) in a contemporary sample of patients with HF and reduced ejection fraction (EF) on established disease-modifying therapy. This study prospectively measured morning fasting hormones in 52 ambulatory and stable HF patients with EF < 50% on disease-modifying therapy (mean age 63 ± 11 years, 29% female, mean LVEF 32 ± 9.6%) and compared them to 54 patients at elevated risk for HF (61 ± 12 years, 28% female) and 62 healthy controls (HC; 61 ± 13 years, 27% female). Main comparisons were performed using one-way analysis of variance. Associations with biomarkers were studied with linear regression. HF patients showed a reduced free triiodothyronine (fT3)/free thyroxine (fT4) ratio compared to HC (0.30 ± 0.06 vs. 0.33 ± 0.05, p = 0.046). Parathyroid hormone (PTH) and cortisol were increased in HF compared to both HC (median [IQR] 59 [50-84] vs. 46 [37-52] ng/L,p < 0.001 and 497 ± 150 vs. 436 ± 108 nmol/L, p = 0.03, respectively) and patients at risk (both p < 0.001). Total testosterone was reduced in male HF compared to HC (14.4 ± 6.6 vs. 18.6 ± 5.3 nmol/L; p = 0.01). No differences in TSH, estradiol, progesterone, and prolactin were found. Lower fT3 levels were found in HF with EF < 40% versus EF 40%-49% (4.6 ± 0.3 vs. 5.2 ± 0.7 pmol/L, p = 0.009). In HF patients, fT3 was an independent predictor of NT-proBNP and high-sensitivity troponin T in multiple regression analysis. PTH was positively associated with NT-proBNP. There is evidence of endocrine hormonal imbalance in HF with reduced EF beyond principal neurohormones and despite the use of disease-modifying therapy.

The ATP-binding cassette proteins ABCB1 and ABCC1 as modulators of glucocorticoid action.

Responses to hormones that act through nuclear receptors are controlled by modulating hormone concentrations not only in the circulation but also within target tissues. The role of enzymes that amplify or reduce local hormone concentrations is well established for glucocorticoid and other lipophilic hormones; moreover, transmembrane transporters have proven critical in determining tissue responses to thyroid hormones. However, there has been less consideration of the role of transmembrane transport for steroid hormones. ATP-binding cassette (ABC) proteins were first shown to influence the accumulation of glucocorticoids in cells almost three decades ago, but observations over the past 10 years suggest that differential transport propensities of both exogenous and endogenous glucocorticoids by ABCB1 and ABCC1 transporters provide a mechanism whereby different tissues are preferentially sensitive to different steroids. This Review summarizes this evidence and the new insights provided for the physiology and pharmacology of glucocorticoid action, including new approaches to glucocorticoid replacement.

Changes in mononuclear cell subsets in capillary and venous blood of patients with psoriasis depending on the treatment

Topical glucocorticoids are conventionally used to treat psoriasis, but such treatment provides a short-term effect, and may cause various complications during long-term usage. A detailed study of the immunopathogenesis of psoriasis has made it possible to use bioengineered drugs that block the main cytokines. It has been shown that IL-36 plays an important regulatory role in pathogenesis of psoriasis. The aim of the study was to study therapeutic effect of patients with psoriasis using topical glucocorticoid hormone versus IL- 36 receptor antagonist (RAIL-36), with respect to clinical course of psoriasis and the subsets of mononuclear cells in venous and capillary blood taken close to the focus of inflammation. 16 patients with psoriasis (group 1a) received 0.1% mometasone cream for 14 days; 20 patients of group 1b received a gel containing 0.4% recombinant RAIL-36 for 14 days. Control group included 20 healthy adults. Treatment efficacy was assessed by PASI, DISHS and DLQI indices. 19 lymphocyte subsets and 3 monocyte subsets were assessed by four-color staining of whole capillary and venous blood with erythrocyte lysis using BD Biosciences (USA) technologies and reagents. It was shown that both drugs led to a decrease in the severity of the disease at the end of treatment. However, 2 weeks after the end of treatment in group 1a, the disease indexes nearly returned to the initial values. Meanwhile, the reduced index levels persisted 2 weeks later in group 1b. Significant deviations (more pronounced in capillary blood) were revealed for the levels of several leukocyte subsets in the psoriasis patients compared with healthy persons. As a result of treatment, we have revealed some changes in the levels of leukocyte subsets common to the two groups, and special differences for the two treatment options, that were more pronounced in capillary blood samples. Both medical preparations used are suitable for treatment of psoriasis.

