Effect of social isolation on 24-h pattern of stress hormones and leptin in rats

This work analyzes the effect of social isolation of growing male rats on 24-h changes of plasma prolactin, growth hormone, ACTH and leptin, and on plasma and adrenal corticosterone concentrations. At 35 days of life, rats were either individually caged or kept in groups (6-8 animals per cage) under a 12:12 h light/dark schedule (lights on at 08:00 h). A significant arrest of body weight gain regardless of unchanged daily food intake was found in isolated rats after 2 weeks of isolation. On the 4th week, rats were killed at 6 time intervals during a 24-h cycle, beginning at 09:00 h. In isolated rats the 24-h pattern of all parameters tested became distorted, as assessed by Cosinor analysis. When analyzed as a main factor in a factorial analysis of variance, isolation decreased plasma prolactin and growth hormone, increased plasma leptin and corticosterone while decreased adrenal corticosterone. Plasma corticosterone levels correlated significantly with plasma ACTH and with adrenal corticosterone levels in group-caged rats only. These changes can be attributed to an effect of mild stress on the endogenous clock that modulates the circadian hormone release.     

Effect of aging on 24-hour pattern of stress hormones and leptin in rats

This work analyzes the 24-hour changes of hypothalamic-pituitary-adrenal (HPA) axis activity and leptin release in aged rats. Three- and 22-month-old male Wistar rats were killed at 6 time intervals during a 24-hour cycle (n=8-10 rats/group). Aging augmented plasma ACTH while it decreased plasma and adrenal gland corticosterone levels. Plasma and adrenal corticosterone levels attained high levels during all the scotophase, concomitantly with the maxima in ACTH levels, whereas in aged rats only a brief plasma corticosterone peak at the early scotophase and no time of day variations of adrenal corticosterone were observed. Aging augmented circulating leptin, with a significant interaction "agextime" in the factorial ANOVA, i.e. only in young rats time of day changes were significant, with the lowest values of leptin at the middle of the light period and higher values at night. When plasma leptin was expressed on body weight basis, the age-related differences became not significant but the daily pattern of plasma leptin found in young rats persisted. Plasma and adrenal corticosterone levels correlated significantly with plasma ACTH only in young rats. Likewise, plasma leptin correlated with plasma corticosterone only in young rats. These changes can be attributed to a disrupting effect of aging on the homeostatic mechanisms modulating HPA activity and leptin release.     

Seasonal, circadian and episodic variations of human immunoreactive beta-MSH, ACTH and cortisol

The 24-hour profile of plasma levels of immunoreactive beta-MSH (IR-beta MSH), ACTH and cortisol was obtained at 15-min intervals in six normal males in summer and winter. In the radioimmunoassay used, dilution curves of human beta-MSH and human beta-LPH were not parallel. A seasonal variation in basal pituitary-adrenal secretion, with higher levels in winter than in summer, was demonstrated. A circadian rhythm was found to be significant for ACTH, IR-beta MSH and cortisol in all investigations. Whereas ACTH and cortisol patterns were largely concordant in all studies, there was a significant desynchronization of the circadian rhythm of IR-beta MSH as compared to ACTH in five cases. Eighty-three percent of the secretory spikes of cortisol but only 68% of the IR-beta MSH spikes were concomitant with an ACTH spike. Correlations between maximal levels of concomitant spikes were higher during the quiescent period of pituitary-adrenal secretion (22.00--04.00) for ACTH-cortisol whereas for ACTH-IR-beta MSH, highest correlations were found during the active early morning secretory phase (04.00--10.00). For the three plasma constituents studied, longer apparent half-lives were found to occur when the basal level before spiking was already elevated, suggesting that ACTH, beta-LPH and cortisol are secreted in bursts superimposed on a continuous basal secretion. Absolute increments of concentration appeared to be relatively independent of the level before spiking. It is suggested that the dissociations between ACTH and IR-beta MSH fluctuations in plasma observed here result from in vitro proteolysis of beta-LPH.     

