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Concept: Cortisol


Cushing disease (CD) is a life-threatening disorder attributed to excess pituitary tumor-derived adrenocorticotrophic hormone (ACTH) and adrenal steroid secretion caused by pituitary tumors. Whereas CD was first described in 1932, the underlying genetic basis driving tumor growth and ACTH secretion remains unsolved. Here, we show that testicular orphan nuclear receptor 4 (TR4, nuclear receptor subfamily 2, group C, member 2) is overexpressed in human corticotroph tumors as well as in human and mouse corticotroph tumor cell lines. Forced overexpression of TR4 in both human and murine tumor cells increased proopiomelanocortin transcription, ACTH secretion, cellular proliferation, and tumor invasion rates in vitro. Conversely, knockdown of TR4 expression reversed all phenotypes. Mechanistically, we show that TR4 transcriptionally activates proopiomelanocortin through binding of a direct repeat 1 response element in the promoter, and that this is enhanced by MAPK-mediated TR4 phosphorylation. In vivo, TR4 overexpression promotes murine corticotroph tumor growth as well as enhances ACTH and corticosterone production, whereas TR4 knockdown decreases circulating ACTH and corticosterone levels in mice harboring ACTH-secreting tumors. Our findings directly link TR4 to the etiology of corticotroph tumors, hormone secretion, and cell growth as well as identify it as a potential target in the treatment of CD.

Concepts: Gene, Hypothalamus, Gene expression, Cancer, Tumor, Cortisol, Adrenocorticotropic hormone, Adrenal cortex





The relationship between growth rate and environmental space is an unresolved issue in teleosts. While it is known from aquaculture studies that stocking density has a negative relationship to growth, the underlying mechanisms have not been elucidated, primarily because the growth rate of populations rather than individual fish were the subject of all previous studies. Here we investigate this problem in the teleost Astyanax mexicanus, which consists of a sighted surface-dwelling form (surface fish) and several blind cave-dwelling (cavefish) forms. Surface fish and cavefish are distinguished by living in spatially contrasting environments and therefore are excellent models to study the effects of environmental size on growth. Multiple controlled growth experiments with individual fish raised in confined or unconfined spaces showed that environmental size has a major impact on growth rate in surface fish, a trait we have termed space dependent growth (SDG). In contrast, SDG has regressed to different degrees in the Pachón and Tinaja populations of cavefish. Mating experiments between surface and Pachón cavefish show that SDG is inherited as a dominant trait and is controlled by multiple genetic factors. Despite its regression in blind cavefish, SDG is not affected when sighted surface fish are raised in darkness, indicating that vision is not required to perceive and react to environmental space. Analysis of plasma cortisol levels showed that an elevation above basal levels occurred soon after surface fish were exposed to confined space. This initial cortisol peak was absent in Pachón cavefish, suggesting that the effects of confined space on growth may be mediated partly through a stress response. We conclude that Astyanax reacts to confined spaces by exhibiting SDG, which has a genetic component and shows evolutionary regression during adaptation of cavefish to confined environments.

