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In infancy, stress responses and emotion regulation are often coupled. Both are impacted by prematurity, though their relationship to one another in the case of infants born preterm is not fully understood. We investigated emotion regulation behaviours, cortisol reactivity and recovery and coupling between emotion regulation and cortisol reactivity to and recovery from a stressor in preterm infants. 53 preterm and 67 full-term infants with mean (range) gestational age at birth 29 +3 (24 +0 -31 +6 ) and 39 +3 (36 +2 -42 +0 ) weeks respectively were exposed to a socio-emotional stressor, the still-face (SF) paradigm, at 9 months of age (corrected for prematurity). The duration of negative affect and self-comforting behaviours exhibited in response to the SF, coded from a 10-minute video-taped interaction, were compared between groups. Saliva was collected from a subset (20 preterm, 24 term infants) at three timepoints: pre-SF and 20- and 30-minutes post SF. Cortisol concentrations at each timepoint were compared between groups. Associations between behavioural measures and cortisol concentrations were explored. There was no significant difference in duration of self-comforting behaviour between preterm and term infants. Preterm infants spent a significantly smaller proportion of time in a negative affective state compared to term infants (0.18 vs 0.25 s, p = 0.03). Salivary cortisol concentration was significantly higher in the preterm compared to the term group 30 min post SF (2.85 vs 1.77 nmol/L, p = 0.009), though findings were no longer significant after adjusting for time of day of sampling and socioeconomic deprivation. After controlling for time of day, greater negative affect was correlated with higher cortisol concentration 30 min post SF in the full-term (r = 0.58, p = 0.004) but not the preterm group (r = -0.01, p > 0.05). Our findings suggest altered response to an acute stressor in preterm infants, manifesting as a muted emotional response, and a lack of coupling between endocrine and behavioural stress response. Replication studies in larger samples would help to further understand biological stress repose in preterm infants and its relationship to behaviour, time of day and deprivation., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

There is a well-established bidirectional association between Type 2 diabetes and mental disorder and emerging evidence for an increased risk of perinatal mental disorder in women with gestational diabetes (GDM). However, the relation between mental disorder prior to pregnancy and subsequent risk of GDM remains relatively unexplored. This is a systematic review and meta-analysis of the risk of GDM in women with a range of preconception mental disorders. Peer-reviewed literature measuring odds of GDM and preconception mood, anxiety, psychotic and eating disorders was systematically reviewed. Risk of bias was assessed using a checklist. Two independent reviewers were involved. 22 observational studies met inclusion criteria; most were retrospective cohorts from English speaking, high income countries. 14 studies were at high risk of bias. There was evidence for an increased risk of GDM in women with schizophrenia (pooled OR 2.44; 95% CI 1.17,5.1; 5 studies) and a reduced risk of GDM in women with anorexia nervosa (pooled OR 0.63; 95% CI 0.49,0.80; 5 studies). There was some limited evidence of an increased risk in women with bipolar disorder. There was no evidence for an association with preconception depression or bulimia nervosa on meta-analysis. There were insufficient studies on anxiety disorders for meta-analysis. This review indicates that there is not a significant risk of GDM associated with many preconception mental disorders but women with psychotic disorders represent a group uniquely vulnerable to GDM. Early detection and management of GDM could improve physical and mental health outcomes for these women and their children., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Adult hair glucocorticoid concentrations reflect months of hypothalamic-pituitary-adrenal axis activity. However, little is known about the determinants of neonatal hair glucocorticoids. We tested associations between perinatal exposures and neonatal hair glucocorticoids. Cortisol and cortisone were measured by LC-MS/MS in paired maternal and infant hair samples collected within 10 days of birth (n = 49 term, n = 47 preterm), with neonatal samples collected at 6-weeks in n = 54 preterm infants. We demonstrate cortisol accumulation in hair increases with fetal maturity, with hair cortisol being higher in term than preterm born infants after delivery (median 401 vs 106 pg/mg; p < 0.001). In term born infants, neonatal hair cortisol is positively associated with maternal hair cortisol concentration (β = 0.240, p = 0.045) and negatively associated with birthweight z-score (β = -0.340, p = 0.006). Additionally, being born without maternal labour is associated with lower hair cortisol concentrations (β = -0.489, p < 0.001) and a lower ratio of cortisol to cortisone (β = -0.484, p = 0.001). In preterm infants, histological chorioamnionitis is associated with a higher cortisol to cortisone ratio in hair (β = 0.459, p = 0.001). In samples collected 6 weeks after preterm birth, hair cortisol concentration is associated with cortisol hair concentrations measured after birth (β = 0.523, p < 0.001), chorioamnionitis (β = 0.250, p = 0.049) and postnatal exposures including intravenous hydrocortisone therapy (β = 0.343, p < 0.007) and neonatal sepsis (β = 0.290, p = 0.017). In summary, neonatal hair cortisol is associated with birth gestation, maternal hair cortisol concentration and fetal growth. Additionally, exposures at delivery are important determinants of hair cortisol, and should be considered in the design of future research investigating how neonatal hair cortisol relates to prenatal exposures or fetal development., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Basic military training (BMT) is a useful model of prolonged exposure to multiple stressors. 8-12 week BMT is associated with perturbations in the hypothalamic-pituitary-adrenal (HPA) axis which could predispose recruits to injury and psychological strain. However, characterisations of HPA axis adaptations during BMT have not been comprehensive and most studies included few if any women., Methods: We studied women undertaking an arduous, 44-week BMT programme in the UK. Anxiety, depression and resilience questionnaires, average hair cortisol concentration (HCC), morning and evening saliva cortisol and morning plasma cortisol were assessed at regular intervals throughout. A 1-h dynamic cortisol response to 1 μg adrenocorticotrophic hormone-1-24 was performed during weeks 1 and 29., Results: Fifty-three women (aged 24 ± 2.5 years) completed the study. Questionnaires demonstrated increased depression and reduced resilience during training (F 6.93 and F 7.24, respectively, both p < 0.001). HCC increased from 3 months before training to the final 3 months of training (median (IQR) 9.63 (5.38, 16.26) versus 11.56 (6.2, 22.45) pg/mg, p = 0.003). Morning saliva cortisol increased during the first 7 weeks of training (0.44 ± 0.23 versus 0.59 ± 0.24 μg/dl p < 0.001) and decreased thereafter, with no difference between the first and final weeks (0.44 ± 0.23 versus 0.38 ± 0.21 μg/dl, p = 0.2). Evening saliva cortisol did not change. Fasting cortisol decreased during training (beginning, mid and end-training concentrations: 701 ± 134, 671 ± 158 and 561 ± 177 nmol/l, respectively, p < 0.001). Afternoon basal cortisol increased during training while there was a trend towards increased peak stimulated cortisol (177 ± 92 versus 259 ± 13 nmol/l, p = 0.003, and 589 ± 164 versus 656 ± 135, p = 0.058, respectively)., Discussion: These results suggest a normal stress response in early training was followed quickly by habituation, despite psychological and physical stress evidenced by questionnaire scores and HCC, respectively. There was no evidence of HPA axis maladaptation. These observations are reassuring for women undertaking arduous employment., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)

Background Maternal early pregnancy overweight (body mass index [BMI] 25.0-29.9 kg/m 2 ) and obesity (BMI ≥ 30 kg/m 2 ) are associated with mental and physical health adversities in the offspring. Prenatal programming of the hypothalamic-pituitary-adrenal (HPA) axis has been put forward as one of the mechanisms that may play pathophysiological role. However, evidence linking maternal overweight and obesity with offspring HPA-axis activity is scarce. We studied if maternal early pregnancy BMI is associated with diurnal salivary cortisol, a marker of HPA-axis activity, in young adult offspring. Methods At a mean age of 25.3 (standard deviation [SD) = 0.6) years, 653 Arvo Ylppö Longitudinal Study participants collected saliva samples for cortisol analyses, at awakening, 15 and 30 min thereafter, 10:30AM, 12:00PM, 5:30PM and at bedtime. Maternal BMI was calculated from weight and height verified by a measurement in the first antenatal clinic visit before 12 weeks of gestation derived from healthcare records. Results Per each one kg/m 2 higher maternal early pregnancy BMI offspring diurnal average salivary cortisol was -1.4% (95% CI:-2.6, -0.2, p FDR  = 0.033) lower, at awakening it was -2.4% (95% CI:-4.0, -0.7, p FDR  = 0.025) lower and the morning average salivary cortisol was -2.0% (95% CI:-3.4, -0.5, p FDR =0.017) lower. These associations were independent of the offspring's own young adulthood BMI, and other important covariates. Conclusion Our findings show that young adult offspring born to mothers with higher early pregnancy BMI show lower average levels of diurnal cortisol, especially in the morning. Whether these findings reflect prenatal programming of the offspring HPA-axis activity warrants further investigation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: Corticosteroid-binding globulin (CBG) transports glucocorticoids in blood. Variation in genes SERPINA6 encoding for CBG, SERPINA2 and SERPINA1 (serpin family A member 6, 2, and 1) have been shown to influence morning