Effect of maternal nutrient restriction in early gestation on responses of the hypothalamic-pituitary-adrenal axis to acute isocapnic hypoxaemia in late gestation fetal sheep

Epidemiological and experimental evidence suggests that maternal undernutrition during pregnancy may alter development of fetal organ systems. We have demonstrated previously that fetal hypothalamic-pituitary-adrenal (HPA) axis responses to exogenous corticotropin-releasing hormone (CRH) + arginine vasopressin (AVP), or adrenocorticotrophin hormone (ACTH), are reduced in fetuses of mildly undernourished ewes. To examine these effects further we tested HPA axis responses to acute isocapnic hypoxaemia in fetal sheep at 114-129 days gestation (dGA), following 15% reduction in maternal nutritional intake between 0 and 70 dGA. Fetuses from control (C) and nutrient-restricted (R) ewes were chronically catheterised and plasma ACTH and cortisol responses were determined at 114-115, 120-123 and 126-129 dGA during hypoxaemia (1 h) induced by lowering the maternal inspired O2 fraction (FI,O2). Basal plasma cortisol concentrations and HPA axis responses at 114-115 and 120-123 dGA did not differ between C and R fetuses. At 126-129 dGA, both plasma ACTH (P < 0.01) and cortisol (P < 0.05) responses were smaller in R fetuses compared to C fetuses. Fetal blood gas status, fetal body weight, body proportions and organ weights did not differ between the groups. We conclude that mild maternal undernutrition alters development of the fetal HPA axis producing a reduction in pituitary and adrenal responsiveness to endogenous stimuli.     

Effect of stress on basophil function in chronic idiopathic urticaria

Background Chronic idiopathic urticaria (CIU) is a distressing skin condition involving recurrent itchy hives lasting 6 weeks or longer. The mechanism involves mast cell and basophil degranulation, which releases inflammatory mediators including histamine. In our clinical practice, we have observed that the onset of CIU is often preceded by a major life event. Objective To investigate the role of the hormones of the hypothalamic–pituitary–adrenal (HPA) axis in the link between psychological stress and CIU. Methods Thirty people with CIU and 30 normal controls were recruited. A flow cytometric CD63 expression assay was used to quantify basophil activation, and serum cortisol concentrations were measured as an indication of stress. Results Both corticotrophin releasing factor (CRF) and adrenocorticotrophic hormone (ACTH) were shown to activate basophils. There was no significant difference between numbers of CIU patients and normal controls responding to CFR, ACTH or cortisol. However, the responses in the CIU patients were stronger than those in normal controls. There was also a trend towards higher serum cortisol concentrations in CIU patients. The basophil response to CRF and ACTH correlated with the serum cortisol concentration in normal controls, but not in CIU patients. Conclusions Although our data have not supported the hypothesis that stress makes a major contribution to CIU, the heightened basophil response to CFR and ACTH and higher levels of serum cortisol do suggest a derangement of the HPA axis in CIU.     

Delayed peak response of cortisol to insulin tolerance test in patients with Prader–Willi syndrome

Deaths among children with Prader–Willi syndrome (PWS) are often related to only mild or moderate upper respiratory tract infections, and many causes of death remain unexplained. Several reports have hypothesized that patients with PWS may experience latent central adrenal insufficiency. However, whether PWS subjects suffer from alteration of the hypothalamus‐pituitary‐adrenal (HPA) axis remains unclear. This study aimed to explore the HPA axis on PWS. We evaluated the HPA axis in 36 PWS patients (24 males, 12 females; age range, 7 months to 12 years; median age 2.0 years; interquartile range [IQR], 1.5–3.4 years) using an insulin tolerance test (ITT) in the morning between 08:00 and 11:00. For comparison, ITT results in 37 age‐matched healthy children evaluated for short stature were used as controls. In PWS patients, basal levels of adrenocorticotropic hormone (ACTH) were 13.5 pg/ml (IQR, 8.3–27.5 pg/ml) and basal levels of cortisol were 18.0 μg/dl (IQR, 14.2–23.7 μg/dl). For all patients, cortisol levels at 60 min after stimulation were within the reference range (>18.1 μg/dl), with a median peak of 41.5 μg/dl (IQR, 32.3–48.6 μg/dl). Among control children, basal level of ACTH and basal and peak levels of cortisol were 10.9 (IQR, 8.5–22.0 pg/ml), 15.6 (IQR, 11.9–21.6 μg/dl), and 27.8 μg/dl (IQR, 23.7–30.5 μg/dl), respectively. Basal and peak levels of cortisol were all within normal ranges, but peak response of cortisol to ITT was delayed in the majority of PWS patients (64%). Although the mechanism remains unclear, this delay may signify the existence of central obstacle in adjustment of the HPA axis.     

