Cortisol Production In Response Research Articles

Regulation of cortisol production during chronic social stress in rainbow trout

Chronic stress resulting from social interactions impacts the endocrine stress response in many vertebrates, including teleost fishes. Juvenile rainbow trout held in pairs form a dominance hierarchy with the subordinate individual exhibiting chronic elevation of plasma cortisol and an attenuated cortisol response to an additional acute stressor. The current study investigated the mechanisms underlying this apparent dichotomy in cortisol production at the level of the head kidney (adrenal homolog). Following four days of chronic social stress, subordinate rainbow trout exhibited elevated plasma cortisol levels that correlated with basal cortisol production by the head kidney in vitro. Subordinate trout had higher transcript abundances of steroidogenic acute regulatory protein and cytochrome p450 side chain cleavage enzyme, which facilitate key steps in steroidogenesis, as well as two paralogs of steroidogenic factor 1. Despite elevation of basal steroidogenesis, acute cortisol production in response to ACTH (in vivo and in vitro) was lower in subordinate trout. Transcript abundances of the ACTH receptor accessory proteins were elevated in subordinate fish, but head kidney cortisol production in response to a cAMP analogue was lower than in dominant fish. Together, the data suggest that the attenuated acute cortisol response of subordinate trout reflects limitations on cortisol production downstream of cAMP signalling in steroidogenic cells of the head kidney, despite the increased basal abundance of key components of the steroidogenic pathway.

Children's fingernail cortisol among BaYaka foragers of the Congo Basin: associations with fathers' roles.

Children and mothers' cortisol production in response to family psychosocial conditions, including parenting demands, family resource availability and parental conflict, has been extensively studied in the United States and Europe. Less is known about how such family dynamics relate to family members' cortisol in societies with a strong cultural emphasis on cooperative caregiving. We studied a cumulative indicator of cortisol production, measured from fingernails, among BaYaka forager children (77 samples, n = 48 individuals) and their parents (78 samples, n = 49) in the Congo Basin. Men ranked one another according to locally valued roles for fathers, including providing resources for the family, sharing resources in the community and engaging in less marital conflict. Children had higher cortisol if their parents were ranked as having greater parental conflict, and their fathers were seen as less effective providers and less generous sharers of resources in the community. Children with lower triceps skinfold thickness (an indicator of energetic condition) also had higher cortisol. Parental cortisol was not significantly correlated to men's fathering rankings, including parental conflict. Our results indicate that even in a society in which caregiving is highly cooperative, children's cortisol production was nonetheless correlated to parental conflict as well as variation in locally defined fathering quality. This article is part of the theme issue 'Multidisciplinary perspectives on social support and maternal-child health'.

Selective Serotonin Reuptake Inhibitors Increase Urinary Free Cortisol in Patients with Carney Complex and Primary Pigmented Nodular Adrenocortical Disease

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent Cushing syndrome predominantly associated with Carney Complex (CNC), a multiple endocrine neoplasia syndrome primarily caused by inactivating defects in PRKAR1A. PPNAD, which has neuroendocrine features, demonstrates cortisol production in response to serotonin as well as increased expression of tryptophan hydroxylase type 2, a serotonin synthesizing enzyme, and the serotonin (5-HT) receptors types 4, 6, and 7. This creates an autocrine/paracrine serotonergic regulatory loop that activates cortisol production. PPNAD can be diagnosed through a 6-day Liddle test (LT) showing a paradoxical increase of >50% from baseline in 24-h urinary free cortisol (UFC) on the 2nd day of high-dose dexamethasone administration (Day 6). Selective serotonin reuptake inhibitors (SSRIs) inhibit the reuptake of serotonin and are widely used for the treatment of depression. We performed a retrospective cohort study of patients with CNC and PPNAD that underwent a LT to evaluate the effect of SSRIs on UFCs, with the hypothesis that SSRI use leads to an exaggerated increase in UFC through presumed activation of the described serotonergic regulatory loop. Of the 34 patients (4–65 y) with CNC and PPNAD that underwent a LT at our institution between 2004 and 2018, 4 took an SSRI during testing. No differences were observed between the SSRI (S) group and the non-SSRI (NS) group in baseline UFCs and the percent increase in UFC on D6. Specifically, the median (IQR) baseline UFC in the S group was 36 (13–252) mcg/24h (nl 4–56) vs 35 (13–98) mcg/24h in the NS group (P=0.95). The percent change in UFC was 208 (93–683)% in the S group and 185 (28–364)% in the NS group (P=0.89). However, there was a difference for overall UFC measurement (across days 1–6 of the LT) in the S group vs the NS group (P=0.03). Age <18 vs 18+ and sex did not have an effect on the outcomes (P=0.17 and P=0.74, respectively). Thus, we conclude that though the percent change in UFC during the LT was similar in both groups, there was a significant difference in overall UFC in the S group when compared to the NS group. These data support an effect of SSRIs and serotonin on UFC and consequently cortisol production in PPNAD. This interesting observation has to be confirmed in more patients with CNC and PPNAD to further elucidate the effects of SSRIs on cortisol production in patents with PPNAD-caused Cushing syndrome, as this may have significant diagnostic and therapeutic implications.

