Effects of incremental cortisol and adrenalectomy on plasma corticosteroid binding capacity in fetal sheep

The effects of incremental cortisol infusion or fetal adrenalectomy on plasma corticosteroid-binding capacity (CBC) were examined in sheep fetuses during late gestation (term approximately 150 days). Cortisol, infused from day 120 at 1.5 mg/day for the first 3 days, 2.5 mg/day for the next 5 days, and 3.5 mg/day for the final 2 days, stimulated a significant rise in plasma CBC and immunoreactive corticosteroid binding globulin (CBG). There was a significant positive correlation between individual values for total plasma cortisol concentrations and CBC values. In contrast, fetal adrenalectomy at day 115 prevented the rise in plasma CBC found in intact fetuses at term. These experiments show that exogenous cortisol, given in a manner that mimics the prepartum rise in fetal plasma cortisol, stimulates CBG biosynthesis, whereas abolition of the cortisol rise prevents the increase in CBG. The study provides strong support for the proposal that the prepartum increase in CBG biosynthesis in fetal sheep occurs in response to the progressive rise in adrenal cortisol output by the fetus towards term.     

Corticosteroid-binding globulin is not decreased in depressed patients

We studied corticosteroid-binding globulin (CBG) in 25 drug-free depressed patients and 33 healthy controls over a wide age-range. CBG was measured at 0800, 1400, 2000 and 2400 h in all subjects. Analysis of variance (ANOVA) with repeated measurement design revealed a significant effect of gender and time, but not of diagnosis (depressed patients vs healthy controls) or age group (< 50/> 50 years). In females, regardless of diagnosis, CBG plasma concentrations were significantly increased, when compared with their male counterparts. Although as a group depressed patients had significantly higher plasma cortisol concentrations (108.0 +/- 23.1 vs 70.7 +/- 10.9 micrograms/l), CBG levels did not differ between the two groups. Thus we did not find hypercortisolemia in depression to be paralleled by a decrease in CBG. However, the exaggerated activity of the hypothalamus-pituitary-adrenocortical system in healthy and depressed females is associated with an increase in plasma CBG.     

Maturational effects of cortisol on the exocrine abomasum and pancreas in fetal sheep

The role of cortisol in the prenatal development of digestive enzymes in the abomasum (prochymosin and pepsinogen) and pancreas (amylase, trypsin, chymotrypsin) has been investigated in the fetal lamb during late gestation. The abomasum and pancreas were collected from 22 unoperated control fetuses (99-145 days gestation; term, 145 +/- 2 days), from seven pairs of twins infused with either saline or cortisol for five days preceding delivery at 127-133 days, and from four 139-143-day-old fetuses adrenalectomized at 120-123 days. Developmental increases (2-8-fold) occurred in protease concentrations in the fetal abomasum and in amylase and chymotrypsin contents in the fetal pancreas. These increases paralleled the normal prepartum rise in fetal plasma cortisol. In addition, the enzyme values were significantly higher in cortisol-infused than in saline-infused fetuses (with the exception of pancreatic amylase) and were significantly lower in adrenalectomized fetuses than in control fetuses at term. The pH of abomasal fluid remained neutral (pH 6.8-8.0) during late gestation and was not affected by cortisol treatment or adrenalectomy. The results suggest that cortisol stimulates the development of the exocrine abomasum and pancreas in fetal sheep and may, thereby, increase the digestive capacity in neonatal lambs. Compared with the pig, another long-gestation species, the sheep has an early development of gastric pepsinogen but a late development of gastric acidity and pancreatic protease activities.     

Phosphatidic acid elicits calcium mobilization and actin polymerization through a tyrosine kinase-dependent process in human neutrophils: a mechanism for induction of chemotaxis

In mammalian species, the fetal adrenal gland plays a key role during late gestation since fetal glucocorticoids are involved in the maturation of the fetus and in the adaptation of the neonate to extra-uterine life. Moreover, in domestic ruminants as well as in the pig, the onset of parturition is triggered by an increased level of fetal plasma glucocorticoids. This prepartum rise of fetal glucocorticoids, which conveys growth and differentiation of adrenocortical cells, is not only under pituitary control but also involves local regulations. We review the actual knowledge of the modalities of fetal adrenal development in the sheep and its regulation by the adrenocorticotropic hormone (ACTH) and other factors.     