The corticotropin-releasing factor stimulation test. An aid in the evaluation of patients with Cushing's syndrome

We investigated the effect of exogenous corticotropin-releasing factor on plasma levels of ACTH and cortisol in 13 patients with ACTH-secreting pituitary adenomas (Cushing's disease) and in 9 patients with other forms of Cushing's syndrome. In all patients with Cushing's disease, ovine corticotropin-releasing factor, given intravenously as a bolus injection (1 microgram per kilogram of body weight), caused a further increase in the already elevated levels of ACTH and cortisol. Successful transphenoidal adenomectomy was followed as early as one week after surgery by normalization or near-normalization of the ACTH and cortisol responses to corticotropin-releasing factor. On the other hand, patients with the ectopic ACTH syndrome, who also had high basal plasma concentrations of ACTH and cortisol, had no ACTH or cortisol responses to corticotropin-releasing factor. This difference in responsiveness between these two patient groups cannot be explained on the basis of different metabolic clearance rates of exogenous corticotropin-releasing factor, as shown by similar disappearance curves of immunoreactive corticotropin-releasing factor from plasma. Patients with Cushing's syndrome of adrenal origin who were hypercortisolemic during testing had undetectable plasma levels of ACTH and no ACTH or cortisol responses to corticotropin-releasing factor. We conclude that stimulation of the pituitary-adrenal axis with corticotropin-releasing factor may be useful in differentiating pituitary from ectopic causes of Cushing's syndrome.     

Combined dexamethasone suppression–corticotrophin-releasing hormone stimulation test in medication-free major depression and healthy volunteers

Background

The hypothalamic–pituitary–adrenal (HPA) axis is dysfunctional in a subgroup of mood disorders.

Methods

We compared cortisol and adrenocorticotropic hormone (ACTH) responses in major depression and healthy volunteers to the combined dexamethasone suppression–corticotrophin-releasing hormone stimulation (DEX–CRH) test. Unlike other published studies, the study patients were medication-free and the healthy volunteers did not have first-degree relatives with a mood or psychotic disorder. Demographics, DSM-IV diagnoses and other clinical parameters were evaluated in major depressive disorder (MDD) and healthy control groups. Participants received an oral dose of 1.5 mg dexamethasone at 11 pm the day before CRH administration. On the following day, at 3 pm, 100 µg of ovine CRH was infused. Blood samples for determination of cortisol and ACTH were collected every 15 min from 3 pm to 4:15 pm. Cortisol and ACTH responses were calculated as areas under the curve.

Results

Controlling for age, baseline (i.e., post-dexamethasone) ACTH levels were higher in depressed patients compared to controls (p=0.01). There was a trend for higher ACTH responses in depressed patients compared to the control group (p=0.08). In depressed patients, cortisol and ACTH responses correlated positively with age, duration of illness and number of hospitalizations.

Limitations

Because of the cross-sectional study design we can only evaluate the nature of potential HPA axis disturbances that were present in patients when they are acutely depressed.

Conclusions

Feedback inhibition of ACTH secretion by cortisol is compromised in MDD, and this is independent of an age effect on the HPA axis function.     

