Hypothalamic-pituitary-adrenal System Research Articles

C.12.03 Answering your questions about duloxetine

When antisocial behavior becomes a persistent pattern that affects diverse domains of children's functioning, psychiatrists refer to oppositional defiant disorder (ODD) or conduct disorder (CD). The term disruptive behavior disorder (DBD) covers both ODD and CD. Research shows that in the absence of effective interventions, the prognosis for DBD children is relatively unfavorable: their disorder can extend into adolescence, manifest itself in delinquency, and convert into other psychiatric symptoms, such as addiction or personality disorders. Although environmental factors have traditionally attracted most attention in explaining the origin and persistence of DBDs, it is important not to overlook the vulnerability of the child in the development of antisocial behavior. Relatively few studies have been conducted on the neurobiological factors involved in the development of DBDs in children. In this paper, we explain how problems in hypothalamic–pituitary–adrenal (HPA) axis and serotonergic system functioning could be important factors in the behavioral problems of DBD children. Low fear of punishment and physiological underactivity may predispose antisocial individuals to seek out stimulation or take risks and may explain poor (social) conditioning and socialization. Findings consistent with this hypothesis are presented. Finally, we explain how stress in general, and adverse early life experiences in particular, could have an impact on the development of the HPA and serotonergic systems. An investigation of the neurobiological factors involved in antisocial behavior disorder might ultimately guide the development of new forms of intervention.

Rearing environment and hypothalamic-pituitary-adrenal regulation in young rhesus monkeys (Macaca mulatta)

A mammal's early social environment has important regulatory effects on its behavior and physiology, and this is especially true for regulation of the hypothalamic-pituitary-adrenal (HPA) system. The present study was designed to test hypotheses that various aspects of the social environment are important influences on HPA regulation. Seven hundred seventy eight, 3- to 4-month-old rhesus monkeys were studied as part of a standardized, 24-hr biobehavioral assessment program, which included blood sampling to determine plasma cortisol concentrations. Results indicate that nursery-rearing results in a reduced cortisol set-point for the HPA system, and, for nursery-reared (NR) animals, more peer exposure during infancy is associated with a higher set-point. Age and sex differences during this period were evident but small in magnitude. These data demonstrate the important regulatory role of the social environment on nonhuman primate physiology and suggest caution in assuming that differences between individuals' cortisol levels reflect only differences in perceptions of the "stressfulness" of events.

Postnatal microbial colonization programs the hypothalamic–pituitary–adrenal system for stress response in mice

Indigenous microbiota have several beneficial effects on host physiological functions; however, little is known about whether or not postnatal microbial colonization can affect the development of brain plasticity and a subsequent physiological system response. To test the idea that such microbes may affect the development of neural systems that govern the endocrine response to stress, we investigated hypothalamic-pituitary-adrenal (HPA) reaction to stress by comparing germfree (GF), specific pathogen free (SPF) and gnotobiotic mice. Plasma ACTH and corticosterone elevation in response to restraint stress was substantially higher in GF mice than in SPF mice, but not in response to stimulation with ether. Moreover, GF mice also exhibited reduced brain-derived neurotrophic factor expression levels in the cortex and hippocampus relative to SPF mice. The exaggerated HPA stress response by GF mice was reversed by reconstitution with Bifidobacterium infantis. In contrast, monoassociation with enteropathogenic Escherichia coli, but not with its mutant strain devoid of the translocated intimin receptor gene, enhanced the response to stress. Importantly, the enhanced HPA response of GF mice was partly corrected by reconstitution with SPF faeces at an early stage, but not by any reconstitution exerted at a later stage, which therefore indicates that exposure to microbes at an early developmental stage is required for the HPA system to become fully susceptible to inhibitory neural regulation. These results suggest that commensal microbiota can affect the postnatal development of the HPA stress response in mice.