Absence of relationship between serum cortisol and critical illness in premature infants

BackgroundInadequate cortisol production in response to critical illness in extremely preterm infants may exacerbate poor outcomes. Despite commonly measuring cortisol concentration and administering hydrocortisone for presumed adrenal insufficiency, the relationship...

Is cortisol production in response to an acute stressor associated with diurnal cortisol production during adolescence?

The goal of the current study was to examine the extent to which cortisol responding to an acute stressor is related to diurnal cortisol patterns during adolescence. Participants were 105 adolescents (10-17 years of age) who experienced a robust social-evaluative stressor and provided saliva samples (before and immediately after, as well as 10, 20, and 30 min after the stressor) to assess both cortisol reactivity and recovery and also provided saliva samples (at wake-up, 30 min after wake-up, 4 pm, and at bedtime) on two consecutive days to measure diurnal cortisol production. Dual process latent growth curve models, one for cortisol reactivity and one for diurnal cortisol, indicated that dampened cortisol reactivity and prolonged cortisol recovery (i.e., less cortisol produced during reactivity but more cortisol produced during recovery) were associated with dampened decreases in cortisol production across the day, suggesting that adolescents are likely to show attenuation in multiple components of HPA axis functioning.

Transition to Kindergarten: Negative Associations between the Emotional Availability in Mother-Child Relationships and Elevated Cortisol Levels in Children with an Immigrant Background.

Background: The transition to child care is a challenging time in a child’s life and leads to elevated levels of cortisol. These elevations may be influenced by the quality of the mother–child relationship. However, remarkably little is known about cortisol production in response to the beginning of child care among children-at-risk such as children with an immigrant background. However, attending kindergarten or any other child day-care institution can for example have a compensating effect on potential language deficits thus improving the educational opportunities of these children.Method: Data of a subsample of N = 24 “hard-to-reach” mother–child dyads was collected in the context of the psychoanalytic early prevention project FIRST STEPS. The project focuses on the earliest integration of children with an immigrant background by supporting parenting capacities in the critical phase of migration and early parenthood. Children’s hair cortisol concentration (HCC) was assessed 1 week before (mean age = 38.77 months) and 3 months after kindergarten entry (mean age = 42.26 months). Hair analysis was conducted for both times of measurement, reflecting the first 3 months after kindergarten entry and 3 months prior. Furthermore, the emotional quality of the mother–child relationship was assessed with the help of the Emotional Availability Scales (EAS; Biringen, 2008) shortly before kindergarten entry when the children were about 3 years old (mean age = 37.2).Results and Conclusion: Children’s mean cumulated HCC was higher after kindergarten entry than before. The increase correlated negatively with several dimensions of the EAS. Repeated measures ANCOVA revealed that particularly responsive children and children who had experienced less intrusive mother–child relationships demonstrated lower elevations in HCC after kindergarten entry. Furthermore, a decreased EA score was found in all EA dimensions, besides the dimension “mother’s non-hostility,” indicating problematic EA within the mother–child relationships of the sample. The results suggest that children with an immigrant background who experience more emotional available mother–child relationships seem to regulate stress induced by kindergarten entry more effectively, indicated by lower cortisol elevations after entry. This implicates that supporting early mother–child relationships by intervention may have a positive effect on the children’s ability to regulate stress induced by kindergarten entry thus promoting child development.

The utility of the corticotropin test to diagnose adrenal insufficiency in critical illness: an update.