Fitness consequences of chronic exposure to different light pollution wavelengths in nocturnal and diurnal rodents

Use of artificial at night (ALAN) exposes the world to continuously increasing levels and distribution of light pollution. Our understanding of the adverse effects of ALAN is based mostly on observational or laboratory studies, and its effects are probably underestimated. Demonstration of direct experimental fitness consequences of ALAN on mammals is missing. We studied the effects of chronic light pollution at different wavelengths on fitness and glucocorticoid hormone levels under semi-natural conditions in two closely related species: the nocturnal common spiny mouse (Acomys cahirinus) and the diurnal golden spiny mouse (Acomys russatus). Our results clearly demonstrate the adverse effects of ALAN exposure on the fitness of both nocturnal and diurnal species, manifested by changes in cortisol levels and reproductive timing, reduced reproductive output and reduced survival, which differed between species and wavelengths. In A. russatus exposure to blue ALAN had the strongest effect on fitness, followed by white and yellow ALAN exposure. In A. cahirinus the results are more complex and suggest it suffered from the combined effects of ALAN and competition. Our research shows that light pollution presents a real threat to both nocturnal and diurnal species, affecting the species fitness directly and through interspecific interactions. Worryingly, these effects are probably not limited to spiny mice. The clear adverse effects we documented, as well as the differences between wave lengths, contribute to our ability to present science-based recommendations to decision makers regarding the use of artificial light at night. Such information and guidelines are highly important nowadays when lighting systems are being replaced to promote energy efficiency.

Season and reproductive activity influence cortisol levels in the Malagasy primate Lepilemur edwardsi.

Throughout the year, wild animals are exposed to a variety of challenges such as changing environmental conditions and reproductive activity. These challenges may affect their stress hormone levels for varying durations and in varying intensities and impacts. Measurements of the glucocorticoid hormone cortisol in the hair of mammals are considered a good biomarker for measuring physiological stress and are increasingly used to evaluate stress hormone levels of wild animals. Here, we examined the influence of season, reproductive activity, sex, as well as body condition on hair cortisol concentrations (HCC) in Lepilemur edwardsi, a small Malagasy primate species. L. edwardsi lives in the seasonal dry forests of western Madagascar, which are characterized by a strongly changing resource availability throughout the year. We hypothesized that these seasonal changes of resource availability and additionally the reproductive cycle of this species would influence HCC of L. edwardsi. Results revealed that hair cortisol concentration of females did not change seasonally or with the reproductive cycle. However, we found a significant increase of hair cortisol levels in males from the early wet season during the early dry season (mating season). This increase is presumably due to changed behavior during the mating season, as sportive lemurs travel more and show aggressive behavior during this time of the year. This behavior is energy-costly and stressful, and presumably leads to elevated HCC. As elevated cortisol levels may impair immune function, L. edwardsi males might also be more susceptible to parasites and diseases, which is unfavorable in particular during a period of low resource availability (dry season).

Biphasic Response of Astrocytic Brain-Derived Neurotrophic Factor Expression following Corticosterone Stimulation.

Novel research studies indicate multivarious interactions of glucocorticoid hormones (GCs) with the brain-derived neurotrophic factor (BDNF), regulating important aspects of neuronal cell physiology. While there is recent evidence of the chronic effects of GC stimulation on BDNF levels, as well as of the role of BDNF stimulation in the type of genomic effects following activation of GC-sensitive receptors, no data exist concerning the acute effects of GC stimulation on BDNF/TrkB gene expression. To address this question, we conducted a chrono-pharmacological study on rodent glial cells, astrocytes, which express the BDNF receptor, TrkB, following corticosterone administration. mRNA levels of BDNF and TrkB were estimated 1, 6, 12 and 24 h post-treatment. Selective inhibitors for GC-sensitive receptors and TrkB were used to decipher the molecular pathways of the effects observed. Our data support a biphasic response of BDNF expression after corticosterone stimulation. This response is characterized by a rapid TrkB phosphorylation-dependent upregulation of BDNF mRNA within the first hour, followed by a glucocorticoid receptor (GR)-dependent downregulation of BDNF mRNA, evident at 6, 12 and 24 h, with a direct impact on the protein levels of mature BDNF. Finally, a second pulse of corticosterone administration 1 h prior to the 6, 12 or 24 h timepoints normalized BDNF expression for the corresponding timepoint (i.e., mRNA levels became indifferent from baseline). These results present for the first time a biphasic regulation of the neurotrophin system based on glucocorticoid rhythmicity, further indicating complex trophic responses to temporal hormonal mechanisms in the brain microenvironment.