24-hour changes in ACTH, corticosterone, growth hormone, and leptin levels in young male rats subjected to calorie restriction

Calorie restriction of young male rats increases plasma prolactin, decreases luteinizing hormone (LH) and testosterone, and disrupts their 24 h secretory pattern. To study whether this could be the consequence of stress, we examined the 24 h variations of plasma adrenocorticotropic hormone (ACTH) corticosterone, growth hormone (GH), leptin, and adrenal corticosterone. Rats were submitted to a calorie restriction equivalent to a 66% of usual intake for 4 weeks, starting on day 35 of life. Controls were kept in individual cages and allowed to eat a normal calorie regimen. Significantly lower ACTH levels were detected in calorie-restricted rats. Plasma corticosterone levels during the light phase of the daily cycle were significantly higher in calorie-restricted rats. Time-of-day variation in plasma ACTH and corticosterone levels attained significance in calorie-restricted rats only, with a maximum toward the end of the resting phase. The daily pattern of adrenal gland corticosterone mirrored that of circulating corticosterone; however, calorie restriction reduced its levels. Plasma ACTH and corticosterone correlated significantly in controls only. Calorie restriction decreased plasma GH and leptin, and it distorted 24 h rhythmicity. In a second study, plasma ACTH and corticosterone levels were measured in group-caged rats, isolated control rats, and calorie-restricted rats during the light phase of the daily cycle. Plasma ACTH of calorie-restricted rats was lower, and plasma corticosterone was higher, compared with isolated or group-caged controls. The changes in the secretory pattern of hormones hereby reported may be part of the neuroendocrine and metabolic mechanisms evolved to maximize survival during periods of food shortage.     

Circadian Variation of Fibrinolytic Activity in Blood

Approximately 35 years ago, it was discovered that spontaneous fibrinolytic activity in blood showed a sinusoidal variation with a period of 24 h; it increased severalfold during the day, reaching a peak at 6:OO p.m. and then dropped to trough levels at 3:00–4:00 a.m. The range of the fluctuation and the 24-h mean levels were highly reproducible within an individual; moreover, the timing of the oscillation was remarkably consistent among individuals, with a fixed phase relationship to external clock time. The biorhythm could not be accounted for simply by variations in physical activity, body posture, or sleepfwake schedule. Gender, ethnic origin, meals, or resting levels of blood fibrinolytic activity also did not influence the basic features of the rhythm. Older subjects, compared to younger ones, showed a blunted diurnal increase in fibrinolytic activity in blood. Recent studies have established that, of the known components of the fibrinolytic system, only tissue-type plasminogen activator (tPA) and its fast-acting inhibitor, plasminogen activator inhibitor- 1 (PAL l), show a marked circadian variation in plasma. In contrast, levels of plasminogen, α₂-antiplasmin, urinarytype plasminogen activator, and a reversible tPA inhibitor vary little or none during the 24 h. Quenching antibodies to tPA have shown that the circadian rhythm of fibrinolytic activity in blood is due exclusively to changes in tPA activity. However, the 24-h fluctuation of plasma tPA activity is phase shifted in relation to the rhythm of immunoreactive tPA, but shows a precise phase inversion with respect to the 24-h variation of PAL 1 activity and antigen. Therefore, plasma tPA activity, as currently measured in vitro, is tightly and inversely related to the levels of PAL 1 throughout the 24-h cycle. The factors controlling the rhythmicity of plasma PAI-1 are not fully elucidated but probably involve a humoral mechanism; changes in endothelial function, circulating platelet release. products, corticosteroids, catecholamines, insulin, activated protein C, or hepatic clearance do not appear to be responsible. Shift workers on weekly shift rotations show a disrupted 24-h rhythm of plasma tPA and PAL 1. In acute and chronic diseases, the circadian rhythmicity of fibrinolytic activity may show a variety of alterations, affecting the 24-h mean, the amplitude, or the timing of the fluctuation. It is advisable, therefore, to define the 24-h pattern of plasma tPA and PAI- 1 in patient groups, before levels based on a single blood sampling time are compared to those of a control population. In normal conditions, the 24-h variation of plasma tPA and PAI- 1 is not associated with parallel circadian changes in effective fibrinolysis, assessed as plasma D-dimer concentrations, presumably because fibrin generation in the circulation is low. In diseases in which fibrin formation is increased, however, the physiological drop of fibrinolytic activity in the morning hours may favour thrombus development at this time of day, in agreement with the reported higher morning frequency of acute thrombotic events.     