Cortisol differentially regulates pituitary-adrenal function in the sheep fetus after disconnection of the hypothalamus and pituitary

We have investigated the effects of a 5 day infusion of cortisol into fetal sheep, in which the hypothalamus and pituitary were surgically disconnected (HPD), on fetal pituitary-adrenal function. Fetal HPD and vascular catheterization were carried out at between 104 and 124 days gestation. Cortisol was administered (3.5 mg 24 h-1) for 120 h between 134 and 140 days (HPD + F group; n = 5) and saline was administered during the same gestational age range to HPD (HPD group; n = 12) and intact fetal sheep (Intact group; n = 6). Cortisol infusion into the HPD fetal sheep did not suppress the mRNA levels for Proopiomelanocortin (POMC) in the fetal anterior pituitary at 139/140 days gestation (POMC mRNA: 18S rRNA: Intact 0.40 +/- 0.05; HPD 0.56 +/- 0.07; HPD + F 0.49 +/- 0.07). Similarly, there was no significant effect of either HPD or cortisol infusion on the plasma concentrations of immunoreactive (ir) ACTH or ACTH(1-39). The adrenal: fetal body weight ratio was significantly higher, however, in the HPD + F (88.4 +/- 8.7 mg kg-1) and Intact groups (84.1 +/- 5.6 mg kg-1) when compared with the HPD fetal sheep (63.7 +/- 5.4 mg kg-1). The ratio of total IGF-II mRNA: 18S rRNA was similar in the adrenals of the Intact (0.48 +/- 0.09), HPD (0.78 +/- 0.09) and HPD + F (0.71 +/- 0.11) groups. The ratios of CYPIIA1, 3 beta-HSD and CYP21A1 mRNA: 18S rRNA were significantly lower in adrenals from the HPD group when compared to those in the Intact group and were not restored to normal by cortisol infusion. We have therefore demonstrated that cortisol does not act directly at the fetal pituitary to suppress POMC synthesis or ACTH secretion in late gestation. Cortisol does, however, stimulate fetal adrenal growth after HPD in the absence of any effects on adrenal IGF-II or steroidogenic enzyme mRNA levels. The data provide evidence that an intact hypothalamic-pituitary axis and cortisol each play an important role in the stimulation of adrenal growth and steroidogenesis which occurs during the last 10-15 days of gestation in the sheep.     

Treatment with growth hormone suppresses cortisol production in man

The effect of biosynthetic human growth hormone (GH) on the cortisol production rate was determined in healthy men (N=8) using the stable isotope dilution technique and mass spectrometry. 1alpha,2alpha-D-Cortisol was infused at a dose of 110+/-9 microg/h for 10 hours (8 AM to 6 PM). Blood samples obtained at 20-minute intervals from 2 PM to 6 PM were pooled during two 2-hour periods. Subsequently, each subject received a daily dose of biosynthetic human GH (4 IU/d subcutaneously [SC]) for 7 days. This resulted in an increase of plasma somatomedin C from a basal level of 0.65+/-0.13 U/mL to 1.18+/-1.2 U/mL on day 7 (P < .0001). Plasma concentrations of corticotropin (ACTH) and cortisol-binding globulin (CBG) were similar before and after administration of GH. Determination of the cortisol production rate was repeated on day 7 of treatment with GH. Due to its physiological diurnal rhythmicity, endogenous production of cortisol during basal conditions was higher (P < .05) between 2 and 4 PM (0.70+/-0.30 mg/h) versus 4 to 6 PM (0.55+/-0.28 mg/h). Following treatment with GH, the values were 0.40+/-0.11 mg/h (2 to 4 PM, P < .01 v day 1) and 0.31+/-0.11 mg/h (4 to 6 PM, P < .01 v day 1). Thus, in healthy men, treatment with SC, GH induces a decrease in endogenous cortisol production rates.     

