Hypothalamo-pituitary-adrenal Axis Function Research Articles

Investigation of the Hypothalamo-pituitary-adrenal (HPA) axis: a contemporary synthesis.

The hypothalamo-pituitary-adrenal (HPA) axis is one of the main components of the stress system. Maintenance of normal physiological events, which include stress responses to internal or external stimuli in the body, depends on appropriate HPA axis function. In the case of severe cortisol deficiency, especially when there is a triggering factor, the patient may develop a life-threatening adrenal crisis which may result in death unless early diagnosis and adequate treatment are carried out. The maintenance of normal physiology and survival depend upon a sufficient level of cortisol in the circulation. Life-long glucocorticoid replacement therapy, in most cases meeting but not exceeding the need of the patient, is essential for normal life expectancy and maintenance of the quality of life. To enable this, the initial step should be the correct diagnosis of adrenal insufficiency (AI) which requires careful evaluation of the HPA axis, a highly dynamic endocrine system. The diagnosis of AI in patients with frank manifestations is not challenging. These patients do not need dynamic tests, and basal cortisol is usually enough to give a correct diagnosis. However, most cases ofsecondary adrenal insufficiency (SAI) take place in a gray zone when clinical manifestations are mild. In this situation, more complicated methods that can simulate the response of the HPA axis to a major stress are required. Numerous studies in the assessment of HPA axis have been published in the world literature. In this review, the tests used in the diagnosis of secondary AI or in the investigation of suspected HPA axis insufficiency are discussed in detail, and in the light of this, various recommendations are made.

Metformin effectively restores the HPA axis function in diet-induced obese rats.

IntroductionThe hypothalamo-pituitary-adrenal (HPA) axis is perturbed in obesity. We previously reported presence of leptin resistance in the brainstem and uncoupling between central noradrenergic tone and the HPA axis in obesity-prone (DIO) rats. Metformin is shown to lower body weight and adiposity, but the underlying mechanism is unclear. We hypothesized that this is associated with restored HPA axis function.MethodsAdult male DIO rats were placed on either a regular chow or HF diet for 7 weeks. Starting week 4, the animals were given either a low dose (60mg/kg) or high dose (300mg/kg) of metformin in drinking water. In addition to body weight and feeding, we examined different arms of the HPA axis to test if metformin can reinstate its function and coupling. To understand potential mechanisms, leptin signaling in the brainstem and circulating free fatty acid levels were also assessed.ResultsMetformin treatment lowered weight gain, fat mass, caloric intake, and serum leptin levels. HPA axis activity as determined by corticotropin-releasing hormone in the median eminence and serum corticosterone was decreased by metformin in a dose-dependent manner, and so was norepinephrine (NE) in the paraventricular nucleus. Importantly, metformin completely normalized the NE-HPA axis uncoupling. While brainstem pSTAT-3 and SOCS-3, key markers of leptin signaling, were not different between groups, circulating saturated and unsaturated free fatty acids were reduced in HF-fed, metformin-treated animals.ConclusionsThese findings suggest that oral metformin can successfully correct HPA axis dysfunction that is associated with lowered circulating free fatty acids in DIO rats, thereby uncovering a novel effect of metformin in the treatment of obesity.

Sex, stress and steroids.

The hypothalamo-pituitary-adrenal (HPA) axis plays a key role in the neuroendocrine response to stress and in maintaining physiological homoeostasis. However, stress that is chronic in nature can lead to HPA axis dysfunction and increase the risk for developing affective disorders, particularly if the stress is experienced during vulnerable periods in life. Sex differences in how the HPA axis responds to stress are well established, with females typically displaying heightened responses. The underlying cause of these sex differences is important to understand, as many neuropsychiatric disorders disproportionately affect females. Much research has provided evidence for gonadal sex steroids in underpinning sex differences in HPA axis responsivity; however, we suggest that neuroactive metabolites of these steroids also play a key role in the brain in mediating sex differences in HPA axis responses to stress. The relationship between neuroactive steroids and stress is complex. Acute stress rapidly increases neuroactive steroid production, which can in turn modulate activity of the HPA axis. However, under chronic stress conditions, stress can impact the brain's capacity to generate steroids, and this in turn has corollary effects on HPA axis function that may increase the propensity for psychopathology, given both HPA axis dysfunction and deficits in neuroactive steroids are implicated in affective disorders. Hence, here we review the evidence from animal and human studies for sex differences in the interactions between neuroactive steroids and the stress axis at various stages of life, under physiological and pathophysiological stress conditions and consider the implications for health and disease.

