Cortisol reactivity to stress predicts behavioral responsivity to reward moderation by sex, depression, and anhedonia.

Depression is associated with blunted reactivity to acute stress, as well as blunted responsivity to rewards. However, the extent to which responses to stress are associated with responses to reward in individuals meeting criteria for a depressive disorder is unknown. The goal of this study was to examine the relation of responses to stress and reward, and to determine if this relation is moderated by depression diagnosis, anhedonia, and sex. Participants included 114 adults (68 depressed, 46 non-depressed; 75% women) recruited from the community. Stress reactivity was operationalized as the total salivary cortisol output to the Trier Social Stress Test (TSST; Kirschbaum et al., 1993). Response bias to monetary reward was assessed following the TSST recovery period with a probabilistic reward task (PRT; Pizzagalli et al., 2005). In men only, total cortisol output during the TSST was more strongly positively associated with response bias to reward across the three blocks of the PRT. In addition, among depressed participants with high levels of anhedonia, higher cortisol output during the TSST was significantly associated with higher overall response bias to reward. We suggest that in men, the stress and reward systems may both respond quickly, and resolve rapidly, in the face of acute stress. Further, in depression, our findings suggest that anhedonia may represent a specific phenotype in which the stress and reward systems are particularly tuned together.

Sublethal, sex-specific, osmotic, and metabolic impairments in embryonic and adult round stingrays from a location exposed to environmental contamination in southern California, USA.

Organic contaminants are known to affect a suite of physiological processes across vertebrate clades. However, despite their ancient lineage and important roles in maintaining healthy ecosystems, elasmobranchs (sharks, skates, and rays) are understudied with regard to sublethal effects of contaminant exposure on metabolic processes. Perturbations resulting from contaminant exposure can divert energy away from maintaining physiological homeostasis, particularly during energetically challenging life stages, such as pregnancy and embryonic development. Using the round stingray (Urobatis halleri) as a model elasmobranch species, we captured adult males and pregnant females (matrotrophic histotrophy) and their embryos from two populations differing in their environmental exposure to organic contaminants (primarily polychlorinated biphenyls (PCBs)). Pregnant females from the PCB-exposed population experienced significant decreases from early- to late-pregnancy in tissue mass and quality not seen in reference females. PCB-exposed pregnant females also failed to maintain plasma urea concentrations as pregnancy progressed, which was accompanied by a loss in muscle protein content. Despite the energetic demands of late-term pregnancy, females had significantly greater liver lipid content than reproductively inactive adult males. PCB-exposed adult males also had high metabolic capacity (i.e., enzyme activity) for most substrate groupings of all sex-site groups, suggesting that males may be even more negatively impacted by contaminant exposure than pregnant females. Evidence that in utero exposure to PCBs via maternal offloading impairs embryo outcomes is accumulating. Embryos from the PCB-contaminated site had lower tissue quality measures and indications that sex-based differences were manifesting in utero as males had higher metabolic capacities than females. This study indicates that accumulated PCB contaminants are not physiologically inert in the stingray.

Substrates and Clearance Products of Fetal Adrenal Glucocorticoid Synthesis in Full-Term Human Umbilical Circulation.

In full-term elective caesarian sections, fetal flow of adrenal substrate steroids to products differs by sex, with males (M) in molar equilibrium whereas females (F) add net molarity and synthesize more cortisol. Using the same sampling design, paired, full-term, arterial, and venous umbilical cord samples and intrapartum chart records were obtained at the time of vaginal delivery (N = 167, 85 male) or emergency C-section (N = 38, 22 male). Eight steroids were quantified by liquid chromatography coupled to tandem mass spectrometry (adrenal glucocorticoids [cortisol, corticosterone], sequential cortisol precursor steroids [17-hydroxyprogesterone, 11-deoxycortisol], cortisol and corticosterone metabolites [cortisone and 11-dehydrocorticosterone], and gonadal steroids [androstenedione, testosterone]). Fetal sex was not significant in any analytic models. Going through both phase 1 and phase 2 labor increased fetal adrenal steroidogenesis and decreased male testosterone relative to emergency C-sections that do not reach stage 2 of labor (ie, head compressions) and elective C-sections with no labor. Sum adrenal steroid molarity arriving in venous serum was almost double the equivalent metric for deliveries without labor. No effects of operative vaginal delivery were noted. Maternal regional anesthetic suppressed venous concentrations, and fetal synthesis replaced that steroid. Approximate molar equivalence between substrate pool depletion and net glucocorticoid synthesis was seen. Paired venous and arterial umbilical cord serum has the potential to identify sex differences that underlie antenatal programming of hypothalamic-pituitary-adrenal axis function in later life. However, stage 2 labor before the collection of serum, and regional anesthetic for the mother, mask those sex differences.