A corticotropin-releasing hormone type I receptor antagonist delays parturition in sheep

In sheep, corticotropin-releasing hormone (CRH) can stimulate the fetal release of ACTH to produce a cortisol surge which leads to the onset of parturition. We tested the hypothesis that fetal CRH is a primary factor in the onset of parturition in sheep by using a Type I CRH receptor antagonist, antalarmin, to block the endogenous action of CRH. Pregnant ewes were cannulated at 130-135 days of gestation. Five catheters were placed into the amniotic sac, fetal femoral artery, fetal tarsal vein, maternal jugular vein and carotid artery. After 5 days' recovery, blood samples from maternal and fetal vessels were collected at the following times: a day before the start of infusion, at [-1, 0, 1, 2, 4, 8 and 24]h, on the first day of infusion, and thereafter daily throughout a 10-day infusion. Animals (n=6 per group) received infusions into a fetal vein of either a vehicle comprising 1:1 mixture of ethanol and polyethoxylated castor oil (Cremophor EL) or antalarmin (50 g/L) in the vehicle at a rate of 0.3 mL/h. The plasma samples were assayed for ACTH and cortisol using commercial RIA kits. Fetuses infused with vehicle delivered at a mean gestational age of 141.8 +/- 0.9 days compared with antalarmin-infused sheep at 148.8 +/- 1.6 days (P = 0.0036, unpaired Student's t-test). Fetal ACTH and cortisol did not change in the antalarmin-infused sheep after 3 days' infusion compared to significant increases in vehicle-infused sheep (P=0.004 and P = 0.016 respectively, ANOVA). These data show that CRH receptor antagonism in the fetus can delay the onset of parturition. It supports the hypothesis that hypothalamic CRH drives fetal production of ACTH and is essential for the onset of parturition triggered by a surge in fetal cortisol.     

Corticosteroid-binding globulin synthesis regulation by cytokines and glucocorticoids in human hepatoblastoma-derived (HepG2) cells

Plasma corticosteroid-binding globulin (CBG) concentrations decrease dramatically in patients with septic shock or burn injury. This decrease suggests that mediators of the acute phase response, such as cytokines and glucocorticoid hormones, might influence clearance as well as liver synthesis of CBG in humans. The present study investigated the effects of interleukin-6 (IL-6), IL-1 beta, and dexamethasone on CBG synthesis by a clone of human hepatoblastoma-derived (HepG2) cell line. In culture medium from HepG2 cells, the immunoconcentration of CBG and the levels of CBG messenger ribonucleic acid (mRNA) were dose dependently decreased in the presence of IL-6 concentrations ranging from 0.1-10 ng/mL. The percent decrease in CBG immunoconcentration was quantitatively similar to the percent decrease in CBG mRNA levels (29 +/- 6% and 39 +/- 15%, respectively, of control values). In contrast, and as expected, IL-6 dose dependently increased the mRNA levels (164 +/- 22% of control values) of alpha 1-antitrypsin, a positive acute phase protein, but did not affect the immunoconcentration of sex hormone-binding globulin, another liver protein. Dexamethasone alone did not significantly affect CBG secretion or mRNA levels, but did dose-dependently increase tyrosine amino-transferase mRNA levels, which increased to 252 +/- 16% of the control values. However, in combination with IL-6, dexamethasone had a significant additive effect on IL-6 inhibition of CBG secretion and mRNAs in HepG2 cells. IL-1 beta dose-dependently stimulated CBG secretion (156 +/- 10% of control values) with no significant effect on CBG mRNA levels. In addition, IL-1 beta significantly decreased the inhibitory effect of IL-6 on CBG secretion, but had no effect on the inhibitory effect of IL-6 on CBG mRNA levels. These results suggest that IL-1 beta acts on the posttranslation processing and/or secretion mechanisms of CBG in HepG2 cells. Together, the present results strongly support the hypothesis that the decrease in plasma CBG concentrations is associated with the increase in IL-6 and glucocorticoid levels reported in patients with septic shock and burn injury.     