Recovery of the Hypothalamo-Pituitary-Adrenal Axis After Transsphenoidal Adenomectomy for Non-ACTH-Secreting Macroadenomas.

Secondary adrenal insufficiency is a potential complication of transsphenoidal adenomectomy (TSA). Most centers test recovery of the hypothalamo-pituitary-adrenal (HPA) axis after TSA, but, to our knowledge, there are no data predicting likelihood of recovery or the frequency of later recovery of HPA function. To assess timing and predictors of HPA axis recovery after TSA. Single-center, retrospective analysis of consecutive pituitary surgeries performed between February 2015 and September 2018. Patients (N = 109) with short Synacthen test (SST) data before and at sequential time points after TSA. Recovery of HPA axis function at 6 weeks, and 3, 6, and 9 to12 months after TSA. Preoperative SST indicated adrenal insufficiency in 21.1% Among these patients, 34.8% recovered by 6 weeks after TSA. Among the 65.2% (n = 15) remaining, 13.3% and 20% recovered at 3 months and 9 to 12 months, respectively. Of the 29% of patients with adrenal insufficiency at the 6-week SST, 16%, 12%, and 6% subsequently recovered at 3, 6, and 9 to 12 months, respectively. Preoperative SST 30-minute cortisol, postoperative day 8 cortisol, and 6-week postoperative SST baseline cortisol levels above or below 430 nmol/L [15.5 μg/dL; AUC ROC, 0.86]; 160 nmol/L (5.8 μg/dL; AUC ROC, 0.75); and 180 nmol/L (6.5 μg/dL; AUC ROC, 0.88), were identified as cutoffs for predicting 6-week HPA recovery. No patients with all three cutoffs below the threshold recovered within 12 months after TSA, whereas 92% with all cutoffs above the threshold recovered HPA function within 6 weeks (OR, 12.200; 95% CI, 5.268 to 28.255). HPA axis recovery can occur as late as 9 to 12 months after TSA, demonstrating the need for periodic reassessment of patients who initially have SST-determined adrenal insufficiency after TSA. Pre- and postoperative SST values can guide which patients are likely to recover function and potentially avoid unnecessary lifelong glucocorticoid replacement.

The Short Synacthen (Corticotropin) Test Can Be Used to Predict Recovery of Hypothalamo-Pituitary-Adrenal Axis Function.

The 250-μg short Synacthen (corticotropin) test (SST) is the most commonly used tool to assess hypothalamo-pituitary-adrenal (HPA) axis function. There are many potentially reversible causes of adrenal insufficiency (AI), but no data to guide clinicians as to the frequency of repeat testing or likelihood of HPA axis recovery. To use the SST results to predict adrenal recovery. A retrospective analysis of 1912 SSTs data. Seven hundred seventy-six patients with reversible causes of AI were identified who had at least two SSTs performed. A subgroup analysis was performed on individuals previously treated with suppressive doses of glucocorticoids (n = 110). Recovery of HPA axis function. SST 30-minute cortisol levels above or below 350 nmol/L (12.7 μg/dL) best predicted HPA axis recovery [area under the curve (AUC) receiver operating curve (ROC) = 0.85; median recovery time: 334 vs 1368 days, P = 8.5 × 10-13]: 99% of patients with a 30-minute cortisol >350 nmol/L recovered adrenal function within 4 years, compared with 49% in those with cortisol levels <350 nmol/L. In the subgroup analysis, delta cortisol (30-minute-basal) best predicted the recovery (AUC ROC = 0.77; median recovery time: 262 vs 974 days, P = 7.0 × 10-6). No patient with a delta cortisol <100 nmol (3.6 μg/dL) and a subsequent 1-year random cortisol <200 nmol/L (7.3 μg/dL) recovered HPA axis function. Cortisol levels across an SST can be used to predict recovery of AI and may guide the frequency of repeat testing and inform both clinicians and patients as to the likelihood of restoration of HPA axis function.