Arginine vasopressin and adrenocorticotropin secretion in response to psychosocial stress is attenuated by ethanol in sons of alcohol-dependent fathers

Familial risk and environmental stress promote the development of alcohol dependence. We investigated whether a positive family history of alcoholism affects the neuroendocrine response to a standardized laboratory stress test in healthy subjects without alcohol use disorders. Twenty-four high-risk subjects with a paternal history of alcoholism (PHA) and 16 family history negative (FHN) controls were evaluated. Psychosocial stress was induced by having subjects deliver a 5-min speech and mental arithmetics in front of an audience on separate days, after drinking either placebo or ethanol (0.6 g/kg) in a randomized sequence. Adrenocorticotropin (ACTH) was measured in 10 plasma samples covering up to 75 min after the stress test. Plasma arginine vasopressin (AVP) was determined before the stressor, at the time of maximum ACTH secretion, and at 75 min after stress onset. The stress test induced a phasic increase in ACTH secretion. At the time of maximum ACTH, AVP was significantly increased in relation to baseline. Compared to placebo, alcohol administration significantly attenuated maximum ACTH concentration in PHA but not FHN subjects, and decreased AVP measured in the same samples in PHA but not FHN subjects. We conclude that activation of the hypothalamic–pituitary–adrenal system by psychosocial stress is accompanied by an increase in peripheral plasma AVP levels. Secretion of both ACTH and AVP suggest that alcohol attenuates the stress response selectively in PHA but not FHN subjects. This might imply some short-term positive alcohol effect in sons of alcoholics, but also constitute a mechanism by which their risk to develop alcohol use disorders is increased.

Daily hassles, cortisol, and the pathogenesis of depression

Daily hassles and/or ongoing stress are associated with increased cortisol secretion in healthy individuals. Hassles are also associated with increased cortisol levels in depressed patients. Considerable evidence suggests that hypercortisolism is involved in the pathogenesis of depressive disorders. Over the past decade, there has been a shift from viewing excessive hypothalamic–pituitary–adrenal (HPA) activity in depression as an epiphenomenon to its having specific effects on symptom formation. The author suggests that increased cortisol secretion caused by daily hassles and/or ongoing stress contributes to the development of depressive disorders. Minor stressful events may lead to depression in vulnerable individuals. Genetic factors interact with environmental factors to influence the vulnerability to stress and mood disorders. The author also proposes that elevated cortisol levels associated with stressful daily events may worsen the condition of depressed patients. The author notes that one of the goals of prevention of stress-related disorders is to help individuals be more competent in managing their behavior and emotions in reaction to negative aspects of their environment, and briefly discusses stress management methods and techniques. The risk of developing depression is determined by a complex interplay between genetic susceptibility, environmental exposures, and aging. These influences also account for long term changes in the regulation of HPA function. Further studies of HPA function may not only advance our understanding of the role of the HPA system in the etiology and pathogenesis of psychiatric disorders, but also be useful in refining conceptions of psychiatric disorders themselves and possible approaches to the treatment of these conditions.

Die Therapie der Depression in der Neurorehabilitation und die neurobiologischen Wirkmechanismen

Depression occurs frequently in patients with physical diseases. It is a significant cause of suffering among these patients associated with a poor outcome with increased morbidity and mortality and often presents diagnostic and management problems. The purpose of this article is to review the evidence on whether antidepressant medication is clinically effective and acceptable in patients with neurological disorders in rehabilitation. Depression is most common in patients following vascular or traumatic brain injury and spinal cord injuries and leads to an additional significant functional and psychosocial impairment. A few controlled and uncontrolled treatment trials provide support that antidepressant therapy improves depressed mood, pathological affect and the cognitive and physical consequences in these diseases. However, medication selection needs careful evaluation according to side effect profiles. Regarding the choice of a particular agent, the data do not support an automatic first choice. The selection of drug will be a matter of clinical judgment, bearing in mind factors including the individual patient's symptoms, the profile of wanted and unwanted effects of the various drugs available, and potential interactions. Clearly more short- and long-term studies are needed to improve differential treatment selection criteria for these patients which are difficult to treat. Among the aetiological factors, several neurochemical changes have been suggested to contribute to depression. In patients with traumatic brain injury, the role of norepinephrine and serotonine in promoting neurological recovery after brain lesions has been discussed. Recent neuroendocrine research has added data pointing to a more integrative approach. Acute and chronic stress as well as a number of psychiatric and neurological disorders are accompanied by profound disturbances of the hypothalamic pituitary adrenal system and recent studies suggest that stress-induced atrophy and loss of hippocampal neurons may contribute to the pathophysiology of depression. Antidepressants act through reinstatement of central corticosteroid receptor function, and additional studies showed that several different classes of antidepressants increase the proliferation of hippocampal cells into neurons. These findings suggest the possibility that increased cell proliferation and increased neuronal number may be a mechanism by which antidepressant treatment overcomes the stress-induced atrophy and loss of hippocampal neurons and may contribute to the therapeutic action of antidepressant treatment.