plasma cortisol and CBG in adults. However, association of this genetic variation with diurnal and stress-induced salivary cortisol remain unknown. This study aims to investigate the effect of genetic variation in SERPINA6/2/1 loci on diurnal and stress-induced salivary cortisol in children., Methods: We studied 186, 8-year-old children with genome-wide genotyping. We generated weighted polygenic risk score (PRS) based on 6 genome-wide significant SNPs (rs11621961, rs11629171, rs7161521, rs2749527, rs3762132, rs4900229) derived from the CORNET meta-analyses. Salivary cortisol was measured across one day and in response to the Trier Social Stress Test for Children (TSST-C)., Results: Mixed models, adjusted for covariates, showed that the PRS x sampling time interactions associated with diurnal (P < 0.001) and stress-induced (P = 0.009) salivary cortisol. In the high PRS group (dichotomized at median) the diurnal salivary cortisol pattern decreased less from awakening to bedtime than in the low PRS group (standardized estimates of sampling time -0.64 vs. -0.73, P < 0.0001 for both estimates). In response to stress, salivary cortisol increased in the high PRS group while it remained unchanged in the low PRS group (standardized estimates of sampling time 0.12, P = 0.015 vs. -0.06, P = 0.16). These results were mainly driven by minor alleles of rs7161521 (SERPINA6) and rs4900229 (SERPINA1)., Conclusions: Genetic variation in SERPINA6/2/1loci may underpin higher hypothalamic-pituitary-adrenocortical axis activity in children., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Psychosocial stress during pregnancy has been proposed as a major contributor of glucocorticoid-mediated programming of the fetal hypothalamic-pituitary adrenal (HPA) axis, with later adverse health consequences. However, evidence linking maternal stress to maternal cortisol values during pregnancy is inconclusive. A possible explanation for this is that other maternal factors overshadow any potential effects of stress on cortisol levels. We studied a large cohort of pregnant women with extensive data on pregnancy characteristics to determine the respective contributions of biological, environmental and psychosocial stress factors to cortisol levels in pregnancy., Methods: We used data from 3039 women from the Amsterdam Born Children and their Development-study cohort. Serum cortisol was measured in blood, collected at the first prenatal visit, at different gestational ages (median=91days, range=40-256days), and at various time points during the day (median=11:45h, range=08:00-18:30h). We assessed associations between maternal serum cortisol in pregnancy and biological factors, lifestyle factors and stress factors, including depression, anxiety, pregnancy-related anxiety, work stress, parenting stress and fatigue., Results: In multivariable analysis, variables that were associated with higher cortisol levels in pregnancy were lower maternal age [1.5nmol/l, 95%CI (0.6-2.4)], being nulliparous [21.5 nmol/l (15.9-27.1)], lower pre-pregnancy body mass index (BMI) [1.3nmol/l (0.3-2.4)], higher C-reactive protein (CRP) [1.0nmol/l (0.4-1.5)], carrying a female fetus [9.2nmol/l (1.8-16.5)], non-smoking [14.2nmol/l (0.6-27.7)], sufficient sleep [8.5nmol/l (0.9-16.1)], and being unemployed [12.7nmol/l (2.2-23.2)]. None of the psychosocial stressors was significantly associated with serum cortisol levels in pregnancy. A total of 32% of all variance in cortisol was explained by gestational age, maternal age, time of day, parity, pre-pregnancy BMI, CRP, fetal sex, smoking behavior, self-reported sleep sufficiency, and employment., Conclusions: Our data suggest that maternal cortisol during pregnancy is mainly affected by biological and lifestyle factors, but not by psychosocial factors. We suggest that psychosocial stress in pregnancy might program the fetus through other mechanisms than through altering maternal cortisol levels., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Prenatal programming of hypothalamic-pituitary-adrenal (HPA) axis activity has long term implications for offspring health. Biological mechanisms underlying programming of the offspring HPA axis are poorly understood. We hypothesised that altered maternal metabolism including higher maternal obesity, glucose and lipids are novel programming factors for altered offspring HPA axis activity. Salivary cortisol levels were measured in 54 children aged 3-5 years under experimental conditions (before and after a delay of self-gratification test). Associations of child cortisol responses with maternal obesity in early pregnancy and with fasting glucose, triglycerides, HDL and total cholesterol measured in each pregnancy trimester were tested. Higher levels of maternal triglycerides and total cholesterol throughout pregnancy were associated with increased offspring cortisol reactivity. The associations were independent of maternal obesity and other confounders, suggesting that exposure to maternal lipids could be a biological mechanism of in utero programming of the offspring's HPA axis., (Copyright © 2017. Published by Elsevier Ltd.)

