Pituitary-adrenal Function Research Articles

Pituitary ACTH and adrenocortical secretion in critically ill dogs.

To evaluate pituitary-adrenal function in a population of critically ill dogs by measuring serial plasma concentrations of basal cortisol, ACTH-stimulated cortisol, and endogenous ACTH. Prospective study. 20 critically ill dogs admitted to an intensive care unit (ICU). Basal plasma cortisol, ACTH-stimulated cortisol, and endogenous ACTH concentrations were measured for each dog within 24 hours of admission and daily until death, euthanasia, or discharge from the ICU. Established reference ranges for healthy dogs were used for comparison. Survival prediction index (SPI) scores were calculated for each dog within 24 hours of admission. No significant difference was found between initial concentrations of basal cortisol, ACTH-stimulated cortisol, and endogenous ACTH in 13 dogs that survived and those in 7 dogs that died. High initial basal endogenous ACTH concentrations were correlated with subsequent high values. Low basal ACTH-stimulated cortisol concentrations were predictive of higher subsequent values. All basal and ACTH-stimulated cortisol concentrations were within or above the reference range in the 52 plasma samples collected from the 20 dogs during hospitalization. The SPI scores correlated with outcome (ie, alive or dead), but none of the plasma hormone concentrations correlated with SPI score or outcome. Results indicate that none of the critically ill dogs in our study population developed adrenal insufficiency during hospitalization in the ICU.

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.

Prefrontal cortical regulation of hypothalamic-pituitary-adrenal function in the rat and implications for psychopathology: side matters.

In recent years, dysfunction of hypothalamic-pituitary-adrenal (HPA) axis function has been implicated in a wide variety of psychiatric conditions. The importance of this system in responding to and coping with stress is well documented, and the integrity of such systems is of obvious significance to good mental health. The prefrontal cortex (PFC) is also heavily implicated in numerous psychopathological conditions. There is thus a growing interest in the potential role the PFC might play in regulating HPA function, and whether abnormalities of these systems are linked. The present paper reviews a number of recent animal studies which have attempted to elucidate the role of the PFC in regulation of HPA axis function, and how these systems may interact. It is concluded that the PFC is involved both in activating HPA responses to stress and in the negative feedback regulation of this system. Cerebral laterality is an important feature of this regulation, with the right PFC being most directly linked to stress-regulatory systems. On this basis, a number of parallels are drawn to the human literature, where asymmetrical disturbances in PFC activity may help explain associated patterns of HPA dysfunction.

The neonatal glucocorticoid treatment-produced long-term changes of the pituitary-adrenal function and brain corticosteroid receptors in rats.

Two distinct periods of sensitivity to elevated glucocorticoid hormone levels during postnatal development of the pituitary-adrenal axis were studied. Wistar rats were injected subcutaneously (s.c.) with cortisol (1 mg/kg) on postnatal days 1-5 or 14-18. The steroid treatment during the first postnatal week resulted in a decrease of the morning basal and stress-induced plasma corticosterone levels in 30 day-old male rats, as well as in rats that were injected with cortisol on the third postnatal week. Stress-induced corticosterone levels in 90-day old cortisol-treated rats were determined in blood samples drawn from the tail vein before the restraint stress, immediately after the 20-min long stress, then 60 and 180 min afterwards. Only the rats treated with cortisol during the third week showed a prolonged stress-induced corticosterone secretion, with the highest corticosterone level in 180 min after the restraint stress. The early neonatal cortisol treatment had no effect on (3)H-corticosterone binding in all studied brain areas of the 90-day old rats. The rats treated with cortisol at the 14-17th postnatal days showed a significantly lower (3)H-corticosterone binding in the frontal cortex, hippocampus, and hypothalamus. These findings suggest that the third week of life in rats is more sensitive to elevated levels of corticosterone than the first one. The high level of glucocorticoids at this period has long-term effects on the efficiency of the negative feedback mechanisms provided by hypothalamus-pituitary-adrenal axis.

Fetectomy alters maternal pituitary-adrenal function in pregnant rhesus macaques.