HPA Axis Function as Biomarker for Atypical and Melancholic Depression

HPA Axis Function as Biomarker for Atypical and Melancholic Depression

Adolescent binge alcohol exposure increases risk assessment behaviors in male Wistar rats after exposure to an acute psychological stressor in adulthood

Teenage binge drinking is a common practice that has been shown to increase the risk for developing mood disorders in adulthood. The hypothalamo-pituitary-adrenal (HPA) axis is often dysfunctional in mood disorder patients, and animal models of adolescent binge alcohol exposure similarly show disordered HPA axis function, even after long periods of alcohol abstinence. Here, we sought to investigate the anxiety-like behavioral consequences of binge alcohol exposure in a Wistar rat model. Male rats were administered alcohol in a binge pattern during peri-puberty, and one month later, anxiety-like behaviors were measured using the elevated plus maze. A subset of the rats then underwent 30min of restraint stress, and the anxiety-like behaviors were measured again. We observed an increase in risk assessment behaviors due to both adolescent binge alcohol exposure and restraint stress, but no differences in canonical anxiety-like behaviors. We also repeated the observation that adolescent binge alcohol induces long-term changes in HPA axis sensitivity. Therefore, we concluded that a history of peri-pubertal binge alcohol exposure subtly alters the behavioral response to subsequent acute psychological stress during adulthood, which may over time contribute to the development of mood disorders. This relatively pragmatic animal model represents a more clinically relevant tool in understanding the molecular mechanisms underlying the long-term effects of adolescent binge drinking.

Gonadal steroid hormones and the hypothalamo-pituitary-adrenal axis.

The hypothalamo-pituitary-adrenal (HPA) axis represents a complex neuroendocrine feedback loop controlling the secretion of adrenal glucocorticoid hormones. Central to its function is the paraventricular nucleus of the hypothalamus (PVN) where neurons expressing corticotropin releasing factor reside. These HPA motor neurons are a primary site of integration leading to graded endocrine responses to physical and psychological stressors. An important regulatory factor that must be considered, prior to generating an appropriate response is the animal's reproductive status. Thus, PVN neurons express androgen and estrogen receptors and receive input from sites that also express these receptors. Consequently, changes in reproduction and gonadal steroid levels modulate the stress response and this underlies sex differences in HPA axis function. This review examines the make up of the HPA axis and hypothalamo-pituitary-gonadal (HPG) axis and the interactions between the two that should be considered when exploring normal and pathological responses to environmental stressors.

Effects of maternal exposure to social stress during pregnancy: consequences for mother and offspring

A suboptimal in utero environment, for example, as a result of maternal stress, can have detrimental effects on the pregnancy and long-term adverse 'programming' effects on the offspring. This article focuses on the effects of prenatal social stress on the mother, her pregnancy and the offspring, since these issues have ethological relevance in both animals and humans. The consequences of social stress exposure depend on when during pregnancy the stress occurs, and many of the effects on the offspring are sex specific. Social stress during early pregnancy tends to result in pregnancy loss, whereas stress exposure later in pregnancy, when the mother has already invested considerable resources in the foetuses, results in programmed offspring of low birth weight: a risk factor for various adulthood diseases. Neuroendocrine and behavioural responses to stress in the offspring are particularly sensitive to foetal programming by prenatal stress, indicated by enhanced hypothalamo-pituitary-adrenal (HPA) axis responses and increased anxiety behaviour, which result from permanent changes in the offspring's brain. The dysregulation of HPA axis function may also interfere with other systems, for example, the hypothalamic-pituitary-gonadal axis, as there is evidence for alterations in steroidogenesis, reproductive potential and impaired reproductive/social behaviours in prenatally stressed offspring. Prenatal social stress also programmes future maternal behaviour, highlighting the potential for negative phenotypes to be transmitted to future generations. The possible mechanisms through which maternal stress during pregnancy is transmitted to the foetuses and the foetal brain is programmed by prenatal stress and the potential to overwrite programming of the offspring are discussed.