Diurnal changes in intestinal apolipoprotein A-IV and its relation to food intake and corticosterone in rats

To further investigate the role of intestinal aplipoprotein A-IV (apo A-IV) in the management of daily food intake, we examined the diurnal patterns in apo A-IV gene and protein expression in freely feeding (FF) and food-restricted (FR; food provided 4 h daily for 4 wk) rats that were killed at 3-h intervals throughout the 24-h diurnal cycle. In FF rats, the intestinal apo A-IV mRNA and protein levels showed a circadian rhythm concomitant with the feeding pattern. The daily pattern of fluctuation of apo A-IV, however, was altered in FR rats, which had a marked increase in intestinal apo A-IV levels during the 4-h feeding period of light phase. In both FF and FR rats, increased plasma corticosterone (Cort) levels temporally coincided with the increasing phase of intestinal apo A-IV mRNA and protein expression. Depletion of Cort by adrenalectomy abolished the diurnal rhythm by decreasing the apo A-IV expression during the dark period but did not change the feeding rhythm. Exposure of adrenalectomized rats to consistent Cort level (50-mg continuous release Cort pellet) resulted in fixed apo A-IV levels throughout the day. These results indicate that intestinal apo A-IV exhibits a diurnal rhythm, which can be regulated by endogenous Cort independently of the light-dark cue. The fact that intestinal apo A-IV levels were consistent with the food intake during the normal diurnal cycle as well as during the cycle of 4-h feeding each day suggests that intestinal apo A-IV is involved in the regulation of daily food intake.     

Circadian variations in concentrations of plasma thyroxine and triiodothyronine in man.

The plasma concentrations of thyroxine (T4), triiodothyronine (T3), and total protein (Pr) were measured at 2-h intervals in 8 male subjects during two 24-h periods. Plasma T4 and T3 levels varied significantly during the day. T4 values were highest at 0900 hours and thereafter declined rapidly reaching lowest levels at 1500-1700 hours (mean decrement, 13.2% of 0.00-hour value). Plasma T3 was highest at 0900 hours and lowest at 1700-1900 hours (mean decrement, 16.7% of 0900-hour value). Fluctuations observed in Pr were not significant. Variations in plasma T4 and T3 appeared concordant with respect to time, since no significant variation was detected in T3:T4 plasma concentration ratios. In view of previous studies that have demonstrated circadian variations in the binding of thyroid hormones by plasma proteins, it is suggested that the observed temporal variations in plasma concentrations of T3 and T4 reflect parallel changes in the capacity or affinity of specific plasma binding proteins of these iodothyronines.     

Stress-induced suppression of testosterone secretion in male alligators

In order to test the effect of acute stress on gonadal hormone secretion in reptiles, six mature male alligators were captured, and a blood sample was taken within 5 min of capture. Additional blood samples were taken at timed intervals for up to 41 hr, and plasma testosterone and corticosterone were measured by radioimmunoassay. Plasma testosterone declined to 50% of the initial value by 4 hr and dropped to less than 10% of initial by 24 hr. Plasma corticosterone increased during the first 12 hr, declined at 24 hr, and rose again at 40 hr. Blood samples from male alligators collected in North and South Carolina, south Florida, and in south Louisiana in two consecutive breeding seasons were also assayed for testosterone and corticosterone. In these populations there were significant differences in mean plasma testosterone and corticosterone levels. Elevated corticosterone levels were consistently seen in alligators caught in traps and from which a blood sample was taken several hours later. Plasma testosterone, although consistently lower in trapped alligators, did not show a negative correlation with plasma corticosterone. Farm-reared alligators bled once, released, and bled again at 24 hr also showed a highly significant suppression of testosterone secretion. These results demonstrate that stress has a rapid and dramatic effect on testicular steroid secretion in both farm-reared and wild alligators.     