Dexamethasone regulates basic fibroblast growth factor, nerve growth factor and S100beta expression in cultured hippocampal astrocytes

Glucocorticoids regulate hippocampal neuron survival during fetal development, in the adult, and during aging; however, the mechanisms underlying the effects are unclear. Since astrocytes contain adrenocortical receptors and synthesize and release a wide variety of growth factors, we hypothesized that glucocorticoids may alter neuron-astrocyte interactions by regulating the expression of growth factors in hippocampal astrocytes. In this study, three growth factors, which are important for hippocampal neuron development and survival, were investigated: basic fibroblast growth factor (bFGF), nerve growth factor (NGF), and S100beta. Enriched type I astrocyte cultures were treated with 1 microM dexamethasone (DEX), a synthetic glucocorticoid, for up to 120 h. Cells and culture medium were collected and total RNA and protein were measured at 6, 12, 24, 48, 72, 96 and 120 h after the initiation of hormone treatment. Growth factor mRNA levels were measured and quantified using solution hybridization-RNase protection assays and protein levels were quantified using ELISA methods. We report that DEX stimulates the bFGF mRNA levels over the 120-h treatment. In contrast, DEX suppresses NGF mRNA continuously over the same period of treatment. DEX induces a biphasic response in S100beta mRNA levels. In addition, some of the changes in gene expression are translated into parallel changes in protein levels of these growth factors. Our results demonstrate that dexamethasone can differentially regulate the expression of growth factors in hippocampal astrocytes in vitro. This suggests that one of the mechanisms through which glucocorticoids affect hippocampal functions may be by regulating the expression of astrocyte-derived growth factors.     

Immunolocalisation of P450(C17) in the fetal sheep adrenal gland during gestation and in response to ACTH and glucocorticoid administration

In sheep, increased output of cortisol from the fetal adrenal gland is critical to organ maturation and parturition. Cortisol synthesis is determined in part by the activity of P450(C17) enzyme. We have used immunohistochemistry and Western immunoblotting to examine the distribution of P450(C17) in the ovine fetal adrenal during gestation, and after ACTH or dexamethasone administration to fetuses between Days 125 and 130. The patterns were compared with changes in 3beta-hydroxysteroid dehydrogenase (3beta-HSD) localisation and levels. Adrenal tissue was obtained from four fetuses at each of Days 63-65, 100, 125-130 and term (>140 days). Further animals were chronically catheterised and infused with ACTH, dexamethasone or saline for 96 h beginning on Day 125. Immunohistochemistry for P450(C17), 3beta-HSD, and phenylethanolamine-N-methyl transferase (PNMT) was conducted using standard techniques. At Day 63-65 of pregnancy immunoreactive (ir-)P450(C17) was present in cords of cells throughout the adrenal gland. Ir-P450(C17) was reduced or was undetectable at Day 100, but had increased by Day 125-130, and was present throughout the zona fasciculata of the adrenal cortex of term animals. An increase in P450(C17) protein was also seen between Day 100 and 125 by Western blotting, and after ACTH treatment. Dexamethasone administration led to a marked reduction in ir-P450(C17) levels. In contrast, ir-3beta-HSD was present in the fetal adrenal cortex between Day 100 and term, and was less affected by ACTH or dexamethasone treatment. We conclude that P450(C17) in the fetal sheep adrenal is responsive to regulation by ACTH, and that changes in its levels correlate with previously reported alterations in patterns of cortisol output by the fetal adrenal gland.     