Sex differences in substrates and clearance products of cortisol and corticosterone synthesis in full-term human umbilical circulation without labor: Substrate depletion matches synthesis in males, but not females.

BACKGROUND: Antenatal impacts on the hypothalamus- pituitary-adrenal axis affect health throughout later life and the impacts on developing males and females often differ. The female fetus at full-term (sampled as scheduled Caesarian section without antecedent labor) both receives more cortisol in umbilical venous blood and adds more cortisol to umbilical arterial circulation than the male. The current study was designed to expand our knowledge of sex-specific, fetal, adrenal steroid synthesis and clearance pathways. METHODS: Paired, full-term, arterial and venous umbilical cord samples were taken at the time of scheduled Caesarian delivery (N = 53, 33 male). Adrenal glucocorticoids (cortisol, corticosterone), cortisol precursor steroids (17-hydroxyprogesterone, 11-deoxycortisol), and cortisol and corticosterone metabolites (cortisone and 11-dehydrocorticosterone), as well as gonadal steroids (testosterone and androstenedione), were quantified by liquid chromatography coupled to tandem mass spectrometry. RESULTS: Both sexes preferentially added corticosterone. Males added more testosterone than females. The female fetus had higher umbilical cord (arterial and venous) concentrations of cortisol, as well as higher total steroid molarity summed across the six adrenal steroids, than males. Depletion of substrate pools of 17-hydroxyprogesterone, 11-deoxycortisol, and cortisone could account for only 20% of net female cortisol synthesis. In contrast, increased fetal synthesis of cortisol was balanced by equivalent molar depletion of substrate pools when the fetus was male. CONCLUSIONS: Preferential fetal corticosterone synthesis in both sexes, and higher concentrations of cortisol in females were confirmed. Differences in adrenal steroidogenesis pathway function in full-term males and females might underlie antenatal programming of hypothalamic-pituitary-adrenal axis function in later life.

The effect of prescribed exercise volume on biomarkers of chronic stress in postmenopausal women: Results from the Breast Cancer and Exercise Trial in Alberta (BETA).

There is epidemiologic and biologic evidence for a role of stress in breast cancer etiology and physical activity mitigates the negative effects of stress. We examined the potential for a dose-response relationship between two volumes of aerobic exercise and biomarkers of chronic stress in post-menopausal women. The Breast Cancer and Exercise Trial in Alberta is a randomized controlled trial with post-menopausal women randomized to either a MODERATE (150 min per week) or HIGH (300 min per week) volume of exercise over a one year intervention period. Fasting serum concentrations of cortisol, cortisone, corticosterone and 11-deoxycortisol at baseline, 12 months (the end of the intervention), and 24 months. Intention-to-treat analyses were performed using general linear models, adjusted for baseline biomarker concentrations. There were modest but non-statistically significant decreases in cortisol (HIGH: -4%, 95% CI: -7%, 2%; MODERATE: -1%, 95%: CI: -14%, 4%) and corticosterone (HIGH: -4%, 95% CI: -12%, 6%; MODERATE: -5%, 95% CI: -14%, 4%) concentrations for both exercise groups between baseline and 12 months, and no difference in cortisone concentrations. Intention-to-treat analysis of 386 (97%) participants showed no statistically significant group differences for changes in biomarker levels at 12 months. Between baseline and 12 months, there were no differences in cortisol or cortisone and, at 24 months all stress hormone levels increased to near-baseline levels with no significant differences between the two intervention groups.

Legacy environmental polychlorinated biphenyl contamination attenuates the acute stress response in a cartilaginous fish, the Round Stingray.