One of the most common dynamic testing procedures for assessment of adrenocortical function is the standard corticotropin or the cosyntropin test. The aim of this review was to examine the evidence base underlying the corticotropin test in the management of the critically ill patient. The principle behind the corticotropin test is the demonstration of an inappropriately low cortisol production in response to exogenous ACTH, a situation analogous to physiological stress. The corticotropin test was originally described in nonstressed subjects, and its applicability and interpretation in the setting of critical illness continues to generate controversy. Attempting to determine the prevalence of an abnormal corticotropin test in critical illness is complicated by the use of different end-points and different populations. Moreover, the test result is also influenced by the assay used for measurement of plasma cortisol. Trials assessing the relationship between corticotropin response and severity of stress and organ dysfunction have produced divergent results, which may reflect differences in the methodology and the association being measured. Moreover, controversy exists with respect to the methodology and the interpretation with respect to the following variables: dose of corticotropin, end-points for assessment of total or free cortisol, effect of plasma cortisol variability, adrenal blood flow and its equivalence with other tests of adrenocortical function. The corticotropin test is used widely in the evaluation of adrenocortical function in the endocrine clinics. Its role in the critically ill patient is less well established. Several confounding variables exist and to have a 'one-size-fits-all' approach with a single end-point in the face of several methodological and pathophysiological confounders may be flawed and may result in the institution of inappropriate therapy. The current evidence does not support the use of the corticotrophin test in critical illness to assess adrenocortical function and guiding steroid therapy in critical illness.

Assessment of the changes in the stress-related salivary cortisol levels to the various dental procedures in children.

Fear and pain are the factors producing stress and there is evidence that dental fear acquired in childhood may persist to influence adult behavior. Dental treatment is often considered as anxiety producing and stressful. To assess the levels of stress displayed by the healthy children undergoing routine dental procedures like oral examination, restoration, and extraction by analyzing salivary levels of cortisol before, during, and after the procedures. Twenty healthy children aged between 4 and 8 years having their first dental visit and requiring at least one restoration and one extraction were selected. In each patient, three procedures were carried out: (i) Routine dental examination, (ii) restoration, and (iii) extraction. Unstimulated salivary samples were collected 10 min before, during the procedure, and 30 min after each procedure at three different visits for comparison of cortisol production in response to anxiety and stress over time. Total 180 samples were collected to determine salivary cortisol levels using UBI-MAGIWEL TM kit and the readings were noted. Statistical Package for Social Sciences (SPSS) software with paired t-test, two independent sample t-tests, and analysis of variance (ANOVA) were used to analyze the findings. A correlation between salivary cortisol and stress in dental procedure was noticed. Cavity preparation is more stressful procedure in children, so alternative methods can be used in anxious children. Stress associated with extraction persists to a postoperative period. No correlation exists in between Corah's anxiety scale and salivary cortisol.

Effect of &amp;lt;i&amp;gt;Ginkgo biloba&amp;lt;/i&amp;gt; Extract Ingestion on Plasma Total Cortisol Levels during an Oral Glucose Tolerance Test in Normal Glucose Tolerant Individuals

Protracted periods of increased cortisol production, as may be seen in an acute illness, may lead to transient hyperglycemia. Increasing evidence suggests that cortisol may then mediate the development of insulin resistance and potentially lead to the development of overt diabetes. Evidence in animal studies also suggests that under conditions of stress Ginkgo biloba extract could reduce plasma cortisol production and so the primary aim of this study was to determine the effect of Ginkgo biloba extract ingestion on plasma cortisol production during an acute period of glucose challenge. Healthy non-diabetic, glucose tolerant volunteers (n = 30, (10/20, M/F); age, 45.7 ± 9.9 years old) completed a randomized, double-blind, placebo-controlled crossover study when they ingested Ginkgo biloba extract (120 mg/day as a single dose) and placebo during each 3-month arm. A standard 75 g oral glucose tolerance test was performed at the end of each cycle and blood was collected and used to measure plasma glucose, insulin, c-peptide and cortisol. Fasting plasma cortisol was significantly lower after the Ginkgo biloba cycle than the placebo cycle (326 ± 149 vs. 268 ± 121 nmol/L, respectively; p = 019). The plasma cortisol area under the curve during the 2-hour test (AUC0-2) was also significantly lower after ingestion of the Ginkgo biloba cycle compared to the placebo (668 ± 265 vs. 530 ± 213 nmol/L/h, respectively; p Ginkgo biloba extract has effect on the hypothalamic-pituitary-adrenal axis leading to reduced basal cortisol levels and reduced cortisol production in response to acute hyperglycemic challenge.