Isotope effect in the binding of tritium and 14C-labelled cortisol to corticosteroid-binding-globulin in serum

We have determined the free cortisol concentration in serum using either the Amicon MPS-1 ultrafiltration-centrifugation method (I) or equilibrium dialysis (II). If procedure I was used we found that [1,2,6,7-3H]-, and [4-14C]cortisol had a lower affinity than unlabelled cortisol for corticosteroid binding globulin (CBG). The binding affinity (Ka) to three separate CBG-containing samples was 8-18 times lower for [1,2,6,7-3H]cortisol and 30-90 times lower for [4-14C]cortisol, when compared with that of unlabelled cortisol. This difference in affinity to CBG was not observed if method II was used for the free cortisol determinations. The observed isotope effect in method I is not caused by unspecific binding to material such as the Amicon MPS-1 chamber or to impurities in the tracer. We suggest that the centrifugation step during ultrafiltration changed the conformation of CBG, thereby reducing its affinity for labelled cortisol. It is concluded that incorrect results will be obtained if radiolabelled is cortisol used for determining the free cortisol content of plasma with the Amicon MPS-1 device.     

Longitudinal evaluation of salivary cortisol levels in full-term and preterm neonates

The aim of the present study was to test the practicability of sequential cortisol determinations in saliva of low birth weight neonates and to evaluate the impact of systemic and inhaled glucocorticoid therapy on saliva concentrations of cortisol in preterm neonates with bronchopulmonary dysplasia (BPD). Salivary cortisol levels were measured by RIA in saliva samples from 10 full-term and 10 preterm healthy neonates and from 20 preterm neonates with BPD during systemic [dexamethasone (DEX); n = 10] or topical steroid therapy [budesonide (BUD); n = 10]. Saliva samples of each individual were collected on 3 consecutive days at 06.00, 12. 00, 18.00 and 24.00 h. Cortisol levels in saliva ranged from 0.8 to 60.6 nmol/l (median 6.5 nmol/l) in full-term neonates, from 0.6 to 52.1 nmol/l (median 5.5 nmol/l) in preterm neonates, from 0.4 to 14. 0 nmol/l (median 1.0 nmol/l) in preterm neonates treated with DEX and from 0.4 to 15.2 nmol/l (median 2.5 nmol/l) in preterm neonates treated with BUD. Autocorrelation analysis revealed a distinct endogenous cortisol rhythm in 2 of the 10 healthy full-term neonates and in 3 of the 10 healthy preterm neonates with a wavelength of 12-30 h. Salivary cortisol levels in preterm neonates treated with DEX or BUD were significantly lower than those measured in healthy preterm neonates. These results demonstrate that the measurement of salivary cortisol levels is a reliable and practicable way of assessing adrenal function in full-term and preterm neonates. This study also shows for the first time that some neonates display an endogenous cortisol rhythm which is not coupled to the exogenous day/night cycle. Furthermore, systemic and nebulized glucocorticoids suppress adrenal function in low-birth-weight neonates. After treatment these children should be closely monitored for potential adrenal insufficiency.     

Coordinate activation of the corticotropic axis by insulin-induced hypoglycemia: simultaneous estimates of beta-endorphin, adrenocorticotropin and cortisol secretion and disappearance in normal men

In the present study, we investigated the coordinate kinetic response of the corticotropic axis to the acute metabolic stress of hypoglycemia by applying deconvolution analysis to adrenocorticotropin (ACTH), beta-endorphin and cortisol concentration-time series generated in seven normal men after intravenous administration of insulin. Hypoglycemic stress resulted in a 22-fold increase in the mean plasma concentration of ACTH to a maximum of 77 +/- 15 pmol/l, in conjunction with a 7.5-fold increase in the mean plasma beta-endorphin concentration, the maximal value of which was 96 +/- 11 pmol/l. Plasma cortisol concentrations increased by 2.6-fold with a mean value of 734 +/- 14 nmol/l. Maximal plasma ACTH and beta-endorphin concentrations were preceded by discrete secretory bursts with peak amplitudes of 10.5 +/- 2.7 and 10.6 +/- 2.0 pmol.l-1.min-1 (20-fold and ninefold increases compared to control), respectively. The mass of ACTH released was 114 +/- 20 pmol/l (3.4-fold increase), which corresponds to a total amount of 1.25 micrograms (50% of daily production and 0.5% of reported pituitary stores), assuming a distribution volume of 40 ml/kg. A total amount of 4.4 +/- 0.7 mg of cortisol was released after insulin-induced hypoglycemia, based on a mean cortisol secretory mass of 1088 +/- 137 nmol/l and a presumed 11.3-1 volume of distribution. Deconvolution-based estimates of the endogenous half-lives of ACTH, beta-endorphin and cortisol were 17 +/- 0.6, 22 +/- 1.7 and 65 +/- 5.3 min, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Levels of corticotropin-releasing hormone messenger ribonucleic acid (mRNA) in the hypothalamic paraventricular nucleus and proopiomelanocortin mRNA in the anterior pituitary during late gestation in fetal sheep