In a population of Round Stingrays (Urobatis halleri) sampled from mainland California (polychlorinated biphenyl [PCB] exposed site, n = 46), relative to a nearby offshore island (reference site, n = 34), we tested the hypothesis that stingrays from the PCB-exposed site would have a compromised stress response. Adult male and pregnant female (pregnancy = matrotrophic histotrophy), stingrays were captured via hook and line at both locations over a breeding season and plasma was sampled either immediately (Baseline, males = 10, females = 31), or after ∼5 min of struggle on the line followed by a 15 min confinement stressor (Stressed, males = 16, females = 23). Biomarkers of the primary stress response (1α-OH-corticosterone) and the secondary response (energy mobilization; glucose, glycogen, and lactate in liver and muscle) were assessed. Females from both sites demonstrated the expected primary stress response of 1α-OH-corticosterone elevation, but the contaminant-exposed males did not. PCB-exposed stingrays, regardless of sex, failed to produce a plasma glucose increase in response to the applied stress, even though the stressor increased liver glucose as expected. This suggests a dysfunction in glucose transport due to PCB exposure. The Round Stingray accumulates lower PCB loads than other, predatory elasmobranchs, and by extension, the stress axis effects could be more severely impacted in those species as well. Lay summary Legacy polychlorinated biphenyl (PCB) contamination continues to adversely affect marine life. We show that PCB-exposure interferes with the ability of pregnant female and adult male stingrays to mobilize the energy necessary to respond appropriately to an acute stress like capture. Other cartilaginous fish species, such as sharks, accumulate considerably more PCB as a result of their predatory diet, and are likely to be more adversely impacted.

Steroid concentrations in maternal serum and uterine histotroph in round stingrays (Urobatis halleri).

Despite a wide range of elasmobranch (sharks, skates and rays) matrotrophic strategies, and thus potentially diverse pathways for maternal-fetal hormone exchange, little attention has been given to uterine steroids during development. Round Stingrays (Urobatis halleri) with matrotrophic histotrophy were captured during every month of their annual reproductive season from post-ovulation to near parturition, and paired samples of plasma and histotroph were analyzed for a suite of steroid hormones using LC-ESI/MRM. Hormone concentrations within and between maternal and uterine compartments were compared using two markers of embryo development. Histotroph had consistently higher detection rates and concentrations of hormones than maternal plasma, especially during early pregnancy when embryos are yolk sac-dependent for nutrition. Peaks in histotroph testosterone concentrations preceded maternal plasma, suggesting that hormones were locally produced within the uterine compartment. Embryonic sexual differentiation based on the presence of visible claspers (male copulatory organs) coincided with peaks in histotroph progesterone, testosterone, 17-hydroxyprogesterone and estradiol, suggesting that, like mammalian pregnancy, elasmobranch embryonic steroids also contribute to their own developmental environment.

Legacy polychlorinated biphenyl contamination impairs male embryonic development in an elasmobranch with matrotrophic histotrophy, the round stingray (Urobatis halleri).

Anthropogenic chemical exposure can result in overall reductions in reproductive success. Using the round stingray (Urobatis halleri) as an elasmobranch model with internal gestation, we measured female fecundity and embryo growth from postovulation to near parturition to test the hypothesis that environmental polychlorinated biphenyl (PCB) contamination would impair reproductive success. Two sites were sampled from southern California, USA: the mainland site was exposed to legacy PCB contamination (with low exposure to other anthropogenic contaminants), and the offshore reference site at Catalina Island was a separate population with low anthropogenic influence. Contaminant-exposed embryos weighed less at each stage of development than reference embryos, while accumulating proportionately more liver mass over development. Furthermore, environmental contamination negatively affected male embryos more than female embryos. The present study is the first study to demonstrate a negative effect of contaminant exposure on elasmobranch embryo growth, with probable fitness costs later in life. Environ Toxicol Chem 2018;37:2904-2911. © 2018 SETAC.

Full-term deliveries without antecedent labor reveal sex differences in umbilical cord glucocorticoid concentrations.

BACKGROUND: Previous studies have shown that pregnant women have higher salivary cortisol levels when the fetus is female. These findings suggest a basis for the sex differences observed in many offspring outcomes after exposure to in utero stress, but it is not known if fetal adrenal glucocorticoid synthesis differs by sex. METHODS: Arterial and venous umbilical cord blood samples were collected immediately after scheduled cesarean delivery (n=52, 25 female). Cortisol and corticosterone concentrations were quantified by liquid chromatography coupled to tandem mass spectrometry. RESULTS: Sex differences were observed for fetal arterial and venous cortisol and venous corticosterone, with higher levels present when the fetus was female. However, sex differences were not observed for fetal synthesis of cortisol, suggesting that the fetus does not control the differences observed in cord blood glucocorticoids. CONCLUSIONS: The presence of sex differences in umbilical cord glucocorticoid concentrations in the absence of sex differences in glucocorticoid synthesis by the fetal adrenal gland suggests that these differences have a maternal or placental origin. Thus, the in utero glucocorticoids in circulation are sex-specific and may have developmental importance for sex differences in psychiatric and neurodevelopment disorders that display sex biases.