Probing the association between dexamethasone-induced cortisol suppression and serotonin transporter availability among drug-free patients with major depressive disorder—A small-sample SPECT study with [123I]ADAM

The association between hypothalamo-pituitary-adrenal (HPA) axis function and the serotonergic system could be involved in the mechanism of depression. However, neuroimaging evidence is scarce. The aim of the present study was to probe the association between dexamethasone suppression test response and serotonin transporter (SERT) availability in drug-free patients with major depressive disorder (MDD). Seventeen MDD patients (five males and twelve females) were recruited. SPECT with [(123)I] ADAM was used to measure the midbrain SERT availability, and HPA axis function was measured by the dexamethasone suppression test (DST). The association was significant when considering all participants (ρ=0.69, p=0.002). This association may have clinical implications for the treatment of MDD.

Multigenerational effects of fetal dexamethasone exposure on the hypothalamic–pituitary–adrenal axis of first- and second-generation female offspring

Synthetic glucocorticoid (sGC) administration to women threatening preterm delivery increases neonatal survival. Evidence shows that fetal exposure to glucocorticoid levels higher than appropriate for current maturation programs offspring development. We examined fetal sGC multigenerational effects on F1 and F2 female offspring hypothalamo-pituitary-adrenal axis (HPAA) function. At 0.7 gestation, pregnant F0 ewes received 4 dexamethasone injections (2 mg, approximately 60 μg/kg(-1) per day(-1), 12 hours apart) or saline (control). F1 female offspring were bred to produce F2 female offspring. Postpubertal HPAA function was tested in F1 and F2 ewes. F1 and F2 ewe lambs showed reduced birthweight and morphometrics. Dexamethasone increased baseline but reduced stimulated HPAA activity in F1 and F2 female offspring. This is the first demonstration that sGC doses in the clinical range have multigenerational effects on hypothalamo-pituitary-adrenal activity in a precocial species, indicating the need for the study of long-term effects of fetal sGC exposure.

Sex, Stress, and Mood Disorders: At the Intersection of Adrenal and Gonadal Hormones

The risk for neuropsychiatric illnesses has a strong sex bias, and for major depressive disorder (MDD), females show a more than 2-fold greater risk compared to males. Such mood disorders are commonly associated with a dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis. Thus, sex differences in the incidence of MDD may be related with the levels of gonadal steroid hormone in adulthood or during early development as well as with the sex differences in HPA axis function. In rodents, organizational and activational effects of gonadal steroid hormones have been described for the regulation of HPA axis function and, if consistent with humans, this may underlie the increased risk of mood disorders in women. Other developmental factors, such as prenatal stress and prenatal overexposure to glucocorticoids can also impact behaviors and neuroendocrine responses to stress in adulthood and these effects are also reported to occur with sex differences. Similarly, in humans, the clinical benefits of antidepressants are associated with the normalization of the dysregulated HPA axis, and genetic polymorphisms have been found in some genes involved in controlling the stress response. This review examines some potential factors contributing to the sex difference in the risk of affective disorders with a focus on adrenal and gonadal hormones as potential modulators. Genetic and environmental factors that contribute to individual risk for affective disorders are also described. Ultimately, future treatment strategies for depression should consider all of these biological elements in their design.

Periconceptional undernutrition suppresses cortisol response to arginine vasopressin and corticotropin-releasing hormone challenge in adult sheep offspring.