Serum amyloid A, a host-derived DAMP in pregnancy?

Serum amyloid A (SAA) is one of the acute phase proteins released primarily from the liver in response to infection, inflammation and trauma. Emerging evidence indicates that SAA may function as a host-derived damage-associated molecular pattern (DAMP) protein to sense danger signals in pregnancy. The plasma SAA levels in maternal circulation are significantly increased in normal parturition, particularly in postpartum, as well as in gestational disorders such as premature preterm rupture of membranes, pre-eclampsia, gestational diabetes, and recurrent spontaneous abortion. It is likely that SAA acts as a non-specific DAMP molecule in response to inflammation and trauma experienced under these conditions. Notably, SAA can also be synthesized locally in virtually all gestational tissues. Within these gestational tissues, under the induction by bacterial products, pro-inflammatory cytokines and stress hormone glucocorticoids, SAA may exert tissue-specific effects as a toll-like receptor 4 (TLR4)-sensed DAMP molecule. SAA may promote parturition through stimulation of inflammatory reactions via induction of pro-inflammatory cytokines, chemokines, adhesion molecules and prostaglandins in the uterus, fetal membranes and placenta. In the fetal membranes, SAA may also facilitate membrane rupture through induction of matrix metalloproteases (MMPs)- and autophagy-mediated collagen breakdown and attenuation of lysyl oxidase-mediated collagen cross-linking. SAA synthesized in extravillous trophoblasts may promote their invasiveness into the endometrium in placentation. Here, we summarized the current understanding of SAA in pregnancy with an aim to stimulate in-depth investigation of SAA in pregnancy, which may help better understand how inflammation is initiated in gestational tissues in both normal and abnormal pregnancies.

Effect of Increased Corticosterone Levels Due to Chronic Stress on Body Weight Changes in Rattus norvegicus

Background: Stressors in everyday life cannot be predicted in various forms; if individuals cannot cope with exposure to stress, it causes chronic conditions. Corticosterone is a biomarker associated with chronic adaptation. Weight loss is associated with an increase in glucocorticoid hormones due to stress which affects the burning of brown fat so that calories are burned.Objective: Analyze the effect of increasing serum corticosterone levels due to chronic stress on changes in body weight of Rattus novergicus.Methods: Samples were 34 Rattus norvegicus which were divided into 2 groups, control and stress treatment using the Chronic Unpredictable Mild Stress (CUMS) method. Serum corticosterone levels were detected by ELISA examination and body weight changes were monitored twice, before and after CUMS was given.Results: Corticosterone in the treatment group was higher (72.84 ± 64.03) than the control group (23.29 ± 8.42). Changes in body weight of the control group (14.62 ± 4.98) were heavier than the treatment group (-10.33 ± 11.24). Statistical test p=0.000 (p &lt;0.05).Conclusion: chronic stress increases corticosterone hormone levels in Rattus novergicus serum and increased levels of corticosterone hormone can reduce body weight.

Pathogenesis of Sepsis

Sepsis is a clinical condition caused by the body's immune response to infection and manifests as SIRS. Systemic inflammatory response syndrome is a state of systemic inflammatory response characterized by two or more of the following conditions. Etiology Sepsis can be caused by various microorganisms and the most etiology of sepsis is bacterial. Gram-negative bacteria cause sepsis about 60% - 70% in developing countries, but in the United States the causes of infection by Gram-positive bacteria begin to increase. This may be due to the large number of uses of invasive procedures, increased hospital acquired pneumonia (HAP) and antibiotic resistance. The body also has anti-inflammatory mechanisms including increased levels of anti-inflammatory cytokines and glucocorticoid hormones. The hormone inhibits the synthesis of cytokines by monocytes and decreases the ability of neutrophils to attach to the vascular endothelium. The inflammatory process in sepsis is not controlled leading to the occurrence of excessive discharge of inflammatory mediators over a long time and goes beyond the anti-inflammatory mechanisms of the body. This leads to various organ dysfunctions including cardiovascular, liver, pulmonary and renal dysfunctions