The interplay between the fetus and mother may play a key role in the regulation of primate pregnancy and parturition. This study was designed to test the hypothesis that fetectomy alters maternal pituitary-adrenal function. Between 117 and 122 days of gestation (term = 167 days), six rhesus macaques underwent surgery for catheter implantation. At surgery the fetuses were removed while the membranes and placenta were left in situ. Six additional intact catheterized pregnant animals served as controls. Animals were maintained under a 12L:12D cycle with lights-on from 0700 to 1900 h. Beginning at least 1 wk after surgery, maternal arterial blood samples were collected at 3-h intervals for 24 h for hormone and catecholamine analysis. This sampling protocol was repeated at weekly intervals until cesarean delivery at 151-157 days of gestation. Following fetectomy, plasma ACTH, dehydroepiandrosterone sulfate (DHEAS), and cortisol levels were significantly lower (36%, 35%, and 44%, respectively) compared with control animals (P;lt 0.05). Despite a significant reduction in overall levels, the rhythm in maternal plasma cortisol was maintained following fetectomy. Plasma dopamine and norepinephrine were also depressed (P;lt 0.05), whereas epinephrine remained unaffected. Our data clearly demonstrate the role of the fetus in the regulation of the maternal pituitary-adrenal axis during gestation. This interaction plays a significant role in the regulation of maternal endocrine function that may influence the initiation of labor.

Alcohol intake, androgen and glucocorticoid steroids in premenopausal women using oral contraceptives: an interventional study

Long-term heavy alcohol intake is associated with endocrinological abnormalities the mechanisms of which are still unclear. The objective of the present study was to investigate the effect of alcohol intake on plasma and urine glucocorticoid and androgen steroid levels in healthy premenopausal women using oral contraceptives. In a placebo-controlled interventional study with a cross-over design including nine premenopausal women using oral contraceptives no effect of tolerance was observed with regard to the magnitude of the acute transient alcohol-induced testosterone elevation after a 1-week alcohol drinking period (0.8 g/kg per day). At non-intoxicated time points elevated plasma testosterone and androstenedione levels were found in the afternoon but not in the morning during the alcohol drinking period compared with placebo. An increase in plasma cortisol levels was observed after the discontinuation of alcohol drinking. No effects were observed in total glucocorticoid conjugates in morning urine spot samples. An increase during the alcohol period relative to placebo was, however, observed in the urine etiocholanolone/androsterone, tetrahydrocortisol/allotetrahydrocortisol as well as the 20-hydroxy-/20-ketosteroid ratios. No consistent effect was observed in the urine (tetrahydrocortisol+allotetrahydrocortisol)/tetrahydrocortisone ratio. It is suggested that the alcohol-induced alterations in plasma glucocorticoid and androgen levels during non-intoxicated conditions are due to a change in the hypothalamic–pituitary–adrenal function. The effects observed in the conjugated urine glucocorticoid and androgen ratios are likely to be mediated by a change in the metabolism of these steroids in the liver. The present results may be of relevance in the development of disturbances in the glucocorticoid as well as sex steroid balance among heavy female drinkers.

Glucocorticoid programming of pituitary–adrenal function: mechanisms and physiological consequences

Increasing epidemiological evidence supports the notion that adverse events in fetal life permanently alter the structure and physiology of the adult offspring, a phenomenon dubbed ‘fetal programming’. In particular, low weight or thinness at birth in humans is associated with an increased risk of cardiovascular and metabolic disorders as well as neuroendocrine dysfunction in adult life. Glucocorticoid administration during pregnancy is well-documented to both reduce offspring birth weight and alter the maturation of organs (hence their use to accelerate fetal lung maturation in premature labour). Here data are reviewed which show, in rodents and other models, that antenatal exposure to endogenous or exogenous glucocorticoids reduces offspring birth weight and produces permanent hypertension, hyperglycaemia, hyperinsulinaemia, altered behaviour and neuroendocrine responses throughout the lifespan. Processes underlying fetal programming include determination of the ‘set point’ of the hypothalamic-pituitary-adrenal (HPA) axis and of tissue glucocorticoid receptor (GR) expression. Similar HPA axis hyperreactivity occurs in lower birth weight humans and may be an early manifestation of the ‘low birth weight’ phenotype.