CRH regulates POMC gene expression and subsequent ACTH biosynthesis and release. In sheep, the preterm rise in fetal plasma ACTH commences at approximately 125 days gestation (dGA; 147 dGA = term), preceding the initiation of adrenocortical steroidogenesis. We hypothesized that an increase in CRH expression in the hypothalamic paraventricular nucleus (PVN) and POMC expression in the anterior pituitary in the late gestation sheep fetus may precede adrenal cortex maturation. Fetal sheep were obtained at 105-107 (n = 4), 128-130 (n = 5), and 138-140 (n = 4) dGA. Hypothalami were cryosectioned and subjected to in situ hybridization for ovine CRH mRNA. In all dGA groups, expression of CRH mRNA was observed throughout the rostrocaudal extent of the fetal PVN. The midrostral region of the fetal PVN where the dorsal and ventral divisions of the rostral PVN merge to form a single structure was selected for quantification. The number of copies of CRH probe hybridized per micron 3 were determined to estimate the quantity of hybridized CRH mRNA; the mean estimated CRH mRNA copy number per micron 3 midrostral PVN were 0.064 +/- 0.012 (105-107 dGA), 0.237 +/- 0.048 (128-130 dGA), and 0.108 +/- 0.034 (138-140 dGA; mean +/- SEM copies per micron 3 PVN). CRH mRNA signal significantly increased between 105-107 and 128-130 dGA (P < or = 0.05); 138-140 dGA levels of mRNA were not different from either 105-107 or 128-140 dGA levels. Regional variation in CRH mRNA levels were observed within the midrostral PVN between groups; at 138-140 dGA, a population of lateral midrostral PVN neurons maintain CRH mRNA levels greater than 105-107 dGA (P < 0.05), similar to those at 128-130 dGA. Fetal anterior pituitary RNA was subjected to Northern analysis for POMC mRNA. POMC mRNA levels in fetal anterior pituitaries were 14.1 +/- 2.2 (105-107 dGA), 28.9 +/- 10.9 (128-130 dGA), and 43.2 +/- 6 (138-140 dGA; mean +/- SEM arbitrary units). A significant increase (P < or = 0.05) was observed at 138-140 dGA compared to levels at 105-107 dGA. We conclude CRH mRNA levels in the fetal PVN increase coincident with increased POMC gene expression and the late gestation rise in fetal plasma ACTH. We speculate that a neuroendocrine stimulus at the fetal PVN may precipitate increased levels of CRH mRNA, initiating the maturation of the fetal hypothalamic-hypophyseal-adrenal axis, thus inducing the events of labor and delivery in sheep.     