Poor maternal nutrition during pregnancy can result in increased disease risk in adult offspring. Many of these effects are proposed to be mediated via altered hypothalamo-pituitary-adrenal axis (HPAA) function, and are sex and age specific. Maternal undernutrition around the time of conception alters HPAA function in foetal and early postnatal life, but there are limited conflicting data about later effects. The aim of this study was to investigate the effect of moderate periconceptional undernutrition on HPAA function of offspring of both sexes longitudinally, from juvenile to adult life. Ewes were undernourished from 61 days before until 30 days after conception or fed ad libitum. HPAA function in offspring was assessed by arginine vasopressin plus corticotropin-releasing hormone challenge at 4, 10 and 18 months. Plasma cortisol response was lower in males than in females, and was not different between singles and twins. Periconceptional undernutrition suppressed offspring plasma cortisol but not adrenocorticotropic hormone responses. In males, this suppression was apparent by 4 months, and was more profound by 10 months, with no further change by 18 months. In females, suppression was first observed at 10 months and became more profound by 18 months. Maternal undernutrition limited to the periconceptional period has a prolonged, sex-dependent effect on adrenal function in the offspring.

Role of Calcium Signaling in the Development of Prenatal Stress-Induced Functional Modifications of the Hypothalamo-Pituitary-Adrenal Axis

We studied the effect of a blocker of calcium L-type channels, nimodipine, influencing rats within the prenatal period on the hormonal reaction of the adrenal glands (measured according to the level of corticosterone in the blood plasma) upon acute stress or upon injection of noradrenaline into the third cerebral ventricle in adult rat offspring (6- to 8-month-old males and females). Mothers in these animals were subjected daily to 1-hlong immobilization within the last week of pregnancy (from the 15th to 21th day). In males, prenatal stress weakened the adrenocortical reaction to acute stress immobilization, while in females such stress moderately intensified the above reaction. Peroral administration of 20 mg/kg nimodipin prior to immobilization of pregnant mothers prevented the development of the mentioned disturbances of the stress-related reaction of the hypothalamo-pituitary-adrenal axis (HPAA) in adult offspring of both sexes. Hormonal reaction of the adrenal cortex to injection of noradrenaline into the third cerebral ventricle of adult rat females, which was absent in prenatally stressed animals, was completely preserved after injection of nimodipin within the prenatal period. At the same time, nimodipin did not influence prenatal stress-induced changes in noradrenergic reactivity of the HPAA in adult males. Injection of nimodipine into pregnant mothers (which were not subjected to immobilization stressing) provided a modifying action on the formation of reactivity of the HPAA in adult offspring, which was manifested in prolongation of the adrenocortical reaction of the HPAA to intraventricular noradrenaline injection in males and females and also in moderate intensification of the hormonal response of the adrenal cortex to acute stress in females. The obtained data indicate that calcium-dependent mechanisms are significantly involved in the process of programming of prenatal stressinduced functional modifications of the HPAA in adult animals, while nimodipin exerts a protective effect with respect to these changes via weakening of calcium signalization in the cerebral regions involved in the control of the HPAA function.

Sex‐ and age‐specific effects of nutrition in early gestation and early postnatal life on hypothalamo‐pituitary‐adrenal axis and sympathoadrenal function in adult sheep

The early-life environment affects risk of later metabolic disease, including glucose intolerance, insulin resistance and obesity. Changes in hypothalamo-pituitary-adrenal (HPA) axis and sympathoadrenal function may underlie these disorders. To determine consequences of undernutrition in early gestation and/or immediately following weaning on HPA axis and sympathoadrenal function, 2- to 3-year-old Welsh Mountain ewes received 100% (C, n = 39) or 50% nutritional requirements (U, n = 41) from 1-31 days gestation, and 100% thereafter. From weaning (12 weeks) to 25 weeks of age, male and female offspring were then either fed ad libitum (CC, n = 22; UC, n = 19) or were undernourished (CU, n = 17; UU, n = 22) such that body weight was reduced to 85% of their individual target, based on a growth trajectory calculated from weights taken between birth and 12 weeks. From 25 weeks, ad libitum feeding was restored for all offspring. At 1.5 and 2.5 years, adrenocorticotropic hormone (ACTH) and cortisol concentrations were measured at baseline and in response to corticotropin-releasing factor (CRF) (0.5 microg kg(1)) plus arginine vasopressin (AVP) (0.1 microg kg(1)). At 2.5 years, HPA axis and sympathoadrenal (catecholamine) responses to a transport and isolation stress test were also measured. In females, post-weaning undernutrition reduced pituitary output (ACTH) but increased adrenocortical responsiveness (cortisol:ACTH area under curve) during CRF/AVP challenge at 1.5 years and increased adrenomedullary output (adrenaline) to stress at 2.5 years. In males, cortisol responses to stress at 2.5 years were reduced in those with slower growth rates from 12 to 25 weeks. Early gestation undernutrition was associated with increased adrenocortical output in 2.5-year-old females only. Pituitary and adrenal responses were also related to adult body composition. Thus, poor growth in the post-weaning period induced by nutrient restriction has sex- and age-specific effects on HPA and sympathoadrenal function. With altered glucose tolerance previously reported in this model, this may have long-term detrimental effects on metabolic homeostasis and cardiovascular function.