Noninvasive technique for the repeated sampling of salivary free cortisol in awake, unrestrained squirrel monkeys.

The use of noninvasive measures of hypothalamic-pituitary-adrenal (HPA) axis function is of growing interest among preclinical and clinical investigators. This report describes a method for the repeated assessment of salivary free cortisol in awake, unrestrained squirrel monkeys (Saimiri sciureus) based on a saliva sampling technique previously developed for rhesus monkeys. Individually housed adult male squirrel monkeys were trained to chew on dental rope attached to a pole, from which saliva was extracted by centrifugation and analyzed for cortisol by radioimmunoassay (RIA). Eight of nine monkeys readily acquired the task, reliably providing adequate saliva samples for the assay. Salivary free cortisol levels were examined in these subjects under basal conditions and in response to two types of neuroendocrine challenge. Levels of salivary free cortisol showed relatively low intra- and interindividual variability, with mean individual morning levels ranging between 17.1 and 37.9 microg/dl. Squirrel monkeys demonstrated a consistent daily rhythm in salivary free cortisol ranging from a high of 27.4 +/- 5.2 microg/dl (mean +/- SEM) at 12 P.M. to a low of 7.5 +/- 1.6 microg/dl at 6 P.M. Intravenous (IV) challenges with 1 microg/kg ACTH, or 10 and 50 microg/kg CRF resulted in significant increases in salivary free cortisol. The described sampling technique provides a reliable and sensitive means for repeated measurement of HPA activity in unrestrained, awake squirrel monkeys. In addition, our findings illustrate several features of HPA system rhythmicity and reactivity using salivary cortisol instead of blood plasma or serum.

High levels of cortisol among adolescent offspring of parents with bipolar disorder: a pilot study

The hypothalamic-pituitary-adrenal (HPA) axis is compromised at several levels in major depressive and bipolar disorder (BD). However, it is not known whether HPA abnormalities predate the onset of these disorders . We conducted a pilot study comparing salivary cortisol levels of 10 adolescent offspring of parents with BD and 10 offspring of parents with no mental disorder (NMD). For two days, samples were collected at awakening and during the day in the adolescents’ natural environment. The offspring of parents with BD had higher mean cortisol levels in the mornings and afternoons than the offspring of parents with NMD. When controlling for age, group differences in cortisol persisted in the afternoon, but not morning samples. None of the adolescents met diagnostic criteria for anxiety, affective, attention-deficit, or conduct disorders. Although preliminary, the results suggest that there is an early abnormality in the HPA system of the offspring of parents with BD.

Neuroendocrine pharmacology of stress

Exposure to hostile conditions initiates responses organized to enhance the probability of survival. These coordinated responses, known as stress responses, are composed of alterations in behavior, autonomic function and the secretion of multiple hormones. The activation of the renin–angiotensin system and the hypothalamic–pituitary–adrenocortical axis plays a pivotal role in the stress response. Neuroendocrine components activated by stressors include the increased secretion of epinephrine and norepinephrine from the sympathetic nervous system and adrenal medulla, the release of corticotropin-releasing factor (CRF) and vasopressin from parvicellular neurons into the portal circulation, and seconds later, the secretion of pituitary adrenocorticotropin (ACTH), leading to secretion of glucocorticoids by the adrenal gland. Corticotropin-releasing factor coordinates the endocrine, autonomic, behavioral and immune responses to stress and also acts as a neurotransmitter or neuromodulator in the amygdala, dorsal raphe nucleus, hippocampus and locus coeruleus, to integrate brain multi-system responses to stress. This review discussed the role of classical mediators of the stress response, such as corticotropin-releasing factor, vasopressin, serotonin (5-hydroxytryptamine or 5-HT) and catecholamines. Also discussed are the roles of other neuropeptides/neuromodulators involved in the stress response that have previously received little attention, such as substance P, vasoactive intestinal polypeptide, neuropeptide Y and cholecystokinin. Anxiolytic drugs of the benzodiazepine class and other drugs that affect catecholamine, GABA A, histamine and serotonin receptors have been used to attenuate the neuroendocrine response to stressors. The neuroendocrine information for these drugs is still incomplete; however, they are a new class of potential antidepressant and anxiolytic drugs that offer new therapeutic approaches to treating anxiety disorders. The studies described in this review suggest that multiple brain mechanisms are responsible for the regulation of each hormone and that not all hormones are regulated by the same neural circuits. In particular, the renin–angiotensin system seems to be regulated by different brain mechanisms than the hypothalamic–pituitary–adrenal system. This could be an important survival mechanism to ensure that dysfunction of one neurotransmitter system will not endanger the appropriate secretion of hormones during exposure to adverse conditions. The measurement of several hormones to examine the mechanisms underlying the stress response and the effects of drugs and lesions on these responses can provide insight into the nature and location of brain circuits and neurotransmitter receptors involved in anxiety and stress.