A Short Period of Maternal Nutrient Restriction in Late Gestation Modifies Pituitary-Adrenal Function in Adult Guinea Pig Offspring

Altered fetal environment can program the hypophyseal-pituitary-adrenal (HPA) axis development and thus affect endocrine function in later life. We hypothesized that 48 h of maternal nutrient restriction during the period of maximal fetal brain growth alters HPA function in adult offspring and leads to modified blood pressure regulation. Pregnant guinea pigs (n = 15) were deprived of food (water ad libitum) or fed normally (n = 13) on days 50 and 51 of gestation, after which they were all fed normally (birth = 68 days). Carotid artery and jugular vein catheters were implanted in adult guinea pig offspring (day 65). Animals were treated with corticotropin (ACTH_1–24; 0.5 µg/kg), corticotropin-releasing hormone (CRH; 0.5 µg/kg) and insulin (5 units/kg), and pituitary-adrenal responses were measured. Guinea pigs were then euthanized and pituitaries removed for analysis of pro-opiomelanocortin (POMC) and glucocorticoid receptor (GR) mRNA levels. There was no effect of prenatal treatment on body weight, blood pressure or heart rate. In male offspring, both basal ACTH (p < 0.007) and basal cortisol (p < 0.05) levels were significantly reduced in animals whose mothers had been nutrient restricted (NR). In contrast, in female offspring, basal plasma ACTH was not different between offspring from NR mothers and controls; however, basal plasma cortisol concentrations were significantly (p < 0.01) elevated at 13.00 h in females born to NR mothers. Responses to HPA challenge were different between offspring from NR mothers and control offspring, and these differences were consistent with alterations in basal adrenocortical function. There was no effect of prenatal treatment on POMC mRNA levels in the pars distalis or pars intermedia. However, GR mRNA levels were significantly (p < 0.05) reduced in adult female offspring born to NR mothers. In conclusion, 48 h of maternal nutrient restriction during pregnancy has a long-term effect on HPA function in adult offspring, and this effect is highly sex specific, but does not result in alteration of blood pressure.

Altered fetal pituitary-adrenal function in the ovine fetus treated with RU486 and meloxicam, an inhibitor of prostaglandin synthase-II.

Term and preterm labor are associated with increased fetal hypothalamic-pituitary-adrenal (HPA) activation and synthesis of prostaglandins (PGs) generated through the increased expression of prostaglandin H synthase-II (PGHS-II) in the placenta. Inhibition of PGHS-II has been advocated as a means of producing uterine tocolysis, but the effects of such treatment on fetal endocrine functions have not been thoroughly examined. Because PGE(2) is known to activate the fetal HPA axis, we hypothesized that administration of meloxicam, a PGHS-II inhibitor, to sheep in induced labor would suppress fetal HPA function. Chronically catheterized pregnant ewes were treated with RU486, a progesterone receptor antagonist, to produce active labor, and then treated with either high-maintenance-dose meloxicam, graded-maintenance-dose meloxicam, or a saline infusion. Maternal uterine contraction frequency increased 24 h after the RU486 injection and the animals were in active labor by 48 +/- 4 h. RU486 injection led to increased concentrations of PGE(2), ACTH, and cortisol in the fetal circulation, and increased concentrations of 13,14 dihydro 15-ketoprostaglandin F(2 alpha) (PGFM) in the maternal circulation. Uterine activity was inhibited within 12 h of beginning meloxicam infusion at both infusion regimes. During meloxicam infusion there were significant decreases in fetal plasma PGE(2), ACTH, and cortisol concentrations, and PGFM concentrations in maternal plasma. In control animals, frequency of uterine contractions, maternal plasma PGFM, fetal plasma PGE(2), ACTH, and cortisol concentrations increased after RU486 administration, and continued to rise during saline infusion until delivery occurred. We conclude that RU486-provoked labor in sheep is associated with activation of fetal HPA function, and that this is attenuated during meloxicam treatment to a level considered compatible with pregnancy maintenance.