Effects of aging on hypothalamic-pituitary-adrenal system function in non-human primates

The study was aimed at characterizing the changes in hypothalamic-pituitary-adrenal (HPA) axis function during aging in monkey models (Papio hamadryas and Macaca mulatta). It has been established by specific radioimmunoassay and enzyme immunoassay that basal plasma levels of adrenal androgenes (dehydroepiandrosterone-DHEA, dehydroepiandrosterone sulfate-DHEAS) and the early precursors of steroid hormones (pregnenolone and 17-hydroxypregnenolone) progressively decrease with age in baboons and macaques, while cortisol and 11-desoxycortisol concentrations do not change. The old female rhesus monkeys exhibited a higher cortisol and corticosterone response, but a lower DHEAS response to corticotropin-releasing hormone (CRH) administration then the young monkeys. The aged rhesus monkeys also exhibited a decrease of the adrenal cortex resiliency, that was manifested in the deceleration of the decrease of cortisol concentrations after the peak values had been reached in response to ACTH 1-39 administration. At the same time the ACTH 1-24 depot test revealed no age-related changes in the maximum capacity of monkey adrenals to synthesize and secrete cortisol. The aged monkeys also developed less sensitivity of the HPA axis to dexametasone suppression test. The age-related hormonal changes may play an important role in the age-related involutive processes and in the disorders of the adaptive ability of old organisms.     

The oCRH stimulation test before and after clinical recovery from depression

A substantial body of data suggests that excessive cortisol secretion in depression may result from a dysregulation at several sites within the hypothalamic-pituitary-adrenocortical (HPA) axis. These alterations in regulatory mechanisms are thought to be the result of a hypothalamic 'overdrive' of corticotropin-releasing hormone (CRH). Previous studies have demonstrated a diminished adrenocorticotropin (ACTH) secretory response, as well as a heightened adrenocortical responsiveness after ovine-CRH administration in depressed patients. In the present investigation, we examined pituitary and adrenocortical responsiveness after an ovine-CRH stimulation test before and during clinical recovery in seven depressed patients. Cumulative ACTH responses increased significantly during clinical recovery (P = 0.014). Paradoxically, maximum and peak cortisol responses increased after recovery, suggesting that heightened adrenocortical responsiveness to ACTH during depression may take longer to 'normalize' than abnormal pituitary responsiveness to ovine-CRH stimulation.     

Functional evaluation of the hypothalamic-pituitary-adrenal axis

The regulation of hypothalamic pituitary-adrenal (HPA) axis is controlled by three major factors: stress, circadian rhythm and negative feedback. Hypothalamic CRF binds to CRF receptor on ACTH cells and stimulates synthesis and secretion of ACTH. However, vasopressin binds to V1b receptor and enhances CRF induced ACTH secretion. ACTH stimulate secretion of cortisol and DHEA-S. Cortisol inhibits secretion of CRF and ACTH with negative feedback mechanism. To evaluate the ability of the hypothalamus to secrete CRF, insulin-induced hypoglycemia and metyrapone tests are used. For evaluation of the secretion of pituitary ACTH and adrenal cortisol, a CRF test is useful. Autonomic secretion of ACTH and/or cortisol is evaluated with a dexamethasone suppression test.     

Allopregnanolone serum concentrations and diurnal cortisol secretion in women with premenstrual dysphoric disorder

Most prior studies in patients with premenstrual dysphoric disorder (PMDD) indicate a blunted hypothalamus–pituitary–adrenal axis function. However, the relationship between neuroactive progesterone metabolites, such as allopregnanolone, and hypothalamus–pituitary–adrenal (HPA) axis function in PMDD patients is relatively sparsely studied. The primary aims of this study were to assess diurnal variation in circulating cortisol and low-dose dexamethasone suppression in PMDD patients and healthy controls, and the relationship between these two HPA axis indices and allopregnanolone serum concentrations. Twenty-six women with prospectively defined PMDD and 30 healthy controls were recruited. Participants underwent diurnal sampling for cortisol serum concentrations and a low-dose dexamethasone suppression test. In addition, morning allopregnanolone serum concentrations were determined. There was no difference in diurnal secretion of cortisol and degree of dexamethasone suppression of cortisol between PMDD patients and healthy controls. However, PMDD patients with high allopregnanolone levels displayed blunted nocturnal cortisol levels in comparison with healthy controls who had low allopregnanolone serum concentrations. In women with PMDD, diurnal secretion of cortisol may be influenced by allopregnanolone levels of the luteal phase. This finding may be attributed to timing of blood sampling in the late luteal phase as well as the individual level of allopregnanolone but could potentially explain the discrepancies in results between studies examining HPA axis function in women with PMDD.     