Natural and experimental cold exposure in adulthood increase the sensitivity to future stressors in a free‐living songbird

Abstract As the global climate shifts, many species are imperilled by changing thermal regimes. Despite rising global temperatures, some populations must contend with more frequent or extreme cold. In these populations, the ability to cope with cold may be an important determinant of fitness. Experiments in captive animals have shown that extreme cold or rapid temperature declines typically elicit an increase in glucocorticoid hormones (mediators of the stress response); however, it is not known whether free‐living adults, which may be better at buffering the effects of cold, show a similar response to ecologically relevant thermal challenges. The effects of cold on the sensitivity to future challenges are also poorly understood. Using targeted manipulations of nest temperature in free‐living tree swallows Tachycineta bicolor and a long‐term dataset (2,888 samples; 8 years), we tested the relationship between cold exposure and glucocorticoid levels in adults. Both natural and experimental cold exposure altered glucocorticoid regulation. This manifested primarily in terms of an upregulation in the sensitivity to future challenges (stress‐induced levels). Experimental cold exposure also increased the initial speed and duration of the acute stress response. Analyses of the long‐term dataset found that baseline glucocorticoids were higher in cold conditions; however, the magnitude of this effect was weak. A sliding window analysis revealed differences in the timeline over which temperature best predicted baseline and stress‐induced glucocorticoids. Although unpredictability is often regarded as a defining factor of stressors, we found that recent ambient temperatures better predicted circulating corticosterone than measures of thermal unpredictability, including the degree of recent temperature change and negative prediction error (the difference between experienced temperatures and long‐term averages). Together, these results suggest that thermally induced increases in the sensitivity to future challenges may prime individuals to respond more strongly or rapidly to worsening conditions, or to subsequent challenges of a different type, without incurring the costs that can result from substantial elevations in baseline glucocorticoids. This kind of preparatory response could be adaptive; however, an increased sensitivity to other challenges could also represent an overlooked cost of changing thermal regimes. Read the free Plain Language Summary for this article on the Journal blog.

Increased lead and glucocorticoid concentrations reduce reproductive success in house sparrows along an urban gradient.

Urbanization is increasing at a rapid pace globally. Understanding the links among environmental characteristics, phenotypes, and fitness enables researchers to predict the impact of changing landscapes on individuals and populations. Although avian reproductive output is typically lower in urban compared with natural areas, the underlying reasons for this discrepancy may lie at the intersection of abiotic and biotic environmental and individual differences. Recent advances in urban ecology highlight the effect of heavy metal contamination on stress physiology. As high levels of glucocorticoid hormones decrease parental investment, these hormones might be the link to decreased reproductive success in areas of high environmental pollution. In this study, we aimed to identify which abiotic stressors are linked to avian reproductive output in urban areas and whether this link is mediated by individual hormone levels. We used fine-scaled estimates (2 m2 spatial resolution) of nighttime light, noise, and urban density to assess their impacts on the physiological condition of adult house sparrows (Passer domesticus). We measured circulating levels of lead and glucocorticoid concentrations in 40 breeding pairs of free-living house sparrows and related these physiological traits to reproductive success. Using structural equation modeling, we found that increased urban density levels linked directly to increased plasma corticosterone and lead concentrations that subsequently led to decreased fledgling mass. Sparrows with increased lead concentrations in plasma also had higher corticosterone levels. Although urban areas may be attractive due to decreased natural predators and available nesting sites, they may act as ecological traps that increase physiological damage and decrease fitness. To illustrate, avian development is strongly explained by parental corticosterone levels, which vary significantly in response to urban density and lead pollution. With fine-scale ecological mapping for a species with small home ranges, we demonstrated the presence and impacts of urban stressors in a small city with high human densities.