Adrenocorticotropin (ACTH) and corticosterone secretion by perifused pituitary and adrenal glands from rodents exposed to 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD)

Although in utero maternal stress has been shown to have lasting effects on rodent offspring, fetal effects of chemically-induced alterations of the maternal hypothalamic-pituitary-adrenal axis (HPA) have not been well studied. This study examined the effects of in vivo 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) exposure on pituitary-adrenal function in the male rat, pregnant female rat and pregnant female mouse. The secretion of adrenocorticotropin (ACTH) and corticosterone (CORT) in pituitary and adrenal glands, respectively, was assessed in ex vivo perifusion cultures. Male and pregnant female (gestation day 8) Sprague–Dawley rats were gavaged once with 10 μg/kg TCDD, pregnant female mice once with 24 μg/kg TCDD, and euthanized 10 days later. Hemi-pituitary (rat) or whole anterior pituitaries (mice) and right adrenal glands from the same animal were quartered, perifused under baseline and stimulated conditions. In both males and pregnant females, TCDD did not affect corticotropin releasing hormone (CRH)-stimulated ACTH secretion. Neither total pituitary ACTH nor plasma ACTH was altered in either sex or species by TCDD treatment. ACTH-stimulated CORT secretion was not affected by TCDD in either sex or species, and adrenal tissue and plasma CORT levels were unchanged in males and pregnant females by TCDD. However, the plasma ACTH:CORT ratio was decreased about 46% in male rats treated with TCDD. Plasma CORT levels were 23-fold higher and plasma ACTH levels were 1.5-fold higher in pregnant females than in male rats. In male versus female rats, adrenal CORT and anterior pituitary ACTH tissue levels were about 7.5- and 1.75-fold higher and ACTH, respectively. Female mouse adrenal tissue CORT was about 4-fold greater than female rat. The reduced plasma ACTH:CORT ratio in the male rat suggests that TCDD disturbs HPA function. Exposure of male rat to a 5-fold higher dose in earlier studies clearly demonstrated effects of TCDD on male rat HPA. The present study identified substantial HPA performance differences between male and pregnant female rats. The failure to detect a response to TCDD in pregnant female rat and mouse could be a function of both TCDD dose and the high level of secretion of both ACTH and CORT in pregnant animals. For the rat or mouse, a single exposure to TCDD during pregnancy does not appear sufficient to induce maternally-mediated developmental, reproductive and behavioral toxicity via the HPA axis.

Evidence for a positive correlation between serum cortisol levels and IL-1beta production by peripheral mononuclear cells in anorexia nervosa.

A hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis has been reported in anorexia nervosa (AN), together with some immunological abnormalities, involving citokine - and particularly Tumor Necrosis-Factor-alpha (TNF-alpha) - production by polymorphonuclear cells. The ability of pro-inflammatory cytokines to activate the HPA axis is well known; however, there are no data demonstrating an interdependence between immunological and endocrine response in AN. To investigate the presence of a correlation between immune response and pituitary-adrenal function, plasma ACTH and serum cortisol concentrations were measured in 13 AN patients and in the same number of controls. TNF-alpha and interleukin (IL)-1beta production by ex-vivo unstimulated and LPS-stimulated peripheral mononuclear cells was also assessed. Circulating cortisol concentrations were higher (p<0.01) in AN (156.7 +/- 45.1 microg/l, mean +/- SD) than in controls (105.9 +/- 25.7 microg/l). Unstimulated IL-1beta release in supernatants of mononuclear cell cultures was slightly but not significantly higher in AN than in controls, while TNF-alpha release was similar in the two groups. A positive correlation was found between IL-1beta concentrations in unstimulated culture supranatants and serum cortisol levels in AN (r=0.782, p=0.002), while in normal subjects there was a trend toward a negative correlation; a slight positive correlation, while not significant, between IL-1beta and plasma ACTH, as well as between TNF-alpha and serum cortisol was also found in AN. These data suggest that the normal relationship between pro-inflammatory cytokines release, particularly IL-1beta, and cortisol secretion is deranged in AN.