Restoring the Salivary Cortisol Awakening Response Through Nasal Continuous Positive Airway Pressure Therapy in Obstructive Sleep Apnea

Partial and largely conflicting data are currently available on the interplay between obstructive sleep apnea (OSA) and hypothalamus-pituitary-adrenal axis (HPA) activity in adult obese men. This study was performed to evaluate the daily trajectories of salivary cortisol, specifically with respect to the salivary cortisol awakening response (CAR), a common method used to assess HPA axis activity. The main findings of this study were that adult male obese subjects who were newly diagnosed with severe OSA showed the following: (1) a flattening of the CAR; (2) levels of cortisol at awakening that were lower than those of the controls; and (3) maintenance of the physiological circadian activity of the HPA axis, with the highest hormone concentrations produced in the morning and the lowest in the evening. This study was also designed to investigate the effects of 3 and 6 mos of treatment with continuous airways positive pressure (CPAP). CPAP use resulted in a significant recovery of the sleep patterns disrupted by OSA; moreover, mild neuropsychological signs of depression and anxiety in severe OSA patients were concomitantly progressively improved by CPAP treatment. Furthermore, this study reports that 3 and 6 mos of CPAP therapy restored the presence of CAR and was able to significantly reduce the difference in the morning cortisol levels between the OSA and control groups. In conclusion, we report here that compared with obese nonapneic matched controls, OSA patients present a dysregulation of HPA axis activity, as shown by the flattening of the diurnal pattern of cortisol production in response to repeated challenge due to hypoxia and sleep fragmentation. This dysregulation was especially detectable in the first hour after awakening and restored after 3 and 6 mos of treatment with CPAP.

145. Temporal associations between IL-6 and cortisol production in response to acute psychosocial stress

Objective Although it is known that there is a temporal, regulatory relationship between cortisol and IL-6, it has not yet been established that such a relationship extends to the neuroendocrine and immune responses to acute psychosocial stress. Methods Healthy adult participants underwent the Trier Social Stress Test. IV blood samples were collected before and after the test (time points 0, +15, +30, +45, +60, +75, +90), and emotional ratings were completed. Results Lower plasma cortisol concentration at time point 0 was correlated with higher IL-6 concentrations at time points +60 and +75 (p = 0.001; p = 0.001). Lower plasma cortisol at time point +15 was also correlated with higher IL-6 at time points +60 and +75 (p Conclusion Subjects with lower baseline plasma cortisol concentrations generated a greater IL-6 response one hour after initiation of the TSST. Greater change in depressive mood, higher BMI, and female gender also contributed to elevated IL-6 response to the TSST. These results suggest that the temporal regulatory relationship between cortisol and IL-6 persists even in the context of acute psychosocial stress.

Alterations in stress responses of the hypothalamic-pituitary-adrenal axis in small for gestational age infants

Mounting epidemiologic evidence and animal models suggest that stressful conditions during the intrauterine period may increase susceptibility to several adult conditions, including metabolic syndrome, cardiovascular disease, and psychiatric disorders. Increased cortisol levels due to alterations in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis are believed to be one mediating mechanism. Infants born after significant exposure to stressful conditions are often small for gestational age (SGA) based on standardized growth norms. Lifelong programming of the HPA axis has been proposed as a mechanism to explain the association between SGA infants and adult disease. However, few studies have measured HPA axis function proximal to birth as done in this study of SGA infants during the first week of life. Participants included 37 infants in two groups based on birth size (gestational age range: 34-41weeks). SGA infants were <10th percentile for age (n=21) and appropriate for gestational age (AGA) infants (n=16) were from 20 to 90th percentile for age. Cortisol response to a heel lance for blood collection was measured for all infants. Hierarchical Linear Modeling was used to test the effect of AGA/SGA group status on cortisol trajectories in response to the stressor. Group was a significant predictor of quadratic slopes (t=2.84, χ(2)=8.19, p=.004) after controlling for the effect of group on intercepts and linear slopes. Predicted growth curves for ln-cortisol were plotted for each group based on regression coefficients. The predicted curves capture the significant group difference in trajectories, as well as the blunted response for the SGA group and the robust peak in cortisol production in response to the stressor for the AGA group. This evidence suggests SGA neonates have blunted HPA axis responses to stressors in comparison to AGA infants. These findings are consistent with animal models showing that adverse intrauterine conditions can result in blunted cortisol responses to acute stressors and may provide a mechanism for adult susceptibility to disease for individuals that are SGA at birth.