Adrenalectomy affects pain behavior of rats after formalin injection

Stressful stimuli can activate the hypothalamo-pituitary-adrenal-axis and the endogenous opioid system. In addition, corticosterone and opioid release might cause analgesia. This rat study used adrenalectomy for corticosterone withdrawal and naloxone administration for opioid antagonism in order to study pain behavior and hypophyseal hormone release in the plasma after a formalin test. Twelve days before the formalin testing, male Sprague Dawley rats underwent adrenalectomy or sham-adrenalectomy, and non-operated rats were used as reference. The number of flinches and the duration of licking or biting behavior were measured during the early and late phase. In reference and sham-operated rats, injection of formalin 5% resulted in a marked pain behavior in the early and late phase with significant increases in ACTH and corticosterone plasma levels. In adrenalectomized rats, pain behavior was decreased during both phases. Naloxone, administered before the late phase, did not alter pain behavior in sham or reference rats, whereas in adrenalectomized rats pain reactivity returned to those levels observed in reference rats. Beta-endorphin plasma levels above the detection limit were more frequently found in adrenalectomized rats. Thyrotropin and prolactin levels were not different between studied groups. We speculate that the observed reduced pain behavior in adrenalectomized rats after formalin, is the result of an increased production of pro-opiomelanocortin, the pro-drug of both adrenocorticotrophic hormone and beta-endorphin.     

Melatonin supplementation decreases prolactin synthesis and release in rat adenohypophysis: correlation with anterior pituitary redox state and circadian clock mechanisms

In the laboratory rat, a number of physiological parameters display seasonal changes even under constant conditions of temperature, lighting, and food availability. Since there is evidence that prolactin (PRL) is, among the endocrine signals, a major mediator of seasonal adaptations, the authors aimed to examine whether melatonin administration in drinking water resembling in length the exposure to a winter photoperiod could affect accordingly the 24-h pattern of PRL synthesis and release and some of their anterior pituitary redox state and circadian clock modulatory mechanisms. Melatonin (3?μg/mL drinking water) or vehicle was given for 1 mo, and rats were euthanized at six time intervals during a 24-h cycle. High concentrations of melatonin (>2000 pg/mL) were detected in melatonin-treated rats from beginning of scotophase (at 21:00?h) to early photophase (at 09:00?h) as compared with a considerably narrower high-melatonin phase observed in controls. By cosinor analysis, melatonin-treated rats had significantly decreased MESOR (24-h time-series average) values of anterior pituitary PRL gene expression and circulating PRL, with acrophases (peak time) located in the middle of the scotophase, as in the control group. Melatonin treatment disrupted the 24-h pattern of anterior pituitary gene expression of nitric oxide synthase (NOS)-1 and -2, heme oxygenase-1 and -2, glutathione peroxidase, glutathione reductase, Cu/Zn- and Mn-superoxide dismutase, and catalase by shifting their acrophases to early/middle scotophase or amplifying the maxima. Only the inhibitory effect of melatonin on pituitary NOS-2 gene expression correlated temporally with inhibition of PRL production. Gene expression of metallothionein-1 and -3 showed maxima at early/middle photophase after melatonin treatment. The 24-h pattern of anterior pituitary lipid peroxidation did not vary after treatment. In vehicle-treated rats, Clock and Bmal1 expression peaked in the anterior pituitary at middle scotophase, whereas that of Per1 and Per2 and of Cry1 and Cry2 peaked at the middle and late photophase, respectively. Treatment with melatonin raised mean expression of anterior pituitary Per2, Cry1, and Cry2. In the case of Per1, decreased MESOR was observed, although the single significant difference found between the experimental groups when analyzed at individual time intervals was increase at early scotophase in the anterior pituitary of melatonin-treated rats. Melatonin significantly phase-delayed expression of Per1, Per2, and Cry1, also phase-delayed the plasma corticosterone circadian rhythm, and increased the amplitude of plasma corticosterone and thyrotropin rhythms. The results indicate that under prolonged duration of a daily melatonin signal, rat anterior pituitary PRL synthesis and release are depressed, together with significant changes in the redox and circadian mechanisms controlling them. (Author correspondence: danielcardinali@uca.edu.ar ; danielcardinali@fibertel.com.ar ).     