Pituitary–adrenal function in adolescent psychiatric patients: impact of depressive symptoms

Background: The aim of this study was to determine whether depressive symptoms affect pituitary–adrenal function in adolescents, as they do in adults. Methods: Salivary cortisol was measured before and after physical exercise in 23 hospitalized adolescent psychiatric patients and 13 age- and sex-matched healthy controls in a placebo-controlled design. In patients, cortisol profiles were assessed from 08:00 to 20:00 h before and after administration of low doses of dexamethasone or the natural steroid hydrocortisone. Patients were classified according to DSM III-R criteria and assigned to either a depressed group ( n=10) or a non-depressed group ( n=13). Subjective depressive symptoms were rated with the 90-item symptom checklist. Results: Physical exercise increased cortisol output significantly in all subjects, but there were no differences between groups. In patients, no differences in basal cortisol levels were found between the depressed and non-depressed groups. Dexamethasone, but not hydrocortisone, was able to suppress cortisol levels in both groups. Differences between groups were only found in total cortisol output over the 3 days when data were analyzed according to the patients ‘subjective’ feelings of depression, with the highest cortisol levels in the ‘subjectively more depressed’ patients. Conclusions: The results obtained only partially support the hypothesis that depressive symptoms in adolescent psychiatric patients determine pituitary–adrenal (mal)function, and appear to depend on the strategy used.

Opposing effects of androgen and estrogen on pituitary-adrenal function in nonpregnant primates.

Maternal administration of androstenedione produces a sustained fall in maternal plasma adrenocorticotropic hormone (ACTH) concentrations in the pregnant nonhuman primate. We hypothesize a negative feedback influence on the maternal hypothalamo-pituitary-adrenal (HPA) axis by androgens in primates. This may reflect an important maternal adaptation during pregnancy in primates preventing premature induction of labor by maternal stress. However, androstenedione is precursor for placental estradiol-17beta synthesis, and infusion of androstenedione into pregnant primates elevates maternal plasma estradiol-17beta to term concentrations. Thus, it could be argued that 1) the effects attributed to androstenedione on the maternal HPA axis are mediated by estrogen rather than by androgen and 2) the negative influence of androgens may be on placental ACTH rather than, or in addition to, pituitary ACTH. To discriminate between androgenic and estrogenic effects of androstenedione on pituitary and/or placental ACTH function in primates we measured plasma ACTH, cortisol, and dehydroepiandrosterone sulfate (DHEAS) concentrations in nonpregnant baboons after treatment with either androstenedione or estradiol-17beta. Nine female baboons were studied between 14 and 22 days postpartum prior to estrous cycling. After 2 days of baseline, a continuous i.v. infusion of androstenedione (1.5 mg/kg per h in 10% intralipid, IL) was started at 0900 h and maintained for 9 days in 3 baboons. A similar protocol was carried out in another 3 baboons that received a continuous i.v. infusion of estradiol-17beta (10 microg/kg per h in 10% IL) instead of androstenedione. Three additional baboons received continuous i.v. IL vehicle alone and served as controls. Arterial blood samples (0.5 ml) for measurement of plasma hormones were taken during baseline and after 1, 3, 5, 7, and 9 days of infusion. Baseline plasma ACTH, DHEAS, and cortisol concentrations were similar among all groups. Plasma ACTH did not change during IL, increased following estradiol-17beta, and fell during androstenedione treatment. Accordingly, plasma cortisol and DHEAS concentrations were also unaltered by IL, and both steroids increased during estradiol-17beta treatment. In contrast, plasma cortisol and DHEAS remained unaltered from baseline during androstenedione treatment, despite the fall in plasma ACTH measured at this time. These data in the nonpregnant baboon 1) are consistent with negative feedback on pituitary ACTH by androgens and 2) demonstrate a positive influence on pituitary-adrenal function by estrogen in primates.