Human intermittent hypoxia-induced respiratory plasticity is not caused by inflammation.

Ventilatory instability, reflected by enhanced acute hypoxic (AHVR) and hypercapnic (AHCVR) ventilatory responses is a fundamental component of obstructive sleep apnoea (OSA) pathogenesis. Intermittent hypoxia-induced inflammation is postulated to promote AHVR enhancement in OSA, although the role of inflammation in intermittent hypoxia-induced respiratory changes in humans has not been examined. Thus, this study assessed the role of inflammation in intermittent hypoxia-induced respiratory plasticity in healthy humans.In a double-blind, placebo-controlled, randomised crossover study design, 12 males were exposed to 6 h of intermittent hypoxia on three occasions. Prior to intermittent hypoxia exposures, participants ingested (for 4  days) either placebo or the nonsteroidal anti-inflammatory drugs indomethacin (nonselective cyclooxygenase (COX) inhibitor) and celecoxib (selective COX-2 inhibitor). Pre- and post-intermittent hypoxia resting ventilation, AHVR, AHCVR and serum concentration of the pro-inflammatory cytokine tumour necrosis factor (TNF)-α were assessed.Pre-intermittent hypoxia resting ventilation, AHVR, AHCVR and TNF-α concentrations were similar across all three conditions (p≥0.093). Intermittent hypoxia increased resting ventilation and the AHVR similarly across all conditions (p=0.827), while the AHCVR was increased (p=0.003) and TNF-α was decreased (p=0.006) with only selective COX-2 inhibition.These findings indicate that inflammation does not contribute to human intermittent hypoxia-induced respiratory plasticity. Moreover, selective COX-2 inhibition augmented the AHCVR following intermittent hypoxia exposure, suggesting that selective COX-2 inhibition could exacerbate OSA severity by increasing ventilatory instability.

Interactions between childhood maltreatment and brain-derived neurotrophic factor and serotonin transporter polymorphisms on depression symptoms.

This study represents the first replication of the BDNF Val66Met ⁎ 5-HTTLPR ⁎ childhood maltreatment effect on self-reported depression symptoms using a rigorous maltreatment interview. Participants included a community sample of 339 adolescents/young adults (age 12-33; 265 female). In the context of childhood neglect, among BDNF Met-carriers, s-allele carriers of 5-HTTLPR reported significantly higher depression than l/l homozygotes, whereas a differential relation of 5-HTTLPR genotype to depression was not seen among BDNF Val/Val homozygotes.

Childhood emotional and sexual maltreatment moderate the relation of the serotonin transporter gene to stress generation.

Emerging evidence suggests that the tendency to generate stressful life events may be, at least in part, genetically determined. However, the role of the early environment in shaping responses to later stressors is crucial to fully specifying biogenetic models of stress generation. The current study examined the moderating role of childhood emotional, physical, and sexual maltreatment on the relation of the serotonin-transporter-linked promoter region (5-HTTLPR) polymorphism of the serotonin transporter gene to proximal independent, dependent, and dependent-interpersonal life events. This question was tested in a cross-sectional community sample of 297 adolescents and young adults. Childhood maltreatment history and proximal life events were assessed with state-of-the-art interviews that provide independent and standardized ratings of the environmental context. Consistent with the stress generation hypothesis, individuals with the risk s-allele of the serotonin transporter gene reported significantly higher rates of dependent and dependent-interpersonal life events than those homozygous for the l-allele, but only in the context of a history of maternal emotional maltreatment or sexual maltreatment. Neither serotonin transporter gene polymorphisms or childhood maltreatment, or their interaction, were associated with reports of independent life events. The current results demonstrate the importance of considering specificity in the early environmental context when examining the relation of genetic factors to the generation of proximal stress.