The stress-vulnerability hypothesis in psychotic disorders: focus on the stress response systems.

The vulnerabilty stress model is an intriguing concept to look into the etiology of psychotic disorders and, in particular, into the "nature nurture" principle. That stress affects a vulnerable nature may be obvious, but its mechanism is not well understood, and many questions remain to be answered, let alone how to define "vulnerability". The present review tries to focus on the core issues of the vulnerability stress concept--identifying vulnerability, the way stress interferes with it, and the possiblilities of modulating their interaction. Attention is drawn to the biologic stress response systems, the autonomic nervous system (ANS), the hypothalamic pituitary adrenal (HPA) system, and the immune system, and highlights the plasticity of the HPA system as the mediator of adaptation.

The effects of drug abuse on the stress responsive hypothalamic-pituitary-adrenal axis and the dopaminergic and endogenous opioid systems.

Drugs of abuse have a significant impact on the stress responsive hypothalamic-pituitary-adrenal (HPA) axis and an abnormal response to stress may mediate the development or maintenance of addictive diseases. In animals, drugs of abuse, such as cocaine, lead to an activation of the HPA axis. Drugs of abuse also have an impact on the endogenous opioid system (EOS) and the dopaminergic system. Each of these systems has also been implicated in the mediation of aggressive behaviors. This brief report focuses on the effects of drugs of abuse on the stress responsive HPA, EOS and dopaminergic systems, and the role of these systems in mediating aggression and comorbidity of substance abuse and aggressive behaviors. Rodents were administered either 'binge' pattern cocaine (15 mg/kg x 3 each day) or the androgenic anabolic steroid nandrolone decanoate and the effects on mRNA levels, receptor binding and circulating levels of stress hormones were analyzed. Both cocaine and nandrolone decanoate significantly impact the HPA axis, the EOS and the dopaminergic systems. Drugs of abuse impact substantially the same neural systems that affect aggressive behavior.

Functional cross-talk between the hypothalamic-pituitary-gonadal and -adrenal axes.

Under normal conditions, the adrenal glucocorticoids, the endproduct of the hypothalamic-pituitary-adrenal (HPA) axis, provide a frontline of defence against threats to homeostasis (i.e. stress). On the other hand, chronic HPA drive and glucocorticoid hypersecretion have been implicated in the pathogenesis of several forms of systemic, neurodegenerative and affective disorders. The HPA axis is subject to gonadal influence, indicated by sex differences in basal and stress HPA function and neuropathologies associated with HPA dysfunction. Functional cross-talk between the gonadal and adrenal axes is due in large part to the interactive effects of sex steroids and glucocorticoids, explaining perhaps why several disease states linked to stress are sex-dependent. Realizing the interactive nature by which the hypothalamic-pituitary-gonadal and HPA systems operate, however, has made it difficult to model how these hormones act in the brain. Manipulation of one endocrine system is not without effects on the other. Simultaneous manipulation and assessment of both endocrine systems can overcome this problem. This dual approach in the male rat reveals that testosterone can act and interact on different aspects of basal and stress HPA function. Basal adrenocorticotropic hormone (ACTH) release is regulated by testosterone-dependent effects on arginine vasopressin synthesis, and corticosterone-dependent effects on corticotropin-releasing hormone (CRH) synthesis in the paraventricular nucleus (PVN) of the hypothalamus. In contrast, testosterone and corticosterone interact on stress-induced ACTH release and drive to the PVN motor neurones. Candidate structures mediating this interaction include several testosterone-sensitive afferents to the HPA axis, including the medial preoptic area, central and medial amygdala and bed nuclei of the stria terminalis. All of these relay homeostatic information and integrate reproductive and social behaviour. Because these modalities are affected by stress in humans, a dual systems approach holds great promise in establishing further links between the neuroendocrinology of stress and the central bases of sex-dependent disorders, including psychiatric, cardiovascular and metabolic disease.