Maternal influences on the ontogeny of basal levels of plasms corticosterone in the rat.

To study the effect of maternal factors on circadian periodicity in plasma corticosterone in weanling rats, base levels of this steroid were assessed at 4-hr intervals over a 24-hr period in both blind and normal offspring of blind or normal dams. Blind litters reared by blind mothers do not show a daily periodicity in plasma corticosterone levels. However, blind litters reared by normal mothers do display significant daily fluctuations in the plasma levels of corticoids. All normal weanlings exhibit a significant daily periodicity in plasma corticosterone. Peak levels of corticosterone in normal weanlings, which were separated from their dams at Day 21 or reared by blind dams, were present at the onset of the dark period (2130). However, in normal weanlings which were not separated from their mothers, maximal corticosterone occurred several hours after lights off. These results demonstrate that the pattern of daily periodicity in plasma corticosterone levels in the weanling rat can be influenced both by maternal factors and by the light cycle.     

Influence of MSH and corticosterone on stimulus control over an operant response

Several previous papers have indicated that MSH/ACTH-like neuropeptides facilitate the reversal of brightness discrimination in a runway task. The present experiment was undertaken to explore the development during both acquisition and reversal of stimulus control over an operant response. Male albino adult rats were treated daily with either 10 micrograms of MSH, 500 micrograms of corticosterone or a placebo in a double blind procedure during the establishment of an on-light control over availability of reinforcement. Having completed this regime the conditions were reversed so that reinforcement was present only when the chamber-light was off. The results indicated that treatment with MSH during acquisition produced a significant decrease in % correct responses compared to animals treated with either the placebo or corticosterone with neither of these latter groups differing from the other. During the reversal phase of training there was a trend for both MSH and corticosterone to lower % correct responses. The discussion focuses on other literature which has shown opposite effects of corticosterone on aversive and appetitively motivated tasks.     

Circadian influences on feeding-induced changes in ACTH and corticosterone secretion in rats.

Food ingestion has a variable influence on pituitary-adrenal hormone secretion depending on the species studied and/or the experimental design. In this study, changes in plasma concentrations of ACTH and corticosterone following 30 min of food ingestion were compared in both 24 h fasted and ad libitum fed rats tested during either the early light cycle or the early dark cycle. In the dark, food ingestion caused significant decreases in both ACTH (to 80% of control) and corticosterone (to 32% of control) in both fasted and ad libitum fed rats. In contrast, in the light, food ingestion by the fasted animal resulted in a doubling of corticosterone concentrations. Such a response was not seen in ad libitum fed animals; however, these animals ate very little during the test. There were no significant changes in ACTH during the light phase. These data indicate that time of day has a significant impact on the responses of the pituitary-adrenal system to food ingestion. This circadian effect may be due to the influence of the endogenous levels of ACTH/corticosterone existing at the time of food ingestion.     

Circadian variation of fibrinolytic activity in blood.