Chronic ethanol exposure increases the non-dominant glucocorticoid, corticosterone, in the near-term pregnant guinea pig.

Maternal-fetal signaling is critical for optimal fetal development and postnatal outcomes. Chronic ethanol exposure alters programming of the fetal hypothalamic-pituitary-adrenal (HPA) axis, resulting in a myriad of neurochemical and behavioral alterations in postnatal life. Based on a recent study which showed that human intra-partum fetal stress increased fetal secretion of corticosterone, the non-dominant glucocorticoid, this investigation tested the hypothesis that an established model of HPA axis programming, chronic maternal ethanol administration to the pregnant guinea pig, would result in preferential elevation of corticosterone, which is also the non-dominant glucocorticoid. Starting on gestational day (GD) 2, guinea pigs received oral administration of ethanol (4 g/kg maternal body weight/day) or isocaloric-sucrose/pair-feeding. Each treatment was administered daily and continued until GD 45, 55, or 65 (approximately 3 days pre-term), when pregnant animals were euthanized and fetuses delivered by Caesarean section. Maternal and fetal plasma samples were collected. After sample preparation (protein precipitation and C-18 solid phase extraction), plasma cortisol and corticosterone concentrations were determined simultaneously by liquid chromatography coupled to tandem mass spectrometry. As predicted, chronic ethanol exposure increased both fetal and maternal plasma corticosterone concentration in late gestation. In contrast, plasma cortisol did not differ across maternal treatments in maternal or fetal samples. The plasma concentration of both maternal glucocorticoids increased with gestational age. Thus, corticosterone, the non-dominant glucocorticoid, but not cortisol, was elevated by chronic ethanol exposure, which may have effects on HPA function in later life.

Cyclooxygenases 1 and 2 differentially regulate blood pressure and cerebrovascular responses to acute and chronic intermittent hypoxia: implications for sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with increased risk of cardiovascular and cerebrovascular disease resulting from intermittent hypoxia (IH)-induced inflammation. Cyclooxygenase (COX)-formed prostanoids mediate the inflammatory response, and regulate blood pressure and cerebral blood flow (CBF), but their role in blood pressure and CBF responses to IH is unknown. Therefore, this study's objective was to determine the role of prostanoids in cardiovascular and cerebrovascular responses to IH. METHODS AND RESULTS: Twelve healthy, male participants underwent three, 6-hour IH exposures. For 4 days before each IH exposure, participants ingested a placebo, indomethacin (nonselective COX inhibitor), or Celebrex(®) (selective COX-2 inhibitor) in a double-blind, randomized, crossover study design. Pre- and post-IH blood pressure, CBF, and urinary prostanoids were assessed. Additionally, blood pressure and urinary prostanoids were assessed in newly diagnosed, untreated OSA patients (n=33). Nonselective COX inhibition increased pre-IH blood pressure (P ≤ 0.04) and decreased pre-IH CBF (P=0.04) while neither physiological variable was affected by COX-2 inhibition (P ≥ 0.90). Post-IH, MAP was elevated (P ≤ 0.05) and CBF was unchanged with placebo and nonselective COX inhibition. Selective COX-2 inhibition abrogated the IH-induced MAP increase (P=0.19), but resulted in lower post-IH CBF (P=0.01). Prostanoids were unaffected by IH, except prostaglandin E2 was elevated with the placebo (P=0.02). Finally, OSA patients had elevated blood pressure (P ≤ 0.4) and COX-1 formed thromboxane A2 concentrations (P=0.02). CONCLUSIONS: COX-2 and COX-1 have divergent roles in modulating vascular responses to acute and chronic IH. Moreover, COX-1 inhibition may mitigate cardiovascular and cerebrovascular morbidity in OSA. CLINICAL TRIAL REGISTRATION URL: www.clinicaltrials.gov. Unique identifier: NCT01280006.

Stress and reproductive hormones reflect inter-specific social and nutritional conditions mediated by resource availability in a bear-salmon system.