Blubber and serum cortisol concentrations as indicators of the stress response and overall health status in striped dolphins

The impacts of environmental changes and anthropogenic threats in marine mammals are a growing concern for their conservation. In recent years, efforts have been directed to understand how marine mammals cope with stressors and to assess and validate stress biomarkers, mainly levels of glucocorticoid hormones (e.g. cortisol) in certain body tissues. The aims of this study were to assess the impact of different causes of stranding (chronically affected and bycaught striped dolphins) on cortisol concentrations in serum and in blubber; and to evaluate the association between cortisol levels in these tissues. Blubber and blood samples were collected from striped dolphins (n = 42) stranded on the Mediterranean coast between 2012 and 2018. Cortisol concentrations were measured by using enzyme immunoassay. A high correlation was found between circulating and blubber cortisol concentrations (R2 = 0.85, p < 0.01). Necropsies and pathological studies concluded that a third of the dolphins were bycaught in fishing nets and released by fishermen (Bycaught animals group), while the other two thirds were euthanized, or died, due to a disease or chronic condition (e.g. calves separated from the mother or animals infected with dolphin morbillivirus or Brucella ceti) that impeded survival (Chronically affected animals group). Cortisol concentrations (mean ± SD) were six times higher in chronically affected animals (35.3 ± 23 ng cortisol/g blubber and 6.63 ± 3.22 μg cortisol/dl serum) compared to those bycaught in fishing nets (6.2 ± 4.3 ng cortisol/g blubber and 1.15 ± 1.51 μg cortisol/dl serum). Results suggests that serum and blubber cortisol concentrations can contribute in inferring the overall health and welfare of free-ranging cetaceans. However, further research is required to understand better the kinetics of blubber cortisol incorporation and removal, the factors involved in these processes, and the local conversion of cortisol in the blubber.

Environmental Stress and the Primate Microbiome: Glucocorticoids Contribute to Structure Gut Bacterial Communities of Black Howler Monkeys in Anthropogenically Disturbed Forest Fragments

Animals living in anthropogenically disturbed habitats are exposed to environmental stressors which can trigger physiological reactions, such as chronic elevations of glucocorticoid hormones. Physiological responses to stressors may induce changes in the gut microbiome, most likely, facilitated by the gut–brain communication. Although these effects have been observed in humans and animal models, elucidating gut bacterial changes in wild animals under natural stressful conditions is still an ongoing task. Here we analyzed the association between physiological stress related to anthropogenic forest disturbance and changes in gut bacterial communities of black howler monkeys (Alouatta pigra) living in forest fragments in Mexico. We measured individuals’ fecal glucocorticoid metabolites (fGCMs) as an index of physiological stress and created inventories of fecal bacterial communities sequencing the 16S rRNA gene to assess gut microbiome change. We evaluated environmental stress by estimating differences in food availability – feeding tree diversity and biomass – in each group’s habitat. We found that both fGCMs and food availability indices were related to gut bacterial community shifts in black howler monkeys. Furthermore, using structural equation modeling, we found that a decrease in food availability, estimated through reductions in feeding tree basal area, increased fGCMs, which in turn induced increases in bacterial richness. Our findings show that the activation of the hypothalamic–pituitary–adrenal (HPA)-axis, which is a physiological response sensitive to environmental stressors such as the ecological disturbance of a habitat, contributes to structure the gut microbiome of arboreal primates in disturbed forests.

Naturally stressed? Glucocorticoid profiles in blubber of blue and gray whales in response to life history parameters.

The goal of the present study was to carry out a thorough methodological validation and describe baseline profiles for glucocorticoid hormones (cortisol and corticosterone) in blubber from blue (n = 77) and gray (n = 103) whales from the eastern North Pacific Ocean. For each species, we modelled cortisol and corticosterone concentrations in response to life history parameters (age, sex, reproductive status) and season or geographic location. In blue whales, cortisol concentrations did not vary significantly by age class, sex, or reproductive status, whereas corticosterone was significantly lower in immature than in adult females (p < .001). In gray whales, cortisol concentrations were significantly higher in lactating whales (p < .05), while corticosterone was significantly different between females and males (p = .001) and elevated in calves (p = .003). In gray whales, corticosterone concentrations were significantly lower in males sampled later in the year (August to November) compared to both sexes sampled between March and August (p = .05), but no seasonal trend occurred in blue whales. Our results indicate that glucocorticoid actions vary between species and sex in large whales. Analysis of multiple hormones improves our understanding of the physiology of maintaining metabolic homeostasis or coping with chronic stressors.