Approximately 35 years ago, it was discovered that spontaneous fibrinolytic activity in blood showed a sinusoidal variation with a period of 24 h; it increased severalfold during the day, reaching a peak at 6:00 p.m. and then dropped to trough levels at 3:00-4:00 a.m. The range of the fluctuation and the 24-h mean levels were highly reproducible within an individual; moreover, the timing of the oscillation was remarkably consistent among individuals, with a fixed phase relationship to external clock time. The biorhythm could not be accounted for simply by variations in physical activity, body posture, or sleep/wake schedule. Gender, ethnic origin, meals, or resting levels of blood fibrinolytic activity also did not influence the basic features of the rhythm. Older subjects, compared to younger ones, showed a blunted diurnal increase in fibrinolytic activity in blood. Recent studies have established that, of the known components of the fibrinolytic system, only tissue-type plasminogen activator (tPA) and its fast-acting inhibitor, plasminogen activator inhibitor-1 (PAI-1), show a marked circadian variation in plasma. In contrast, levels of plasminogen, alpha 2-antiplasmin, urinary-type plasminogen activator, and a reversible tPA inhibitor vary little or none during the 24 h. Quenching antibodies to tPA have shown that the circadian rhythm of fibrinolytic activity in blood is due exclusively to changes in tPA activity. However, the 24-h fluctuation of plasma tPA activity is phase shifted in relation to the rhythm of immunoreactive tPA, but shows a precise phase inversion with respect to the 24-h variation of PAI-1 activity and antigen. Therefore, plasma tPA activity, as currently measured in vitro, is tightly and inversely related to the levels of PAI-1 throughout the 24-h cycle. The factors controlling the rhythmicity of plasma PAI-1 are not fully elucidated but probably involve a humoral mechanism; changes in endothelial function, circulating platelet release products, corticosteroids, catecholamines, insulin, activated protein C, or hepatic clearance do not appear to be responsible. Shift workers on weekly shift rotations show a disrupted 24-h rhythm of plasma tPA and PAI-1. In acute and chronic diseases, the circadian rhythmicity of fibrinolytic activity may show a variety of alterations, affecting the 24-h mean, the amplitude, or the timing of the fluctuation. It is advisable, therefore to define the 24-h pattern of plasma tPA and PAI-1 in patient groups, before levels based on a single blood sampling time are compared to those of a control population.(ABSTRACT TRUNCATED AT 400 WORDS)     

Entrainment of circadian rhythms of cholesterol‐LDL,corticosterone and motor activity by feeding schedules in rats

Abstract

The daily variations of locomotor activity, plasma and adrenal corticosterone levels and cholesterol‐LDL were studied in male Wistar rats with food ad libitum and feeding restricted to the first 4 hours of the light phase in LD 12:12..

Under LD 12:12 (light on from 9:00 to 21:00h) rats with food ad libitum were eating and moving during the dark period and the locomotor activity clearly showed a biphasic pattern with three harmonic components. Plasma and adrenal corticosterone levels increased during the light period and reached a maximum value just before the dark period whereas the acrophase of cholesterol‐LDL is found at the beginning of the light phase.

The acrophases of activity, plasma and adrenal corticosterone levels in the restricted feeding schedule rats occurred in the first three hours of lighting and the cholesterol‐LDL acrophase at the beginning of the dark phase.

These results confirm a previous report that the shift of feeding to the light phase seems to cause a concomitant phase‐shift in all the variables measured.     

Hormonal studies of young lean and obese Zucker rats

Plasma concentrations of insulin, corticosterone, T3, T4 and glucose were measured at 6 hour intervals throughout 24 hours in undisturbed, 34-day-old lean (Fa/?) and genetically obese (fa/fa) Zucker rats. fa/fa rats had higher plasma concentrations of insulin at all sampling times and higher plasma concentrations of corticosterone at 0300 and 0900 hours. Neither T3 nor T4 levels differed between phenotypes at any sampling time. Fasting for 24 hours at 34 days abolished the hyperinsulinaemia of fa/fa rats and raised the plasma corticosterone concentrations of both phenotypes. Before weaning there were no phenotypic differences in the plasma insulin or corticosterone concentrations measured at two sampling times in undisturbed rats. Following an intra-gastric glucose load however, fa/fa rats became hyper-insulinaemic compared with similarly treated Fa/? animals. Pancreatic insulin contents were higher in fa/fa rats at 34 days of age, but not before weaning. Somatostatin contents of the pancreas, hypothalamus and cerebral cortex did not differ between phenotypes at either 18 or 34 days of age. In conclusion, the elevated plasma concentrations of insulin and corticosterone in young fa/fa rats may contribute to their greater lipid deposition and lower protein deposition.     