Vasopressin as a target for antidepressant development: an assessment of the available evidence

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is one of the key biological abnormalities described in major depressive disorder, occurring in 30-50% of depressed subjects. Corticotropin-releasing hormone (CRH) and vasopressin (AVP) are the main regulators of this stress system, with the two neuropeptides acting synergistically in bringing about adrenocorticotropin (ACTH) release from the anterior pituitary and cortisol from the adrenal gland. Based on the demonstration of elevated cerebrospinal fluid levels of CRH in depressives, and other evidence, it has been postulated that excess CRH and the resultant increased HPA forward drive form the basis of neuroendocrine dysregulation in depression. However, there is an accumulating body of evidence to support a significant role for AVP in the regulation of pituitary-adrenal activity in health and also in depressive disorder. This review, based on a Medline search from 1980 to 2001, focuses on the functional neuroanatomy, receptor pharmacology, VP synergism with CRH, and the data from clinical and pre-clinical studies that support an important role for AVP in the pathophysiology of major depression. We suggest that future antidepressants may target the vasopressinergic system.     

Hyperactivity of the HPA axis is related to dietary restraint in normal weight women

The objective of our study was to investigate the relationship between hypothalamus/pituitary/adrenal (HPA) axis functioning and dietary restraint in normal weight (BMI between 20 and 25 kg/m²) men and women. We therefore assessed in 38 men and 38 women HPA axis functioning, through measuring 5-hour cortisol exposure and cortisol feedback functioning through a dexamethasone (4 mg) suppression test. Eating behavior was assessed through the Three Factor Eating Questionnaire and body composition through hydro densitometry and deuterium dilution method. No relationship between HPA axis functioning and dietary restraint was found in men. Normal weight women with a restraint score ≥ 9 showed increased cortisol concentrations over a 5-hour time period, increased cortisol concentrations after a dexamethasone (4 mg) suppression test, higher BMI, and higher body fat percentage, when compared to women with a restraint score < 9. Moreover, a positive relationship was found between cortisol concentrations over a 5-hour time period and dietary restraint in combination with the disinhibition score (R² = 0.23, p < 0.001). We conclude that in normal weight women hyperactivity of the HPA-axis is related to dietary restraint especially in combination with disinhibition.     

Evidence for existence of cortical androgen-stimulating hormone.

An animal model using dexamethosone-suppressed, castrated dogs was developed to test the hypothesis that a pituitary hormone other than ACTH modulates adrenal androgen (AA) secretion. Plasma samples were obtained every 15 min during infusions of saline, synthetic alpha 1-24 corticotropin, porcine 1-39 corticotropin (ACTH), or bovine pituitary gland extract (PE) in a wide range of doses. Androstenedione (A), dehydroepiandrosterone (DHA), and cortisol (F) were quantified by radioimmunoassay. When the ratio of AA levels was related to those of F, in order to correct for ACTH content in the PE, the slopes of the dose-response curves for corticotropin and PE were different at the 0.01 level. For A the dose-response slope for the PE was 0.18 +/- 0.5 SE, whereas that of ACTH was 0.02 +/- 0.01. For the DHA response the slopes were 0.17 +/- 0.04 for the PE and 0.04 +/- 0.03 for ACTH. Related studies showed no increase in AA levels in response to luteinizing hormone-releasing hormone, bovine growth hormone (GH), bovine prolactin, ovine thyroid-stimulating hormone (TSH), or synthetic aqueous arginine vasopressin (AVP). We conclude that a pituitary factor other than ACTH, prolactin, GH, luteinizing hormone, follicle-stimulating hormone, TSH, or AVP may be responsible for the observed increase in AA concentrations.     

Corticotropin releasing hormone increases apparent potency of adrenocorticotropic hormone stimulation of cortisol secretion.

HYPOTHESIS: Corticotropin releasing hormone (CRH) has a regulatory effect on cortisol secretion in addition to its classic effect of stimulating adrenocorticotropic hormone (ACTH) secretion. REVIEW: There is growing evidence of "long-loop" and paracrine adrenal stimulation by CRH. Data from a study of the ovine-corticotropin releasing hormone (oCRH) stimulation test in 13 sexually abused girls and 13 normal controls was used in Montecarlo simulations of the hypothalamic-pituitary-adrenal axis, to get estimates of adrenal sensitivity to ACTH and cortisol elimination kinetics before and after oCRH administration. In both controls and sexually abused girls, ACTH had an apparent greater effect on cortisol secretion after administration of oCRH compared to its effect during the baseline period. This lends support to the hypothesis and suggests that it should be tested experimentally.     