Glucocorticoid signaling and regulatory T cells cooperate to maintain the hair-follicle stem-cell niche.

Maintenance of tissue homeostasis is dependent on the communication between stem cells and supporting cells in the same niche. Regulatory T cells (Treg cells) are emerging as a critical component of the stem-cell niche for supporting their differentiation. How Treg cells sense dynamic signals in this microenvironment and communicate with stem cells is mostly unknown. In the present study, by using hair follicles (HFs) to study Treg cell-stem cell crosstalk, we show an unrecognized function of the steroid hormone glucocorticoid in instructing skin-resident Treg cells to facilitate HF stem-cell (HFSC) activation and HF regeneration. Ablation of the glucocorticoid receptor (GR) in Treg cells blocks hair regeneration without affecting immune homeostasis. Mechanistically, GR and Foxp3 cooperate in Treg cells to induce transforming growth factor β3 (TGF-β3), which activates Smad2/3 in HFSCs and facilitates HFSC proliferation. The present study identifies crosstalk between Treg cells and HFSCs mediated by the GR-TGF-β3 axis, highlighting a possible means of manipulating Treg cells to support tissue regeneration.

The Effects of Chronic Variable Stress and Photoperiod Alteration on the Hypothalamic–Pituitary–Adrenal Axis Response and Behavior of Mice

The hypothalamic–pituitary–adrenal (HPA) axis mediates the physiological response to stressors and also synchronizes different physiological systems to environmental cues. Changes in day length (i.e., photoperiod) as well as chronic exposure to stressors are known to impact the HPA axis activity regulating the levels of glucocorticoid hormones. Over-exposure to inappropriate levels of glucocorticoids has been implicated in increased disease risk. In the present study, we examined the impact of chronic stress, using a chronic variable stress (CVS) paradigm, in combination with changes in photoperiod on physiological and behavioral measures, as well as on the reactivity and regulation of the HPA axis, in male and female mice. Six weeks of CVS, regardless of the photoperiod condition, decreased the body weight and attenuated the HPA axis reactivity to an acute stressor in both sexes. The attenuated HPA axis reactivity observed in stressed animals was related to reduced Pro-opiomelanocortin (POMC) mRNA levels in the pituitary of females. The gene expression analyses of key regulators of the HPA axis also indicated a sex-dependent effect with opposite patterns in the pituitary and adrenal glands. CVS effects on behavior were limited and related to an anxiety-like phenotype in both sexes, regardless of photoperiod condition. Our findings highlight sex-specific differences in the HPA axis and also sex-dependent effects of CVS on physiological parameters.

Perceived predation risk predicts glucocorticoid hormones, but not reproductive success in a colonial rodent

The Cort-Adaptation hypothesis suggests that elevated glucocorticoids (GCs) can facilitate an adaptive response to environmental and physiological challenges. Most previous studies have focused on avian species, which may limit their generalizability to mammals, where lactation is known to be a major physiological challenge. Furthermore, the effect of predation risk on GC levels has not been tested in the Cort-Adaptation hypothesis. We sought to test this hypothesis in a colonial prey species, black-tailed prairie dogs (Cynomys ludovicianus). We predicted that individuals located near fewer neighboring conspecifics would perceive an increased risk of predation and, in turn, have increased GCs (measured through hair cortisol concentration (HCC)) and reduced annual reproductive success compared to more centrally located individuals. We also investigated other putative influences on HCC: age, lactation status, body condition, and season of hair growth. Levels of vigilance behavior were higher for those with fewer neighboring conspecifics, suggesting variation in perceived risk of predation. Further, the risk of predation appeared to represent a chronic, detrimental stressor as evidenced by a significant increase in HCC for prairie dogs with fewer neighbors. Lactation status and season also influenced HCC. We found support for the Cort-Adaptation hypothesis where increased HCC during the reproductive season correlated with whether a female produced a litter, but not litter size, suggesting a minimum threshold of GCs is required for successful reproduction in this species. Our work illustrates that HCC may operate as an indicator of perceived predation risk, but care should be taken to consider the variety of factors influencing GC homeostasis, in particular lactation, when drawing conclusions using HCC as a marker of long-term stress.