Low Doses of Dexamethasone Suppress Pituitary-Adrenal Function but Augment the Glycemic Response to Acute Hypoxemia in Fetal Sheep during Late Gestation

Despite the widespread use of antenatal glucocorticoid therapy in obstetric practice, little is known about the effects of synthetic glucocorticoids on the fetal capacity to respond to episodes of acute hypoxemia, such as may occur during labor and delivery. This study investigated the effects of prolonged fetal exposure to low concentrations of dexamethasone on the fetal ACTH, cortisol, and glycemic responses to an episode of acute hypoxemia during the period of dexamethasone treatment in sheep. At 118 d of gestation (term is approximately 145 d), 11 fetal sheep had catheters implanted under halothane anesthesia. From 124 d, five fetuses were infused i.v. continuously with dexamethasone (1.80 +/- 0.15 microg x kg(-1) x h(-1) in 0.9% saline at 0.5 mL/h) for 48 h, and the other six fetuses received saline solution i.v. at the same rate. At 45 h of infusion, acute hypoxemia was induced in all fetuses for 1 h by reducing the maternal inspired fraction of oxygen. During glucocorticoid treatment, fetal plasma dexamethasone concentrations increased to 3.9 +/- 0.2 nM by 24 h and remained elevated for the rest of the infusion period. During hypoxemia, a similar fall in fetal arterial PO2 occurred in both saline-infused and dexamethasone-treated fetuses. In control fetuses, significant increases in plasma ACTH and cortisol concentrations and in blood glucose concentrations occurred during hypoxemia. Dexamethasone treatment prevented the increases in fetal plasma ACTH and cortisol, and augmented the blood glucose response, induced by hypoxemia. These data indicate that prolonged fetal exposure to low concentrations of dexamethasone suppresses pituitary-adrenal function, but augments the glycemic response, to acute hypoxemia in fetal sheep during late gestation.

Early-life exposure to endotoxin alters hypothalamic-pituitary-adrenal function and predisposition to inflammation.

We have investigated whether exposure to Gram-negative bacterial endotoxin in early neonatal life can alter neuroendocrine and immune regulation in adult animals. Exposure of neonatal rats to a low dose of endotoxin resulted in long-term changes in hypothalamic-pituitary-adrenal (HPA) axis activity, with elevated mean plasma corticosterone concentrations that resulted from increased corticosterone pulse frequency and pulse amplitude. In addition to this marked effect on the development of the HPA axis, neonatal endotoxin exposure had long-lasting effects on immune regulation, including increased sensitivity of lymphocytes to stress-induced suppression of proliferation and a remarkable protection from adjuvant-induced arthritis. These findings demonstrate a potent and long-term effect of neonatal exposure to inflammatory stimuli that can program major changes in the development of both neuroendocrine and immunological regulatory mechanisms.

Alterations in Hypothalamic–Pituitary–Adrenal Function Correlated with the Onset of Murine SLE in MRL +/+ and lpr/lpr Mice

Systemic lupus erythematosus (SLE) is a spontaneously occurring, chronic autoimmune disease that can manifest neuropsychiatric abnormalities. The pathways mediating these central changes are not known; however, neuroendocrine alterations associated with inflammation may play a role. Predisposition to and progression of autoimmune disease has been associated with altered hypothalamic–pituitary–adrenal (HPA) function and inflammation has been reported to alter hypothalamic regulation of HPA responses. We investigated whether disease progression in a murine model of systemic lupus erythematosus (MRL +/+. MRL lpr/lpr) resulted in altered expression of HPA regulatory peptides at the level of the hypothalamus and how these alterations related to circulating levels of corticosterone, corticosterone binding globulin, and autoantibody titers. We report that as MRL +/+ and MRL lpr/lpr mice age and circulating levels of autoantibodies increase, there is a decrease in hypothalamic CRH mRNA expression and finally an increase in AVP mRNA expression. We also report that associated with increased autoantibody levels, disease progression, and altered hypothalamic peptide expression there is an increase in circulating levels of corticosterone and a trend for levels of corticosterone binding globulin to decrease. Our data complement previous observations of altered peptidergic regulation of the HPA axis and increased HPA activity during chronic inflammation in exogenously induced rodent models of chronic inflammation and indicate that similar processes may occur in spontaneous murine models of SLE.