Ontogeny of 11 beta-hydroxysteroid dehydrogenase in ovine fetal kidney and lung

Eleven-beta-hydroxysteroid dehydrogenase (11 beta-HSD) is an enzyme which degrades 11-hydroxycorticosteroids to biologically inactive 11-oxocorticosteroids (cortisone and 11-dehydrocorticosterone). In some tissues, the activity of this enzyme prevents binding of cortisol to mineralocorticoid receptors. The present experiments were designed to test the hypothesis that the fetal kidney contains 11 beta-HSD, that the activity of 11 beta-HSD in fetal kidney increases near term, and that the fetal lung does not contain significant 11 beta-HSD activity. In kidney and lung tissue from 23 fetal sheep ranging in age between 86 and 145 days' gestation, we measured 11 beta-HSD activity. We found significant activity in fetal kidney (14-85% conversion from cortisol to cortisone) but no measurable activity in fetal lung (0-9%). The activity of 11 beta-HSD was significantly related to fetal gestational age (r = 0.76, n = 14). We conclude that 11 beta-HSD activity in the fetal kidney develops as a function of fetal gestational age, and that activity cannot be demonstrated in fetal lung. We speculate 11 beta-HSD in the fetus might function to alter the sensitivity of target organs to glucocorticoids, as well as to mineralocorticoids, and that the absence of activity in the lung allows a high sensitivity of pulmonary tissue to cortisol at the end of gestation.     

The combined dexamethasone/corticotropin-releasing hormone stimulation test is more closely associated with features of diurnal activity of the hypothalamo-pituitary-adrenocortical system than the dexamethasone suppression test

BACKGROUND: The dexamethasone suppression test (DST) is a widely used endocrine test in psychiatry, but was reported to not allow reliable inferences with regard to the basal activity of the hypothalamo-pituitary-adrenocortical (HPA) system. We compared the association of the standard DST and the combined dexamethasone/corticotropin-releasing hormone (DEX/CRH) challenge with parameters of diurnal cortisol profiles. METHODS: We performed a DEX/CRH challenge and 24-hour cortisol profiles in 25 depressed patients (mean age: 47.4 +/- 16.0 years) and 33 age-matched healthy controls (mean age: 51.4 +/- 19.3 years). RESULTS: A path analysis showed cortisol area under the curve (AUC) after CRH (= DEX/CRH status) to be dependent upon minimal 24-hour cortisol and evening frequency of pulsatile cortisol release. In contrast, postdexamethasone cortisol (= DST status) was related to 24-hour mean cortisol. Simple linear regressions supported an association of cortisol AUC with several parameters of the diurnal cortisol profiles, which was not true for the standard DST. CONCLUSIONS: We conclude that the combined DEX/CRH challenge test is more closely associated with the activity of the HPA system than the standard DST in healthy and depressed subjects.     

Plasma cortisol and appetitively motivated arousal in monkeys.

Six adult male rhesus monkeys subjected to appetitive conditioning once every 48 hrs showed significantly more emotional arousal during positive- than negative-conditioning sessions. Appetitive conditioning suppressed the increase in plasma cortisol found in control conditions, and dissociation between cortisol and arousal indicated that plasma glucocorticoids are an insensitive arousal index. Previous similar findings with rats suggest that hormonal regulatory mechanisms are different for rodents and primates. (24 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Glucocorticoid binding in mammary tissue slices of cattle in various reproductive states

Unlabeled cortisol and dexamethasone reduced tritiated cortisol and tritiated dexamethasone binding to 700 X g supernatant and precipitate fractions of mammary tissue slices from virgin heifers and from multiparous cows that were 1-mo prepartum (nonlactating), lactating (non-pregnant), or dry (nonpregnant, nonlactating). Unlabeled progesterone, testosterone, and 17beta-estradiol had no effect on tritiated glucocorticoid binding in 700 X g supernatant and precipitate fractions from these mammary tissue slices. The 700 X g fractions in mammary tissue slices from all cattle bound cortisol and dexamethasone with high affinity (Kd 10-10M). There were 1263 and 1955 molecules of cortisol and dexamethasone bound per mammary cell, respectively, in mammary tissue slices from lactating non-pregnant cows; in comparison virgin heifers bound 413 and 651 molecules of cortisol and dexamethasone; dry, non-pregnant cows bound 336 and 536 molecules of cortisol and dexamethasone; and 1-mo prepartum nonlactating cows bound 532 molecules of cortisol. Mammary tissue slices from cattle in reproductive states examined contained a major non-specific component which bound cortisol in both 700 X g tissue fractions. Since mammary tissue slices from lactating cattle bound more molecules of glucocorticoids than mammary slices from cattle in other reproductive states, we speculate specific glucorticoid binding may be associated with lactation.     