Retrospective Evaluation of the Dexamethasone Suppression Test as a Predictor of Response to Electroconvulsive Therapy in Patients With Comorbid Major Depressive Disorder and Posttraumatic Stress Disorder

There is evidence that response to dexamethasone suppression test (DST) can be predictive of treatment outcomes in major depressive disorder (MDD). The purpose of this study was to explore if DST response, at both 1 and 0.5 mg of dexamethasone doses, is predictive of the effectiveness of electroconvulsive therapy (ECT) in depression symptom reduction in patients with comorbid posttraumatic stress disorder (PTSD) and MDD who are treated with ECT. We performed a chart review of all patients with both PTSD and MDD receiving ECT from January 2002 through December 2008, who had DST performed before starting ECT. A total of 32 patients meeting these criteria were identified. Those patients were divided into 3 groups based on their response to the DST: enhanced suppressors (n = 13), normal suppressors (n = 14), and nonsuppressors (n = 5). Posttraumatic stress disorder and MDD outcomes after completion of the primary ECT treatment series were measured. Results were stratified by pretreatment DST responses. Nonsuppressors showed significantly more response to ECT, in both MDD and PTSD symptom scales, as compared with normal suppressors and enhanced suppressors. Normal suppressors showed significantly more response to ECT than enhanced suppressors. Electroconvulsive therapy did not appear to be effective in depression symptom reduction for enhanced suppressors. This study suggests that DST results may be predictive of depression symptom reduction in response to ECT in patients with comorbid PTSD and MDD, with patients suppressing morning cortisol production in response to 0.5 mg of dexamethasone showing little improvement. In addition, this study lends further evidence that ECT is an effective treatment for some patients with comorbid MDD and PTSD.

Psychopathic personality traits and cortisol response to stress: The role of sex, type of stressor, and menstrual phase

Previous research indicates that psychopathic personality traits are associated with lower cortisol secretion in response to stress in men but not in women. The current study explored whether prior null results for women were related to the latency of the cortisol stress response to two different types of stressors. Additionally, accuracy of self-reported menstrual phase was explored via salivary progesterone levels. A mixed-sex sample of 145 participants characterized by high (36 men, 37 women) and low (34 men, 38 women) scores on a screening measure of psychopathic personality traits were randomly assigned to either a performance-based stressor task or a social rejection stressor task. Salivary hormone samples were taken just prior to task onset (baseline) and at 0, 20, 40, and 60 min post-stressor. Results indicated that both men and women characterized by psychopathic personality traits exhibited lower stress-induced cortisol levels to the performance-based task in comparison with controls at 20 min post-stressor. The social rejection task produced a cortisol response 20 min post-stressor in the male controls only. Removal of women with low progesterone from the analyses strengthened the psychopathy group differences. Results could suggest that deficient cortisol production in response to stress might be another important neurobiological feature associated with psychopathic traits, and that biological verification of menstrual phase is an important aspect to obtaining accurate cortisol results in women.

Effects of endogenous and exogenous hypercortisolemia on low-dose adrenocorticotropin test outcome in humans

The results of low-dose ACTH testing may be impaired during endogenous or exogenous hypercortisolemia in various clinical situations. The hypothesized inhibitory effects of hypercortisolemia on adrenal responsiveness to low-dose ACTH were tested in two model situations in healthy humans. Nine young healthy women underwent low-dose ACTH test in 5 modifications. In ACTH-ACTH test, ACTH (1 microg iv) was given at 09:00 h and 10:00 h. Two control tests consisted of single ACTH bolus at 09:00 h or at 10:00 h. In hydrocortisone (HC)-ACTH test, HC (20 mg po) was given at 08:30 h and ACTH was injected at 10:00 h. Control test consisted of single HC administration at 08:30 h. Cortisol response after the 2nd ACTH test was significantly lower vs the 1st ACTH bolus (Deltamax: 166+/-32 nmol/l vs 276+/-15 nmol/l, p<0.05) in ACTH-ACTH test. Responses of other steroids after both ACTH injections were comparable. ACTH bolus during HC-induced hypercortisolemia caused a slight increase in cortisol level and prevented its decrease, seen after HC administration alone. Adrenal cortisol production in response to ACTH bolus under different incipient conditions (baseline, physiological, and pharmacological hypercortisolemia; 180+/-16, 173+/-21, and 177+/-53 nmol.min.l-1, respectively) did not significantly differ (p=0.8). Endogenous and exogenous hypercortisolemia did not influence adrenal cortisol response to low-dose ACTH test indicating lack of its negative feedback at adrenal level.