Chronic exposure to a high-fat diet affects stress axis function differentially in diet-induced obese and diet-resistant rats

Consumption of a high-fat (HF) diet is a contributing factor for the development of obesity. HF diet per se acts as a stressor, stimulating hypothalamo-pituitary-adrenal (HPA) axis activity resulting in elevated glucocorticoid levels; however, the mechanism behind this activation is unclear. We hypothesized that consumption of an HF diet activates HPA axis by increasing norepinephrine (NE) in the paraventricular nucleus (PVN) of the hypothalamus, leading to elevation in corticotrophin-releasing hormone (CRH) concentration in the median eminence (ME) resulting in elevated serum corticosterone (CORT). To test this hypothesis, diet-induced obese (DIO) and diet-resistant (DR) rats were exposed to either chow or HF diet for 6 weeks. At the end of 6 weeks, NE in the PVN was measured using HPLC, CRH in the ME, and CORT and leptin levels in the serum were measured using RIA and ELISA, respectively. The gene expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in NE synthesis, and leptin receptor in brainstem noradrenergic nuclei were also measured. HF diet increased PVN NE in both DIO and DR rats (P<0.05). However, this was accompanied by increases in CRH and CORT secretion only in DR animals, but not in DIO rats. Leptin receptor mRNA levels in the brainstem noradrenergic areas were not affected in both DIO and DR rats. However, HF diet increased TH mRNA levels only in DIO rats. Significant differences occur in all the arms of HPA axis function between DIO and DR rats. Further studies are needed to determine whether this could be a causative factor or a consequence to obesity.

Chronic maternal stress affects growth, behaviour and hypothalamo–pituitary–adrenal function in juvenile offspring

Maternal stress during pregnancy, particularly that combined with low socioeconomic status (SES), has been linked to an increased risk for impaired behavioural and emotional development and affective disorders in children. In animal models, acute periods of prenatal stress have profound effects on hypothalamo-pituitary-adrenal (HPA) function and behaviour. However, few studies have determined the impact of chronic exposure to stress in animal models. The objective of this study was to determine the effects of chronic maternal stress (CMS) during the 2nd half of pregnancy and nursing on growth, locomotor behaviour and HPA axis function in juvenile guinea pig offspring. Pregnant guinea pigs were exposed to a random combination of variable stressors every other day over the 2nd half of gestation and from postnatal day (pnd) 1 until weaning (pnd25). CMS mothers displayed increased basal salivary cortisol levels in the later stages of pregnancy compared to control mothers ( p < 0.05). The male offspring of CMS mothers had a lower bodyweight, which was maintained to weaning ( p < 0.01). In open-field testing, CMS male offspring showed a decrease in activity compared to controls ( p < 0.05). There was no effect of CMS on bodyweight or activity in female offspring. In contrast, both male and female offspring born to CMS mothers displayed increased ( p < 0.05) basal salivary cortisol at pnd25, but a blunted adrenocortical response to exposure to the novel open-field enclosure. In conclusion, CMS leads to modification of growth trajectory, locomotor activity and adrenocortical responses to stress in juvenile offspring. Further, males appear considerably more vulnerable to these effects than females.