Food availability can influence the nutritional and social dynamics within and among species. Our investigation focused on grizzly and black bears in coastal British Columbia, Canada, where recent and dramatic declines in their primary prey (salmon) raise concerns about potentially negative effects on bear physiology. We examined how salmon availability relates to stress and reproductive hormones in coastal grizzly (n = 69) and black bears (n = 68) using cortisol and testosterone. In hair samples from genotyped individuals, we quantified salmon consumption using stable isotope analysis and hormone levels by enzyme immunoassay. To estimate the salmon biomass available to each bear, we developed a spatially explicit approach based on typical bear home-range sizes. Next, we compared the relative importance of salmon consumption and salmon availability on hormone levels in male bears using an information theoretical approach. Cortisol in grizzly bears was higher in individuals that consumed less salmon, possibly reflecting nutritional stress. In black bears, cortisol was better predicted by salmon availability than salmon consumption; specifically, individuals in areas and years with low salmon availability showed higher cortisol levels. This indicates that cortisol in black bears is more strongly influenced by the socially competitive environment mediated by salmon availability than by nutritional requirements. In both species, testosterone generally decreased with increasing salmon availability, possibly reflecting a less competitive environment when salmon were abundant. Differences between species could relate to different nutritional requirements, social densities and competitive behaviour and/or habitat use. We present a conceptual model to inform further investigations in this and other systems. Our approach, which combines data on multiple hormones with dietary and spatial information corresponding to the year of hair growth, provides a promising tool for evaluating the responses of a broad spectrum of wildlife to changes in food availability or other environmental conditions.

Stress and reproductive hormones in grizzly bears reflect nutritional benefits and social consequences of a salmon foraging niche.

Physiological indicators of social and nutritional stress can provide insight into the responses of species to changes in food availability. In coastal British Columbia, Canada, grizzly bears evolved with spawning salmon as an abundant but spatially and temporally constrained food source. Recent and dramatic declines in salmon might have negative consequences on bear health and ultimately fitness. To examine broadly the chronic endocrine effects of a salmon niche, we compared cortisol, progesterone, and testosterone levels in hair from salmon-eating bears from coastal BC (n = 75) with the levels in a reference population from interior BC lacking access to salmon (n = 42). As predicted, testosterone was higher in coastal bears of both sexes relative to interior bears, possibly reflecting higher social density on the coast mediated by salmon availability. We also investigated associations between the amount of salmon individual bears consumed (as measured by stable isotope analysis) and cortisol and testosterone in hair. Also as predicted, cortisol decreased with increasing dietary salmon and was higher after a year of low dietary salmon than after a year of high dietary salmon. These findings at two spatial scales suggest that coastal bears might experience nutritional or social stress in response to on-going salmon declines, providing novel insights into the effects of resource availability on fitness-related physiology.

Postmigratory body condition and ovarian steroid production predict breeding decisions by female gray-headed albatrosses.

Carryover effects have been documented in many migratory bird species, but we know little about the physiological mechanisms that mediate those effects. Here we show that the energetic, endocrine, and aerobic characteristics of postmigratory female gray-headed albatrosses (Thalassarche chrysostoma) can affect their decision to breed. All females in this study, whether breeding or not, were secreting ovarian steroids when they arrived at the breeding colony at Bird Island, South Georgia, which suggests that all were responding to seasonal cues. However, deferring, nonbreeding birds were characterized by a steroid profile of high progesterone (P4) and low testosterone (T), whereas breeding birds showed the opposite pattern. Deferring birds also had low body mass, hematocrit, and hemoglobin. These results suggest that postmigratory condition can influence patterns of ovarian steroidogenesis and that the maintenance of high P4 without subsequent conversion to T favors breeding deferral. Whereas breeding females normally convert P4 to T, which is a key deterministic step toward 17ß-estradiol synthesis, vitellogenesis, and follicle development, deferring females did not make this conversion and instead maintained high levels of P4, perhaps due to inhibition of the hydroxylase-lyase enzyme complex, thus rendering them infertile for the current season. Results are discussed within the context of the biennial breeding system of this species, and comparisons with other biennially and annually breeding albatrosses are made.

The human fetus preferentially secretes corticosterone, rather than cortisol, in response to intra-partum stressors.