Evaluation of function and disorders of the adrenal gland in neonates

Majority of sick full term newborns have adequate adrenal cortical function in response to stress. Acutely ill neonates with a basal cortisol level less than 15 μg/dL (414 nmol/L) suggest adrenal insufficiency and require function testing of adrenal function. In premature infant, immaturity of hypothalamic-pituitary adrenal axis (HPA axis), may limit the ability to increase cortisol production in response to stress. The response to low dose ACTH and CRH appears to be useful as an additional test of adrenal function. CRH stimulation has been used increasingly in neonates. The ACTH and CRH stimulated cortisol response of more than 17 μg/dL (469 nmol/L) indicates a normal response.

Association of Hypothalamic-Pituitary-Adrenal Axis Function with Neuropsychological Performance in Children with Mild/Moderate Asthma

The present study examines the relationship between hypothalamic-pituitary-adrenal (HPA) axis function and child psychological/neuropsychological function in a group of children with mild to moderate asthma. The goal of the study was to determine whether child neuropsychological functioning and psychological functioning were associated with cortisol production in response to adrenocorticotropic hormone(ACTH) stimulation when assessed as area under the curve. Data for this study were gathered from 63 children who participated in an ancillary study within the Childhood Asthma Management Program (CAMP) during the pre-randomization phase of the CAMP trial. At 2 of the 8 CAMP clinical centers participants completed an ACTH stimulation test after an overnight stay in the General Clinical Research Center. Gender differences on baseline cortisol and change in cortisol 30 minutes after infusion of ACTH were present. Results further indicated significant associations between cortisol production and measures of child neuropsychological function. Stepwise multiple regression analysis revealed that cortisol change could be predicted by measures of gender, working memory, and arousal maintenance, providing support for the hypothesis that cortisol plays a modest role in the neuropsychological function of children with mild and moderate asthma. In contrast, cortisol production was not associated with child reports of psychological functioning. Limitations to the methods employed in this study are discussed.

Fetal control of parturition in marsupials.

Among marsupials, the control of birth is best understood in the tammar wallaby. The young is tiny relative to the mother and is highly altricial. Adult female tammar wallabies weigh 5 kg, whereas the neonate weighs about 400 mg. However, despite this small size, there is clear evidence that the fetus provides the signal that sets the timing of birth through several mechanisms. A fetal signal activates a nitric oxide-guanylate cyclase system in the myometrium that may maintain myometrial inactivity, and this is down-regulated at term. There is also up-regulation of prostaglandin (PG) production in the gravid endometrium during the last two days of gestation that parallels increased placental PG synthesis, and a pregnancy-specific up-regulation of oxytocin receptors in the gravid myometrium that increases the responsiveness of the gravid uterus to mesotocin. These changes facilitate parturition, but an acute fetus-derived signal appears to trigger parturition. The fetal signal is probably related to glucocorticoid production. The fetal adrenal matures and is able to synthesize cortisol by Day 22 of the 26-day gestation. The fetal adrenals double in size between Day 24 and term, and their cortisol content increases over 10-fold. The pituitary of the neonate contains presumptive corticotrophs, and the adrenals increase cortisol production in response to adrenocorticotrophin. Prostaglandin E2, which is produced by the placenta, is also a potent stimulant of fetal adrenal cortisol synthesis. Treatment of tammars in late gestation with the cortisol agonist, dexamethasone, triggers birth around 23 h later. There is thus a strong case that fetal adrenal cortisol plays a key role in the preparation for birth and the timing of it. Further studies are in progress to more clearly define the mechanisms behind these actions of cortisol.

Expression of steroidogenic enzyme messenger ribonucleic acid and cortisol production in adrenocortical cells isolated from halothane-sensitive and halothane-resistant pigs.