Inescapable shock induces resistance to the effects of dexamethasone

Administration of bacterial endotoxin (lipopolysachharide; LPS) elevates proinflammatory cytokines, such as interleukin-1β (IL-1β) and IL-6, and activates the hypothalamic-pituitary-adrenal (HPA) axis. Corticosterone (CORT), the glucocorticoid (GC) effector hormone of the HPA axis in rats, inhibits both proinflammatory cytokine production/release and activity of the HPA axis itself. Exposure to chronic or repeated stressors often induces resistance to the effects of GCs. The following experiments were conducted to test the hypothesis that an acute stressor, inescapable tailshock (IS), alters responsivity of the HPA axis and proinflammatory cytokine system to dexamethasone (DEX), a synthetic GC. First, we examined the ability of various doses of DEX to suppress proinflammatory cytokine and HPA activity in response to LPS challenge 24 h after either home cage (HCC) or IS treatment. Upon finding resistance to DEX in IS animals, we examined the duration of the altered response to DEX by testing animals 1, 4 and 21 days after IS. To test whether IS animals were selectively resistant to the suppressive effects of DEX on the response to LPS, the ability of DEX to suppress HPA activity in response to a non-inflammatory stressor, exposure to an elevated “pedestal”, was assessed. Again, DEX resistance was observed in IS animals. Finally, we examined whether changes in the responsivity to DEX were dependent upon the controllability of the stressor. The induction of DEX resistance was independent of the degree of behavioral control that the animal had over the stressor. Thus, a single session of IS induces DEX resistance of both HPA axis and cytokine responses measured in vivo.

Increased hypothalamic expression of prolactin in lactation: involvement in behavioural and neuroendocrine stress responses.

Prolactin (PRL) has recently been shown to exert an anxiolytic effect in male and virgin female rats, as well as an inhibitory tone on hypothalamic-pituitary-adrenal (HPA) axis activity. Reduced emotional and neuroendocrine stress responses have been described in lactation, a time of high blood PRL levels. Here we tested brain PRL-receptor (PRL-R)-mediated effects on anxiety, maternal behaviour, HPA axis and oxytocin stress responses in lactating rats. Chronic intracerebroventricular (i.c.v.) infusion of antisense oligonucleotides against the long form of the PRL-R (AS; osmotic minipump, 0.5 microg/0.5 microL/h) in order to downregulate brain PRL-R expression increased the anxiety-related behaviour on the elevated plus maze (P < 0.01) compared with mixed bases- and vehicle-treated rats. Also, PRL-R AS treatment impaired maternal behaviour (P < 0.05), whereas physiological parameters of lactation (weight gain of the litter, number of milk ejection reflexes during a 20-min suckling period) were not affected. PRL-R AS treatment further evoked an increase (P < 0.05) in the stress-induced adrenocorticotropin release, demonstrating an inhibitory role of PRL on HPA axis responses in lactation. Inhibition of stress responses of the oxytocin system by brain PRL was evidenced by higher stress-induced (P < 0.05) plasma oxytocin concentration in PRL-R AS-treated lactating rats and, in contrast, decreased stress-induced oxytocin release (P < 0.01) in chronic i.c.v. ovine PRL-treated (1 microg/0.5 microL/h) virgin rats. Finally, an increased expression of the hypothalamic PRL gene was seen by RT-PCR in pregnancy and lactation, suggesting an activated state of the brain PRL system during the peripartum period. In summary, activation of the brain PRL system in the peripartum period significantly contributes to emotional and neuroendocrine adaptations, including downregulation of the responsiveness of the HPA axis and oxytocin systems to stressors seen at this time.