CONTEXT: Fetal stress is relevant to newborn outcomes. Corticosterone is rarely quantified in human clinical endocrinology and is found at much lower concentrations than cortisol. However, fetal corticosterone is a candidate hormone as a fetal stress signal. OBJECTIVE: Test the hypothesis that preferential fetal corticosterone synthesis occurs in response to fetal intra-partum stress. DESIGN: Cross-sectional comparison of paired serum corticosteroid concentrations in umbilical artery and vein from 300 women providing consent at admission to a General Hospital Labor and Delivery unit. Pre-term and multiple births were excluded, leaving 265 healthy deliveries. MAIN OUTCOME MEASURES: Corticosterone and cortisol concentrations determined by LC-MS/MS for umbilical cord venous (V) and arterial (A) samples and used to calculate fetal synthesis (A-V) and proportional fetal synthesis ([A-V]/V). Chart-derived criteria stratified samples by type of delivery, maternal regional analgesia, augmentation of contractions, and clinical rationale for emergent Caesarian delivery. RESULTS: Cortisol concentrations were higher than corticosterone concentrations; however, the fetus preferentially secretes corticosterone (148% vs 49% proportional increase for cortisol) and differentially secretes corticosterone as fetal stress increases. Fetal corticosterone synthesis is elevated after passage through the birth canal relative to Caesarian deliveries. For vaginal deliveries, augmentation of contractions does not affect corticosteroid concentrations whereas maternal regional analgesia decreases venous (maternal) concentrations and increases fetal synthesis. Fetal corticosterone synthesis is also elevated after C-section indicated by cephalopelvic disproportion after labor, whereas cortisol is not. CONCLUSIONS: The full-term fetus preferentially secretes corticosterone in response to fetal stress during delivery. Fetal corticosterone could serve as a biomarker of fetal stress.

Hair as a meaningful measure of baseline cortisol levels over time in dogs.

Cortisol measurements of hair are becoming a valuable tool in monitoring chronic stress. To further validate this approach in domestic dogs, we compared the variability of cortisol immunoreactivity in hair with that in saliva and feces of dogs housed under constant social and physical conditions. Fecal (n = 268), and hair (n = 21) samples were collected over 3 mo from 7 dogs housed in a kennel and kept for training veterinary students in minimally invasive procedures. Salivary samples (n = 181) were collected 3 times daily twice weekly during the last month of the study. Hair and salivary samples were analyzed by enzyme immunoassay and feces by radioimmunoassay. HPLC coupled with tandem mass spectrometry was used to confirm the presence of cortisol in 3 hair samples. Variability of cortisol was compared across sample types by using repeated-measures ANOVA followed by paired t tests. Within dogs, cortisol immunoreactivity was less variable in hair than in saliva or feces. Averaged over time, the variability of fecal samples approached that of hair when feces were collected at least 4 times monthly. As predicted, the stable social and environmental condition of the dogs maintained repeatability over time and supported the hypothesis that data from hair samples reflect baseline cortisol levels. These findings indicate that determining cortisol immunoreactivity in hair is a more practical approach than is using samples of saliva or feces in monitoring the effects of long-term stressors such as social or physical environments and disease progression.

Rumination and impaired cortisol recovery following a social stressor in adolescent depression.

Response styles theory promotes rumination as a central cognitive construct driving negative mood and depression, and past research suggests that at least part of the mechanism driving rumination's depressogenic effect is through inhibiting the individual's ability to shift attentional focus away from negative environmental stimuli. In the current study, we hypothesized that high trait rumination would be associated with impaired recovery of the body's biological response to psychological stress. In a community sample of depressed (n = 31) and non-depressed (n = 33) adolescents we assessed rumination and the more adaptive trait of distraction and problem-solving with the Children's Response Styles Questionnaire (CRSQ; Abela 2000), and diagnostic status was confirmed using the Child and Adolescent Schedule of Affective Disorders and Schizophrenia (K-SADS; Kaufman et al. Journal of the American Academy of Child and Adolescent Psychiatry 36:980-988, 1997). Participants completed the Trier Social Stress Test (TSST; Kirschbaum et al. Neuropsychobiology 28:76-81, 1993), and the focus of our analyses was the change in salivary cortisol concentration between peak cortisol output (25 min post-stressor) and a sample taken during the "Recovery" period 65 minutes post-stressor. Consistent with the predictions of response style theory, among the depressed adolescents only, high trait rumination was associated with delayed post-stressor cortisol recovery, whereas high trait distraction and problem-solving was associated with more rapid recovery. In contrast, response styles were not associated with cortisol recovery in the non-depressed group. These findings implicate impaired post-stress cortisol recovery as a potential mechanism underlying the pathological effect of rumination on the development and maintenance of Major Depressive Disorder (MDD).