Concepts: Evolution, Cortisol, Actinopterygii, Mexican tetra


Most species living in temperate zones adapt their physiology and behavior to seasonal changes in the environment by using the photoperiod as a primary cue. The mechanisms underlying photoperiodic regulation of stress-related functions are not well understood. In this study, we analyzed the effects of photoperiod on the hypothalamic-pituitary-adrenal axis in photoperiod-sensitive Fischer 344 rats. We first examined how photoperiod affects diurnal variations in plasma concentrations of adrenocorticotropic hormone (ACTH) and corticosterone. ACTH levels did not exhibit diurnal variations under long- and short-day conditions. On the other hand, corticosterone levels exhibited a clear rhythm under short-day condition with a peak during dark phase. This peak was not observed under long-day condition in which a significant rhythm was not detected. To analyze the mechanisms responsible for the photoperiodic regulation of corticosterone rhythms, ACTH was intraperitoneally injected at the onset of the light or dark phase in dexamethasone-treated rats maintained under long- and short-day conditions. ACTH induced higher corticosterone levels in rats examined at dark onset under short-day condition than those maintained under long-day condition. Next, we asked whether melatonin signals are involved in photoperiodic regulation of corticosterone rhythms, and rats were intraperitoneally injected with melatonin at late afternoon under long-day condition for 3 weeks. However, melatonin injections did not affect the corticosterone rhythms. In addition, photoperiodic changes in the amplitude of corticosterone rhythms were also observed in melatonin-deficient C57BL/6J mice, in which expression profiles of several clock genes and steroidgenesis genes in adrenal gland were modified by the photoperiod. Our data suggest that photoperiod regulates corticosterone rhythms by altered adrenal sensitivity through melatonin-independent mechanisms that may involve the adrenal clock.

Concepts: Hypothalamus, Cortisol, Circadian rhythm, Adrenocorticotropic hormone, Adrenal cortex, ACTH stimulation test, Adrenal gland, Anterior pituitary


Stress responses within dyads are modulated by interactions such as mutual emotional support and conflict. We investigated dyadic psychobiological factors influencing intra-individual cortisol variability in response to different challenging situations by testing 132 owners and their dogs in a laboratory setting. Salivary cortisol was measured and questionnaires were used to assess owner and dog personality as well as owners' social attitudes towards the dog and towards other humans. We calculated the individual coefficient of variance of cortisol (iCV = sd/mean*100) over the different test situations as a parameter representing individual variability of cortisol concentration. We hypothesized that high cortisol variability indicates efficient and adaptive coping and a balanced individual and dyadic social performance. Female owners of male dogs had lower iCV than all other owner gender-dog sex combinations (F = 14.194, p<0.001), whereas owner Agreeableness (NEO-FFI) scaled positively with owner iCV (F = 4.981, p = 0.028). Dogs of owners high in Neuroticism (NEO-FFI) and of owners who were insecure-ambivalently attached to their dogs (FERT), had low iCV (F = 4.290, p = 0.041 and F = 5.948, p = 0.016), as had dogs of owners with human-directed separation anxiety (RSQ) or dogs of owners with a strong desire of independence (RSQ) (F = 7.661, p = 0.007 and F = 9.192, p = 0.003). We suggest that both owner and dog social characteristics influence dyadic cortisol variability, with the human partner being more influential than the dog. Our results support systemic approaches (i.e. considering the social context) in science and in counselling.

Concepts: Anxiety, Psychology, Human, Male, Sex, Cortisol, Dog, Ownership


Primary aldosteronism (PA) secondary to excessive and/or autonomous aldosterone secretion from the renin angiotensin system (RAS) accounts for approximately 10% of cases of hypertension and is primarily caused by bilateral adrenal hyperplasia (BAH) or aldosterone-producing adenomas (APAs). Although the diagnosis has traditionally been supported by low serum potassium levels, normokalemic and even normotensive forms of PA have been identified expanding further the clinical phenotype. Morever, recent evidence has shown that serum aldosterone correlates with increased blood pressure in the general population and even moderately raised aldosterone levels are linked to increased cardiovascular morbidity and mortality. In addition, aldosterone antagonists are effective in blood pressure control even in patients without evidence of dysregulated aldosterone secretion. These findings indicate a higher prevalence of aldosterone excess among hypertensive patients than previously considered that could be attributed to disease heterogeneity, aldosterone level fluctuations related to an adrenocorticotropin (ACTH) effect, or inadequate sensitivity of current diagnostic means to identify apparent aldosterone excess. In addition, functioning aberrant receptors expressed in the adrenal tissue have been found in a subset of PA cases that could also be related to its pathogenesis. Recently a number of specific genetic alterations, mainly involving ion homeostasis across the membrane of zona glomerulosa, have been detected in approximately 50% of patients with APAs. Although specific genotype/phenotype correlations have not been clearly identified, differential expression of these genetic alterations could also account for the wide clinical phenotype, variations in disease prevalence and performance of diagnostic tests. In the present review, we critically analyze current means used to diagnose PA along with the role that ACTH, aberrant receptor expression and genetic alterations may exert, and provide evidence for an increased prevalence of aldosterone dysregulation in patients with essential hypertension and pre-hypertension.