Autoradiographic and in situ hybridization localization of corticotropin‐releasing factor 1 and 2 receptors in nonhuman primate brain

Two different corticotropin-releasing factor (CRF) receptors, CRF1 and CRF2, have been identified in rat and human brain. Although the two receptor subtypes show a markedly different distribution in the rat brain, their distribution in the primate brain has not been described previously. In this study, the neuroanatomic distribution of CRF1 and CRF2 receptor binding sites in rhesus monkey (Macaca mulatta) was assessed by using iodine 125 ([125I)-Tyr0]-sauvagine with or without the selective CRF1 receptor antagonist CP-154,526–1. Radiolabeled human cRNA probes were used to map the distribution of the two receptor mRNAs with in situ hybridization. Both CRF1 and CRF2 receptors were found in the pituitary and throughout the neocortex (especially, in prefrontal, cingulate, striate, and insular cortices), amygdala, and hippocampal formation of the monkey brain. This is in contrast to the distribution of these receptors reported in the rat brain, in which generally only the CRF1 receptor is found in the pituitary and neocortex. These results suggest that, in primates, both CRF1 and CRF2 receptors may be involved in mediating the effects of CRF on cognition, behavior, and pituitary-adrenal function. The presence of CRF1 (but not CRF2) receptors within the locus coeruleus, cerebellar cortex, nucleus of the solitary tract, thalamus, and striatum and of CRF2 (but not CRF1) receptors in the choroid plexus, certain hypothalamic nuclei, the nucleus prepositus, and the nucleus of the stria terminalis suggests that each receptor subtype also may have distinct functional roles within the primate central nervous system. J. Comp. Neurol. 408:365–377, 1999. © 1999 Wiley-Liss, Inc.

Behavior and pituitary-adrenal function in large white and Meishan pigs

Six-wk-old piglets of both sexes from European Large White (LW, n = 36) and Chinese Meishan (MS, n = 24) breeds were individually exposed to a novel environment, a stressful stimulation. Behavioral and pituitary-adrenal reactivity were investigated. When compared with LW, MS pigs displayed low locomotion (18.5 ± 2.2 vs. 41.0 ± 3.8 squares crossed/10 min; P < 0.0001), and defecation scores (0.58 ± 0.15 vs. 4.86 ± 0.37 fecal boli; P < 0.0001). Basal concentrations of cortisol were higher in MS (96.1 ± 1.1 vs. 44.9 ± 1.1 ng/ml; P < 0.0001), although no differences between breeds were found in basal concentrations of adrenocorticotropic hormone (ACTH). In response to novel environment exposure, the ACTH increase was greater in LW than in MS, but the cortisol response was not different on a log scale. To further investigate the pituitary-adrenal differences between the two breeds, the 24-hr profile of ACTH and cortisol plasma concentrations, a corticotropin-releasing factor (CRF) and a coupled dexamethasone-ACTH test were studied. Five castrated male 9-wk-old piglets from each breed were fitted surgically with a jugular vein catheter. A classic marked circadian rhythm of cortisol and a weak nycthemeral variation of ACTH were found. Cortisol concentrations were approximately twice higher in MS exclusively during the early light phase (from 0800–1200 hr) of the cycle, but no significant interbreed difference was found in the circadian rhythm of ACTH. Administration of CRF (1 μg/kg iv) induced the same significant increase in plasma ACTH and cortisol concentrations in both breeds. Administration of ACTH (10 μg/kg iv) increased significantly cortisol concentrations and revealed no difference in plasma cortisol response to ACTH. These data suggest that the hypercortisolism of MS pigs is of adrenal origin, and related to extrapituitary factors that control the adrenal sensitivity during the light phase of the diurnal cycle.

Effect of multiple courses of antenatal corticosteroids on pituitary-adrenal function in preterm infants

AIMTo evaluate the pituitary–adrenal function of preterm infants whose mothers received multiple courses (8 or more doses) of antenatal dexamethasone.METHODSThe pituitary–adrenal function of 14 preterm infants whose mothers received eight...