Stress susceptibility in pigs is inherited by a single recessive gene (Hal(n)), and homozygous individuals can be identified by exposure to halothane anesthesia. Previous studies have shown that in stress-susceptible pigs, exposure to a high ambient temperature resulted in a twofold increase in corticotropin (ACTH) and lower plasma cortisol. To determine whether there is a fundamental difference in adrenocortical function between halothane-sensitive (HAL-S) and halothane-resistant (HAL-R) pigs, independent of other factors influencing the hypothalamic-pituitary-adrenal (HPA) axis, we compared cortisol responses to ACTH and 8-bromo-cyclic AMP (8-Br-cAMP) in HAL-S and HAL-R pig adrenocortical cells in vitro. We also determined directly the accumulation of four different mRNAs encoding cholesterol side-chain cleavage cytochrome P450 (P450(scc)), 17alpha-hydroxylase cytochrome P450 (P450(17alpha)), 21-hydroxylase cytochrome P450 (P450(c21)) and 11beta-hydroxylase cytochrome P450 (P450(11beta)) in HAL-S pig adrenal cells and compared them to HAL-R pigs. A time- and dose-dependent increase in medium content of cortisol and cAMP was observed after ACTH treatment. 8-Br-cAMP also caused a time- and dose-dependent increase in cortisol production in the medium. Addition of ACTH or 8-Br-cAMP to HAL-S and HAL-R male Lanyu small-ear miniature pig adrenocortical cells increased cortisol production in a dose- and time-related manner. However, cells isolated from HAL-S pigs had a lower cortisol production in response to ACTH or 8-Br-cAMP compared to those from HAL-R pigs. Treatment of cultured cells with 8-Br-cAMP (0.5 mM) for 18 h resulted in a significant increase in P450(scc), P450(17alpha), P450(c21), and P450(11beta) mRNA levels. In the absence of 8-Br-cAMP, the four genes were expressed constitutively in both HAL-S and HAL-R pig adrenal cells. Densitometric scanning of the autoradiograph indicated that the relative amounts of P450(scc) and P450(17(alpha)) mRNAs in HAL-S pig adrenal cells were between 48% and 53% of those detected in HAL-R pig adrenal cells (P < 0.05). No difference in the amounts of P450(c21) and P450(11beta) was seen in HAL-S and HAL-R pig adrenal cells. Addition of 8-Br-cAMP (0.5 mM) resulted in a uniform increase in the levels of all four P450 mRNAs in both HAL-S and HAL-R pig adrenal cells. However, the amounts of P450(scc) mRNA in HAL-S pig adrenal cells were 67% (P < 0.05) of those measured in HAL-R pig adrenal cells, whereas the amounts of P450(17alpha ), P450(c21), and P450(11beta) mRNAs were similar in these cells. Our data suggest an HPA axis defect in HAL-S pigs at the adrenal level. This defect appears to be at the level of P450scc gene expression, which could be partially related to reduced cortisol production by ACTH stimulation.

Angiotensin II- and phorbol ester-induced steroidogenesis by ovine adrenocortical cells: effect of sex and the gonadal status of the donor animal.

1. Angiotensin II (AngII) is well recognized as a regulator of adrenal cortisol production in the sheep in vivo, but studies to date have failed to reveal this action on cultured ovine adrenocortical cells. Similarly, phorbol myristate acetate (PMA), an activator of protein kinase C, also has little effect on cortisol production from ovine adrenocortical cells in vitro. Previous studies have, however, only looked at the responses to single concentrations of AngII or PMA, but have led to the suggestion that important differences exist between adrenocortical cells of the sheep and other species. 2. We have extended previous studies by examining cortisol production by ovine adrenocortical cells over 3 h in response to a broad range of concentrations of either AngII (10(-10) to 10(-6) mol/L) or PMA (10(-10) to 10(-5) mol/L). In addition, we have investigated the possible role of gonadal factors in regulating these responses by comparing cultures derived from intact and gonadectomized male and female sheep. 3. Angiotensin II caused concentration-dependent increases (P < 0.05) in cortisol production in all cultures, with cortisol production in response to AngII being greater (P < 0.05) in cultures from intact male sheep than in the cultures from orchidectomized males or intact females. Cortisol production in response to AngII was modest in all groups (two- to 2.6-fold increases). 4. Phorbol myristate acetate elicited a concentration-dependent inhibition (P < 0.01) of basal cortisol production in adrenocortical cultures from all groups. Phorbol myristate acetate produced a greater inhibition (P < 0.05) of cortisol production in cultures from intact male sheep than either the orchidectomized males or intact females. 5. These findings demonstrate that ovine adrenocortical cells are responsive in a concentration-dependent fashion to AngII and PMA. In addition, sex and gonadal factors may play an important role in regulating the responsiveness of adrenocortical cells to these factors.