Interactions between evening and nocturnal cortisol secretion and sleep parameters in patients with severe chronic primary insomnia

Recent research provides evidence for an interaction between sleep and the activation of the hypothalamic–pituitary–adrenal (HPA)-axis, but detailed studies in patients are still missing. We investigated hourly evening and nocturnal plasma cortisol secretion and sleep in seven male patients with severe chronic primary insomnia and age- and gender-matched controls. Evening and nocturnal cortisol levels were significantly increased in patients. Evening cortisol correlated with the number of nocturnal awakenings in patients and controls. Additionally, patients showed significant correlations between sleep parameters and the first 4 h of nocturnal cortisol secretion. These results are indicative of changes in the HPA system in insomnia and may reflect a pathophysiological mechanism of chronic insomnia resulting in a vicious cycle of both disturbed HPA functions and chronic insomnia according to the arousal hypothesis of insomnia.

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.

Perinatal malnutrition programs sympathoadrenal and hypothalamic-pituitary-adrenal axis responsiveness to restraint stress in adult male rats.

In humans, an altered control of cortisol secretion was reported in adult men born with a low birth weight making the hypothalamic-pituitary-adrenal (HPA) axis a possible primary target of early life programming. In rats, we have recently shown that maternal food restriction during late pregnancy induces both an intrauterine growth retardation and an overexposure of fetuses to maternal corticosterone, which disturb the development of the HPA axis in offspring. The first aim of this work was to investigate, in adult male rats, whether perinatal malnutrition has long-lasting effects on the HPA axis activity during both basal and stressful conditions. Moreover, as the HPA axis and sympathetic nervous system are both activated by stress, the second aim of this work was to investigate, in these rats, the adrenomedullary catecholaminergic system under basal and stressful conditions. This study was conducted on 4-month-old male rats malnourished during their perinatal life and on age-matched control animals. Under basal conditions, perinatal malnutrition reduced body weight and plasma corticosteroid-binding globulin (CBG) level but increased mineralocorticoid receptor (MR) gene expression in CA1 hippocampal area. After 30 min of restraint, perinatally malnourished (PM) rats showed increased plasma noradrenaline, adrenocorticotropin hormone (ACTH) and corticosterone concentrations similarly as controls, but calculated plasma-free corticosterone concentration was significantly higher and adrenaline level lower than controls. During the phase of recovery, PM rats showed a rapid return of plasma ACTH and corticosterone concentrations to baseline levels in comparison with controls. These data suggest that in PM rats, an elevation of basal concentrations of corticosterone, in face of reduced CBG and probably increased hippocampal MR lead to a much larger impact of corticosterone on target cells that mediate the negative-feedback mechanism on the activities of both the HPA axis and sympathoadrenal one.

Development of pituitary-adrenal endocrine function in the marmoset monkey: infant hypercortisolism is the norm.

Early life stress, involving activation of the hypothalamic-pituitary-adrenal (HPA) system, is associated with altered functioning of stress-related systems in adulthood. In the rat, postnatal development is characterized by low basal HPA activity and stress hyporesponsiveness, and infant exposure to atypical glucocorticoid levels leads to chronic alteration of HPA function and HPA-dependent peripheral and central processes. There have been few studies of primate HPA ontogeny, and here we report a study of changes in pituitary-adrenal function between birth and adulthood in the common marmoset monkey. In this simian primate, basal plasma ACTH and cortisol levels were actually elevated in neonates (ACTH, 141 +/- 28 pg/ml; cortisol, 1903 +/- 326 microg/dl) and wk 4 infants (ACTH, 114 +/- 9 pg/ml; cortisol, 290 +/- 8 microg/dl) relative to month 2 infants, juveniles (month 6), subadults (month 12), and adults (>2 yr; ACTH, 37 +/- 4 to 61 +/- 8 pg/ml; cortisol, 101 +/- 2 to 195 +/- 4 microg/dl). In contrast to older life stages, neonates lacked circadian change in their plasma cortisol levels, and this state of consistently high cortisol was associated with large adrenal glands in addition to high ACTH levels. Cerebrospinal fluid cortisol levels were, in accord with plasma levels, higher in wk 4 infants than in juveniles and subadults. In terms of stress response, month 2 infants demonstrated ACTH and cortisol peak stress responses similar to those at older life stages (infant stress cortisol, 185 +/- 36% of basal; subadult stress cortisol, 174 +/- 6% of basal); whereas infant ACTH recovery was also similar to that in older subjects, their cortisol poststress recovery was retarded. This primate, it is proposed, provides an excellent complementary model in which to test hypotheses derived from the rat model relating to HPA system ontogeny and the chronic effects and biomedical implications of hypercorticoidism during early life.