Hormonal and behavioral responses to stress in lactating and non-lactating female common marmosets (Callithrix jacchus)

In several mammalian species, hypothalamic-pituitary-adrenal (HPA) and behavioral responses to stressors are down-regulated in lactating females, possibly preventing stress-induced disruptions of maternal care. Experimental elevations of HPA axis hormones have been found to inhibit maternal behavior in lactating common marmoset monkeys (Callithrix jacchus), raising the question of whether lactating female marmosets also have blunted endogenous responses to stress. Therefore, we compared HPA and behavioral responses to standardized stressors in reproductively experienced female common marmosets that were undergoing ovulatory cycles and that either were (N = 7) or were not lactating (N = 8). Each marmoset underwent (1) a restraint stressor during the early follicular phase of the ovarian cycle (approximately 5 weeks postpartum for lactating females) and (2) exposure to a simulated hawk predator during the early to mid-luteal phase (approximately 7 weeks postpartum for lactating females). Lactating females were tested in the presence of one of their infants. Blood samples were collected before, during, and immediately after each test for determination of plasma adrenocorticotropic hormone (ACTH) and cortisol concentrations. Both stressors caused significant elevations in plasma ACTH and cortisol levels, and significant decreases in cortisol:ACTH ratios; however, lactating and non-lactating females showed no significant differences in their endocrine or behavioral responses to either stressor, or in baseline ACTH or cortisol levels. These findings suggest that in contrast to several other mammalian species, lactating female marmosets maintain full behavioral and HPA responsiveness to stress, at least in the presence of their infants.     

Gene polymorphisms associated with temperament

When individuals are exposed to stressful environmental challenges, the response varies widely in one or more of three components: psychology, behavior and physiology. This variability among individuals can be defined as temperament. In recent years, an increasing large body of evidence suggests that the dimensions of temperament, as well as personality, psychological disorders and behavioral traits, are influenced by genetic factors, and much of the variation appears to involve variation in genes or gene polymorphisms in the hypothalamic–pituitary–adrenocortical (HPA) axis and the behavior-controlling neurotransmitter networks. Here, we review our current understanding of the probabilistic impact of a number of candidate gene polymorphisms that control temperament, psychological disorders and behavioral traits in animals and human, including the gene polymorphisms related to corticotrophin-releasing hormone (CRH) production and adrenal cortisol production involved in the HPA axis, and a large number of gene polymorphisms in the dopaminergic and serotonergic neurotransmitter networks. It will very likely to assist in diagnosis and treatment of human relevant disorders, and provide useful contributions to our understanding of evolution, welfare and conservation, for animals in the wild and in production systems. Additionally, investigations of gene–gene and gene–environment complex interactions in humans and animals need further clear illustration.     

Chronic subcutaneous leptin infusion diminishes the responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis in female rhesus monkeys

The fat derived protein leptin has its anorexic action through a number of neuropeptides including an upregulation of corticotropin releasing hormone (CRH) expression in the hypothalamus. However, the influence of leptin on these neuropeptides may be different during stress. The present study used ovariectomized female rhesus monkeys (n=8) to further define the effect of leptin on HPA responsivity. To accomplish this, we assessed the effects of constant leptin infusion on cortisol and ACTH secretion in both a predictable and unpredictable situation as well as in response to dexamethasone suppression-CRH stimulation test. We hypothesized that leptin would attenuate the increase in cortisol and ACTH to a novel, unpredictable situation and would enhance glucocorticoid negative feedback and diminish the response to CRH. Animals were assessed under control placebo conditions and during a 28 day infusion with recombinant human leptin (6 microg/kg/day, SC). Within each treatment condition, HPA responsivity was assessed during no estradiol replacement and acute estradiol replacement that produced serum concentrations of approximately 40 pg/ml. However, the results indicated that neither estradiol alone or in combination with leptin had any consistent effect on the outcome measures. Compared to the control condition, leptin had no effect on the cortisol diurnal rhythm; however, evening but not morning plasma ACTH concentrations were significantly lower during leptin infusion. In contrast, the response in plasma cortisol and ACTH to an unpredictable situation was significantly attenuated by chronic leptin infusion. Furthermore, leptin enhanced glucocorticoid negative feedback and blunted CRH-induced increase in both cortisol and ACTH. Taken together, these data suggest that in the female monkey, leptin has little effect on basal cortisol. However, when the HPA axis is activated, leptin attenuates the neuroendocrine response by enhancing glucocorticoid negative feedback. These data underscore the potential importance of leptin in maintaining homeostasis through its diverse interaction with the HPA axis.     