Concepts: Kidney, Hypertension, Blood pressure, Aldosterone, Cortisol, Renin-angiotensin system, Renin, Hyperaldosteronism





Many very preterm (i.e., <32 weeks of gestation) newborns fail to mount an adequate adrenocortical response to stress or illness, termed relative adrenal insufficiency. Conversely, later in life these infants show features of increased glucocorticoid bioactivity, such as abdominal adiposity, insulin resistance, raised blood pressure, shorter stature and internalizing problem behavior.

Concepts: Childbirth, Obesity, Insulin resistance, Aldosterone, Corticosteroid, Glucocorticoid, Cortisol, Metabolic syndrome


Psychosocial stress alters several physiological parameters resulting in multiple disorders, particularly compromising the immune system thereby provoking various diseases including liver disorders. However, the plausible underlying mechanisms remain elusive. Recent literature provides mechanistic evidences of detrimental effects of psychosocial stress on physiology of different body organs including liver. The data of stress-induced pathophysiological changes in liver functions and obesity were systematically collected from PubMed, ScienceDirect and the Web of Science Databases published in English. Stress and glucocorticoids (GCs) control food intake and energy expenditure through appetite stimulators neuropeptide Y (NYP) and agouti-related protein (AgRP) in hypothalamus. Principle effectors of the activated hypothalamic-pituitary-adrenal (HPA) axis in response to psychosocial stress are proopiomelanocortin (POMC)-derived adrenocorticotropic hormone (ACTH) and GCs. Stress-induced GCs hyper-secretion triggers glucocorticoid receptor (GR)-dependent transcriptional factor, nuclear factor kappa B (NFκB), which interferes TNFα-IL6 and keap1-Nrf2 pathways in liver regeneration and obesity through fine-tuning of TNFα, IL6 and Nrf2 signaling. In this review, it is contrived upon existing evidence to put forward a model whereby exposure to life-stress has a prominent impact over weight gain and can alter the regenerative mode of a damaged liver through Keap1-Nrf2 and TNFa-IL6 pathways.

Concepts: Immune system, Obesity, Liver, Cortisol, Appetite, Leptin, Cushing's syndrome, Agouti-related peptide


Using oral contraceptives has been implicated in the aetiology of stress-related disorders like depression. Here, we followed the hypothesis that oral contraceptives deregulate the HPA-axis by elevating circulating cortisol levels. We report for a sample of 233 pre-menopausal women increased circulating cortisol levels in those using oral contraceptives. For women taking oral contraceptives, we observed alterations in circulating phospholipid levels and elevated triglycerides and found evidence for increased glucocorticoid signalling as the transcript levels of the glucocorticoid-regulated genes DDIT4 and FKBP5 were increased in whole blood. The effects were statistically mediated by cortisol. The associations of oral contraceptives with higher FKBP5 mRNA and altered phospholipid levels were modified by rs1360780, a genetic variance implicated in psychiatric diseases. Accordingly, the methylation pattern of FKBP5 intron 7 was altered in women taking oral contraceptives depending on the rs1360780 genotype. Moreover, oral contraceptives modified the association of circulating cortisol with depressive symptoms, potentially explaining conflicting results in the literature. Finally, women taking oral contraceptives displayed smaller hippocampal volumes than non-using women. In conclusion, the integrative analyses of different types of physiological data provided converging evidence indicating that oral contraceptives may cause effects analogous to chronic psychological stressors regarding the regulation of the HPA axis.

Concepts: DNA, Scientific method, Gene, Genetics, Transcription, RNA, Cortisol, Glucocorticoid receptor