Development of Pituitary-Adrenal Endocrine Function in the Marmoset Monkey: Infant Hypercortisolism Is the Norm

Early life stress, involving activation of the hypothalamic-pituitary-adrenal (HPA) system, is associated with altered functioning of stress-related systems in adulthood. In the rat, postnatal development is characterized by low basal HPA activity and stress hyporesponsiveness, and infant exposure to atypical glucocorticoid levels leads to chronic alteration of HPA function and HPA-dependent peripheral and central processes. There have been few studies of primate HPA ontogeny, and here we report a study of changes in pituitary-adrenal function between birth and adulthood in the common marmoset monkey. In this simian primate, basal plasma ACTH and cortisol levels were actually elevated in neonates (ACTH, 141 ± 28 pg/ml; cortisol, 1903 ± 326 μg/dl) and wk 4 infants (ACTH, 114 ± 9 pg/ml; cortisol, 290 ± 8 μg/dl) relative to month 2 infants, juveniles (month 6), subadults (month 12), and adults (>2 yr; ACTH, 37 ± 4 to 61 ± 8 pg/ml; cortisol, 101 ± 2 to 195 ± 4 μg/dl). In contrast to older life stages, neonates lacked circadian change in their plasma cortisol levels, and this state of consistently high cortisol was associated with large adrenal glands in addition to high ACTH levels. Cerebrospinal fluid cortisol levels were, in accord with plasma levels, higher in wk 4 infants than in juveniles and subadults. In terms of stress response, month 2 infants demonstrated ACTH and cortisol peak stress responses similar to those at older life stages (infant stress cortisol, 185 ± 36% of basal; subadult stress cortisol, 174 ± 6% of basal); whereas infant ACTH recovery was also similar to that in older subjects, their cortisol poststress recovery was retarded. This primate, it is proposed, provides an excellent complementary model in which to test hypotheses derived from the rat model relating to HPA system ontogeny and the chronic effects and biomedical implications of hypercorticoidism during early life.

Nocturnal secretion of TSH and ACTH in male patients with depression and healthy controls

Profound alterations of the hypothalamic-pituitary-thyroid (HPT) and the hypothalamic-pituitary-adrenal (HPA) systems at the hypophyseal level have been described in affective disorder. To precisely characterize the basal alterations of both axes during sleep, we simultaneously investigated sleep EEG and the secretion of thyrotropin, ACTH and cortisol in nine drug-free male patients with depression in comparison to 10 healthy age and sex matched controls. In depressed patients the nearly diametrical nocturnal secretion of thyrotropin and ACTH was disturbed by significantly blunted thyrotropin values (TSH AUC 51.96±5.68 vs. 87.23±13.63, P<0.05) and elevated ACTH values (ACTH AUC 1804±161 vs. 1538±130, P<0.05) compared to controls. Moreover, cross correlation analysis revealed a highly negative association of 0 lag between thyrotropin and ACTH and between thyrotropin and cortisol in the control sample, indicating a physiological nocturnal negative correlation of HPT and HPA system. In the patients sample these associations were weak and reached not statistical significance. Therefore, as a descriptive tool, the ratio TSH/ACTH revealed a significant group difference between controls and patients in the first half of the night (TSH/ACTH AUC 6.50±0.42 vs. 3.35±0.31, P<0.05). Sleep-EEG analysis showed a shortened REM latency, a decrease of stage 2 and an increase of awake time in the patients. Our data support the hypothesis that both hypophyseal hormones reflect a common dysregulation of both systems in depression probably due to impaired action of TRH-related corticotropin-release-inhibiting-factor (CRIF). The ratio TSH/ACTH might be a tool to characterize alterations of both the HPT and HPA axis in depression during the first half of the night.