Comparison between the central effects of CRH and AVP in steers

In cattle, the in vivo effects of centrally administered corticotropin-releasing hormone (CRH) or arginine vasopressin (AVP) from the perspective of stress regulation have not been fully elucidated. We compared behavioral, adrenocorticotropic, and autonomic nervous responses to intracerebroventricularly infused bCRH or AVP in steers. Intracerebroventricular infusions of both bCRH and AVP (0.2, 2, 10 and 20 nmol/500 mul/30 min) evoked a dose-related increase in plasma concentrations of ACTH and cortisol. At 10 nmol, the AUC response of cortisol concentration to bCRH tended to be higher than that in response to AVP (p=0.075). There were significant differences among treatments in the total number of head shaking (Friedman's test, chi2=22.79, p=0.004), upright posture (chi2=16.80, p=0.032), head rubbing (chi2=23.93, p=0.002), tongue playing (chi2=27.18, p=6.58E(-4)), and bleating (chi2=26.84, p=7.54E(-4)). AVP 10 and 20 nmol treatments induced more head shaking and tongue playing than vehicle treatment (Nemenyi multiple comparisons: p<0.1). Ten nmol (32.8+/-40.2 times) and 20 nmol (34.8+/-19.9 times) of bCRH induced bleating, but no dosage of AVP induced bleating. These findings indicate that both bCRH and AVP could activate HPA axis in steers when infused intracerebroventricularly and that bCRH was more potent to stimulate HPA axis than AVP. As for the effects on behavioral function, high dosages of both peptides induced stereotyped behaviors and the types of stereotyped behaviors induced were different between bCRH and AVP.     

Blunted HPA axis response to stress is related to a persistent Dysregulation Profile in youth

The Child Behavior Checklist Dysregulation Profile (DP) in youth has been shown to be a predictor of psychopathology later in life. We examined the activity of the hypothalamic pituitary adrenal (HPA) axis in youth with remitted, new, persistent, and no DP. Data from 489 youth (47% boys) participating in a Dutch longitudinal general population study were included (Wave 1 mean age = 11.5, Wave 2 = 14.2). Wave 2 diurnal cortisol patterns and levels in response to a laboratory stress paradigm were compared in youth with DP at Wave 1 only, Wave 2 only, both Waves, and neither Wave. Youth with the DP at Wave 2 only or at both time points showed blunted cortisol responses to stress relative to the other two groups. There were no group or sex differences in diurnal cortisol activity. More research is needed to determine how the association between DP symptoms and HPA axis functioning changes over time.     

The hypothalamic-pituitary-adrenal (HPA) axis in habitual smokers.

Nicotine is a strong activator of the hypothalamus pituitary adrenal (HPA) axis. Smoking of only two cigarettes consistently activates the HPA axis of habitual smokers. However, while being a habitual smoker only induces small changes of basal HPA axis activity, smoking induces an attenuated responsiveness of the HPA axis to psychological stress, but not to injection of corticotropin releasing hormone (CRH) or physiological load. The latter points to alterations at hypothalamic or other central structures. The further consequences of decreased HPA axis responsiveness are discussed. Chronic inflammation of the airways is a common consequence of habitual smoking, and smokers often present with low-grade systemic inflammation, which may be mediated by HPA axis alterations. However, habitual smokers' monocytes are reported to show an increased sensitivity towards the inflammation suppressing effects of cortisol, while on the one hand, inflammation of the airways appears to be relatively resistant towards glucocorticoid treatment. In conclusion, this pattern of attenuated cortisol responses and decreased glucocorticoid sensitivity may be causally related to disinhibition of inflammatory processes and thereby further stimulate adverse health outcomes, such as airway inflammation or atherosclerosis.