Modeling pulsativity in the hypothalamic–pituitary–adrenal hormonal axis

A new mathematical model for biological rhythms in the hypothalamic–pituitary–adrenal (HPA) axis is proposed. This model takes the form of a system of impulsive time-delay differential equations which include pulsatile release of adrenocorticotropin (ACTH) by the pituitary gland and a time delay for the release of glucocorticoid hormones by the adrenal gland. Numerical simulations demonstrate that the model’s response to periodic and circadian inputs from the hypothalamus are consistent with those generated by recent models which do not include a pulsatile pituitary. In contrast the oscillatory phenomena generated by the impulsive delay equation mode occur even if the time delay is zero. The observation that the time delay merely introduces a small phase shift suggesting that the effects of the adrenal gland are “downstream” to the origin of pulsativity. In addition, the model accounts for the occurrence of ultradian oscillations in an isolated pituitary gland. These observations suggest that principles of pulse modulated control, familiar to control engineers, may have an increasing role to play in understanding the HPA axis.

Fresh insights into glucocorticoid-induced diabetes mellitus and new therapeutic directions.

Glucocorticoid hormones were discovered to have use as potent anti-inflammatory and immunosuppressive therapeutics in the 1940s and their continued use and development have successfully revolutionized the management of acute and chronic inflammatory diseases. However, long-term use of glucocorticoids is severely hampered by undesirable metabolic complications, including the development of type 2 diabetes mellitus. These effects occur due to glucocorticoid receptor activation within multiple tissues, which results in inter-organ crosstalk that increases hepatic glucose production and inhibits peripheral glucose uptake. Despite the high prevalence of glucocorticoid-induced hyperglycaemia associated with their routine clinical use, treatment protocols for optimal management of the metabolic adverse effects are lacking or underutilized. The type, dose and potency of the glucocorticoid administered dictates the choice of hypoglycaemic intervention (non-insulin or insulin therapy) that should be provided to patients. The longstanding quest to identify dissociated glucocorticoid receptor agonists to separate the hyperglycaemic complications of glucocorticoids from their therapeutically beneficial anti-inflammatory effects is ongoing, with selective glucocorticoid receptor modulators in clinical testing. Promising areas of preclinical research include new mechanisms to disrupt glucocorticoid signalling in a tissue-selective manner and the identification of novel targets that can selectively dissociate the effects of glucocorticoids. These research arms share the ultimate goal of achieving the anti-inflammatory actions of glucocorticoids without the metabolic consequences.

Assessing population-level stress through glucocorticoid hormone monitoring in wastewater

Stress is oftentimes overlooked in societies, despite its life-threatening impact. Here, we assessed the feasibility of measuring endogenous stress hormones to estimate population-level stress by wastewater-based epidemiology (WBE). Two primary glucocorticoids, cortisol and cortisone, were monitored in wastewater by liquid chromatography tandem mass spectrometry (LC-MS/MS), to assess changes in these physiological markers of stress in a student population (n = 26,000 ± 7100) on a university campus in the southwestern U.S. Daily composite samples were collected for seven consecutive days each month during the Fall (Autumn) 2017 and Spring 2018 academic semesters (n = 134). Reproducible weekly patterns were seen in stress hormone excretion, with the highest levels occurring on Mondays (124 ± 44 μg d−1 per person) and Tuesdays (127 ± 54 μg d−1 per person) and the lowest on Sundays (87 ± 32 μg d−1 per person). Stress levels on weekdays (defined by class schedules Monday-Thursday) were significantly higher than on weekends (p < 0.05). During both Fall and Spring semesters, per person stress levels of these hormones were significantly higher (p < 0.05) during the first two months of each semester, 162 ± 28 μg d−1 per person (August), 104 ± 29 μg d−1 per person (September), 180 ± 14 μg d−1 per person (January), and 114 ± 54 μg d−1 per person (February) than in the remaining measured weeks in the semester, including finals week captured in both semesters. Overall Spring semester stress levels (113 ± 45 μg d−1 per person) were significantly higher than the Fall (94 ± 42 μg d−1 per person), p < 0.01. This study is the first to demonstrate the utility of endogenous biomarkers, specifically glucocorticoid hormones, to monitor population health status (in this instance community stress) in near real-time by wastewater assessments.