Erythropoietin Inhibits Basal and Stimulated Corticotropin-Releasing Hormone Release from the Rat Hypothalamus via a Nontranscriptional Mechanism

Brain hypoxia-ischemia induces a local increase in the levels of erythropoietin (EPO) and vascular endothelial growth factor (VEGF); this condition is also associated with acute activation of the hypothalamo-pituitary-adrenal (HPA) axis, suggesting that increased levels of EPO and VEGF in the hypothalamus may play a role in the control of HPA function. Thus, in this study we used rat hypothalamic explants to investigate whether EPO and VEGF can directly modulate CRH release; the latter was assessed by RIA measurement of the peptide in the incubation medium and hypothalamic tissue. EPO and VEGF effects were studied in short-term (1-3 h) experiments under basal conditions or after stimulation with 56 mM KCl or 10 microM veratridine. We observed that EPO (1-10 nm) significantly reduced CRH release and, in parallel, increased intrahypothalamic CRH content. VEGF tended to reduce CRH release without reaching statistical significance. Moreover, EPO, but not VEGF, inhibited KCl- and veratridine-stimulated CRH release and counteracted the parallel decrease in intrahypothalamic CRH induced by the two secretagogues. EPO effects were not mediated by modification of CRH gene expression, either in the absence or the presence of KCl or veratridine; in this paradigm, KCl and veratridine per se did not modify CRH gene expression. Our findings suggest that EPO contributes to the regulation of the HPA axis activation; in pathological conditions such as brain ischemia, this growth factor may control the HPA axis function, preventing possible detrimental effects of HPA overactivation.

The hypothalamo–pituitary–adrenal axis in chronic fatigue syndrome and fibromyalgia syndrome

The hypothalamo–pituitary–adrenal (HPA) axis plays a major role in the regulation of responses to stress. Human stress-related disorders such as chronic fatigue syndrome (CFS), fibromyalgia syndrome (FMS), chronic pelvic pain and post-traumatic stress disorder are characterized by alterations in HPA axis activity. However, the role of the HPA axis alterations in these stress-related disorders is not clear. Most studies have shown that the HPA axis is underactive in the stress-related disorders, but contradictory results have also been reported, which may be due to the patients selected for the study, the methods used for the investigation of the HPA axis, the stage of the syndrome when the tests have been done and the interpretation of the results. There is no structural abnormality in the endocrine organs which comprise the HPA axis, thus it seems that hypocortisolemia found in the patients with stress-related disorder is functional. It may be also an adaptive response of the body to chronic stress. In this review, tests used in the assessment of HPA axis function and the HPA axis alterations found in CFS and FMS are discussed in detail.

Atomoxetine increases salivary cortisol in healthy volunteers

It has been proposed that acute hypothalamo-pituitary-adrenal (HPA) axis challenge using noradrenergic drugs may be of utility in assessing the functional integrity of central noradrenaline pathways. Atomoxetine (formerly tomoxetine) is a highly selective noradrenaline reuptake inhibitor, which has recently been licensed for the treatment of attention deficit hyperactivity disorder (ADHD). The aim of this study was to assess the effects of acute atomoxetine on salivary cortisol levels for the first time.A total of 60 healthy male volunteers received 60 mg atomoxetine, 30 mg citalopram, or placebo per os in a double-blind parallel groups design (n = 20 per group). Salivary cortisol, blood pressure and pulse rates were recorded at baseline and at +1.0, +1.5, +2.5 and +3.5 hours after capsule administration.60 mg atomoxetine led to highly significant increases in salivary cortisol and a moderate increase in pulse rate, in the absence of significant effects on blood pressure. 30 mg citalopram had no significant effects on cortisol or cardiovascular parameters. These data support the utility of atomoxetine neuroendocrine challenge for evaluating central noradrenaline pathways, which may be of future use in neuropsychiatric patient studies. Furthermore, the effects of atomoxetine on HPA axis function may have clinical implications given the use of this agent in the treatment of ADHD.