Sex differences in adrenocortical sensitivity and resistance to cerebrovascular damage in rats under strong stress]

Dynamics of changes in adrenal and plasma corticosterone and the development of cerebrovascular lesions were studied in both male and female rats, exposed to strong stress (combined immobilization and intermittent found sound for 2 hours). Plasma corticosterone levels in stressed females were 460% and 660% of the control values when measured on stress minute 10 and 120. The corresponding values in male rats were 220% and 360%. The stress-induced dilatation of brain vessels and the increases in vascular permeability were less pronounced in females than in males, when studied 0.1 and 24 hours after termination of stress. The number of brain perivascular haemorrhages was markedly reduced in females compared with males. It is supposed that higher resistance to stress-induced cerebrovascular lesions in females may be attributed to higher functional reserves of steroidogenesis.     

Increased hypothalamic-pituitary-adrenal axis activity and hepatic insulin resistance in low-birth-weight rats

Individuals born with a low birth weight (LBW) have an increased prevalence of type 2 diabetes, but the mechanisms responsible for this association are unknown. Given the important role of insulin resistance in the pathogenesis of type 2 diabetes, we examined insulin sensitivity in a rat model of LBW due to intrauterine fetal stress. During the last 7 days of gestation, rat dams were treated with dexamethasone and insulin sensitivity was assessed in the LBW offspring by a hyperinsulinemic euglycemic clamp. The LBW group had liver-specific insulin resistance associated with increased levels of PEPCK expression. These changes were associated with pituitary hyperplasia of the ACTH-secreting cells, increased morning plasma ACTH concentrations, elevated corticosterone secretion during restraint stress, and an approximately 70% increase in 24-h urine corticosterone excretion. These data support the hypothesis that prenatal stress can result in chronic hyperactivity of the hypothalamic-pituitary-adrenal axis, resulting in increased plasma corticosterone concentrations, upregulation of hepatic gluconeogenesis, and hepatic insulin resistance.     

The relation between maternal restraint and food deprivation, plasma corticosterone, and induction of cleft palate in the offspring of mice.

The blood level of corticosterone was measured in mice following the injection on day 14 of pregnancy of a dose of corticosterone sufficient to cause a low frequency of cleft palate in the fetuses. This was compared with the blood levels present during maternal restraint and food deprivation that produced a similar frequency of cleft palate. The mean blood level over the 24 h following injection of corticosterone was 660 mug/100 ml, and during a similar period of restraint was 485 mug/100 ml. Other mice were subjected either to restraint or food deprivation for 24 h beginning day 14 of pregnancy, the plasma corticosterone levels measured during that time, and the frequency of cleft palate in late fetuses compared with the individual plasma corticosterone levels during treatment. There was a significant (P less than 0.025) correlation between high maternal corticosteroid levels and the frequency of cleft palate in the offspring of the restrained mice but not in the food-deprived animals. It is suggested that in some stressed mice endogenous plasma corticosterone can reach levels sufficient to account for the development of cleft palate.     

Plasma gonadotrophins, prolactin and corticosterone concentrations in male mice exposed to high altitude

Groups of sexually-naive male NFR/N mice were maintained at sea level or exposed to simulated altitudes of 18 000 ft (5486 m) or 22 000 ft (6705 m) for 1, 3, 7, 14 or 28 days. Plasma LH concentrations were slightly but not significantly depressed after 1 day of hypoxia. Plasma FSH values were reduced (P < 0.05) after 1, 7, 14 and 28 days of exposure to 22 000 ft when compared to the values in the other groups. Prolactin concentrations fluctuated considerably, but were not uniformly affected by high altitude exposure. Exposure to 18 000 ft resulted in an elevation of plasma corticosterone concentration (P < 0.05) for 3 days, which was followed by a decline to control group values, whereas at 22 000 ft corticosterone levels remained elevated. These findings indicate that plasma LH values are transiently reduced during the initial 24 h of exposure to high altitude and that plasma FSH concentrations are depressed in a sustained manner during severe hypoxia.