Intrauterine cortisol, aldosterone, and corticosteroid binding globulin-like activity during early porcine pregnancy and the estrous cycle

Studies were conducted to determine whether the corticosteroids cortisol and aldosterone, and corticosteroid-binding globulin (CBG) were present in the porcine early-embryonic environment. Cortisol was measured in uterine flushings from white crossbred gilts at Days 7, 10, 13, and 16 of the estrous cycle and pregnancy. Total content of cortisol increased (p < 0.01) between Days 13 and 16, and immunoreactive CBG (ir-CBG) increased (p < 0.01) between Days 10 and 13, in both cyclic and pregnant gilts. In a separate study with Chinese Meishan gilts, total cortisol and aldosterone content of uterine flushings increased (p < 0.02) between Days 10 and 15 of the estrous cycle and pregnancy. In another study with white crossbred gilts, CBG-like binding activity in uterine flushings was low at Day 10, then increased over 100-fold at Day 15 (p < 0.01). However, levels of CBG-like binding activity on Day 15 were 100-fold lower than those of ir-CBG measured in the previous study and could bind less than 4% of the uterine luminal cortisol. Differences between ir-CBG and CBG binding might be due to the ability of the CBG antibody to recognize either biologically inactive CBG or structurally similar molecules. CBG-like binding activity, which appeared unrelated to glucocorticoid receptors, was also present in the endometrial cytosol of white crossbred gilts. Concentrations (fmol/mg protein) of endometrial CBG-like activity decreased (p = 0.03) between Days 10 and 15 of the estrous cycle and pregnancy, did not differ with reproductive status, and on Day 15 were comparable to concentrations in uterine flushings but threefold lower (p < 0.01) than those in the serum. Equilibrium dissociation constants for CBG-like binding activities were comparable among the three locations. These studies indicate that corticosteroids are present-primarily in the free form-within the porcine uterine lumen and could influence early porcine conceptus development. Endometrial CBG-like binding activity could mediate actions of cortisol or progesterone on uterine function.     

Semiquantitative reverse transcription-polymerase chain reaction analysis of mRNA for growth factors and growth factor receptors from normal and healing rabbit medial collateral ligament tissue

By studying western lowland gorillas (Gorilla gorilla gorilla, n = 8) in zoological gardens via ethological and non-invasive physiological techniques, we have demonstrated that their postpartum maternal behavior is related negatively to their postpartum urinary titers of cortisol. On the basis of this finding, it is proposed that postpartum stress contributes to disrupted maternal behavior in the gorilla in captivity. Morning urine samples were collected with a mean sampling interval of 1.6 days from Day 14 prepartum to Day 14 postpartum (n = 11 pregnancies). Creatinine-indexed (Cr) urinary cortisol titers declined significantly between Day 9 to 1 prepartum (0.634 +/- 0.014 microg/mg of Cr, mean +/- SEM) and Day 1 to 6 postpartum (0.396 +/- 0.030 microg/mg of Cr, mean +/- SEM; p < 0.01-0.001). For each pregnancy, the relative postpartum decline in urinary cortisol was calculated as (microg of cortisol/mg of Cr Day 1 to 4)/(microg of cortisol/mg of Cr Day -4 to -1). Values ranged from 0.35 to 1.12, were independent of absolute prepartum cortisol titers, and were interpreted as evidence of inter-female differences in postpartum hypothalamo-pituitary-adrenal axis activity and, therefore, postpartum stress. This postpartum stress index was negatively correlated with the amount of time (0-100%) that females carried and supported their 0-14 day-old infants in a ventral position during locomotion (r(s) = -0.68, p < 0.05) and tended to be negatively correlated with the total amount of time (0-100%) they spent in ventro-ventral contact with their infants (r(s) = -0.58; p < 0.10). This study provides the first physiological evidence that postpartum stress is an important etiologic factor in gorilla maternal failure in captive environments.