Background: The maternal hypothalamic-pituitary-adrenal-axis (HPAA) undergoes dramatic activation during pregnancy. Increased cortisol and corticotrophin-releasing-hormone (CRH) associate with low birthweight and preterm labor. In non-pregnant obesity, the HPAA is activated but circulating cortisol levels are normal or lower than in lean women. We hypothesized that maternal cortisol levels would be lower in obese pregnancy, and would associate with increased fetal size and length of gestation., Method: Fasting serum cortisol was measured at 16, 28 and 36 weeks gestation and at 3-6 months postpartum in 276 severely obese and 135 lean women. In a subset of obese (n=20) and lean (n=20) we measured CRH, hormones that regulate bioavailable cortisol (corticosteroid-binding-globulin, estradiol, estriol, and progesterone). Urinary glucocorticoid metabolites were measured in pregnant (obese n=6, lean n=5) and non-pregnant (obese n=7, lean n=7) subjects., Results: Maternal cortisol and HPAA hormones were lower in obese pregnancy. Total urinary glucocorticoid metabolites increased significantly in lean pregnancy, but not in obese. Lower maternal cortisol in obese tended to be associated with increased birthweight (r=-0.13, p=0.066). In obese, CRH at 28 weeks correlated inversely with gestational length (r=-0.49, p=0.04), and independently predicted gestational length after adjustment for confounding factors (mean decrease in CRH of -0.25 pmol/L (95% CI -0.45 to -0.043 pmol/L) per/day increase in gestation)., Conclusion: In obese pregnancy, lower maternal cortisol without an increase in urinary glucocorticoid clearance may indicate a lesser activation of the HPAA than in lean pregnancy. This may offer a novel mechanism underlying increased birthweight and longer gestation in obese pregnancy., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Maternal emotional distress symptoms, including life satisfaction, anxiety and depressed mood, are worse in Severely Obese (SO) than lean pregnancy and may alter placental genes regulating fetal glucocorticoid exposure and placental growth. We hypothesised that the associations between increased maternal distress symptoms and changes in placental gene expression including IGF2 and genes regulating fetal glucocorticoid exposure are more pronounced in SO pregnancy. We also considered whether there were sex-specific effects. Placental mRNA levels of 11β-HSDs, NR3C1-α, NR3C2, ABC transporters, mTOR and the IGF2 family were measured in term placental samples from 43 lean (BMI≤25kg/m(2)) and 50 SO (BMI≥40kg/m(2)) women, in whom distress symptoms were prospectively evaluated during pregnancy. The mRNA levels of genes with a similar role in regulating fetal glucocorticoid exposure were strongly inter-correlated. Increased maternal distress symptoms associated with increased NR3C2 and IGF2 isoform 1(IGF2-1) in both lean and SO group (p≤0.05). Increased distress was associated with higher ABCB1 and ABCG2 mRNA levels in SO but lower ABCB1 and higher 11β-HSD1 mRNA levels in lean (p≤0.05) suggesting a protective adaptive response in SO placentas. Increased maternal distress associated with reduced mRNA levels of ABCB1, ABCG2, 11β-HSD2, NR3C1-α and IGF2-1 in placentas of female but not male offspring. The observed sex differences in placental responses suggest greater vulnerability of female fetuses to maternal distress with potentially greater fetal glucocorticoid exposure and excess IGF2. Further studies are needed to replicate these findings and to test whether this translates to potentially greater negative outcomes of maternal distress in female offspring in early childhood., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Stress and inflammation are thought to play a role in the risk of developing a psychotic disorder. We aimed to identify stress-related biomarkers for psychosis transition in help-seeking individuals with an at-risk mental state (ARMS). We studied 39 ARMS subjects who were attending an Early Intervention Service. We included a control group of 44 healthy subjects (HS) matched by sex and age. Stressful life events and perceived stress were assessed. Stress-related biomarkers were determined in serum (cortisol, prolactin, C-reactive protein and albumin), plasma (fibrinogen) or saliva (morning cortisol, cortisol awakening response). All ARMS were followed-up at our Unit for at least one year. We divided the ARMS group into two subgroups based on the development of a psychotic disorder (ARMS-P, N = 10) or not (ARMS-NP, N = 29). ARMS-P reported more stressful life events and perceived stress than HS and ARMS-NP groups. In relation to baseline stress biomarkers, ARMS-P subjects had increased prolactin and lower albumin levels in serum, when compared to ARMS-NP and HS groups. These results did not change when repeated in a subsample of antipsychotic-naïve ARMS subjects. We also found significant differences between groups in the cortisol secretion after awakening. In a multinomial logistic regression adjusting for age, sex and life stress, prolactin was a predictor of psychosis transition whereas albumin levels had a protective effect. Our study underscores the role of stress and stress-related biomarkers (cortisol awakening response, prolactin and albumin) in the pathogenesis of psychosis., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Little is known about the associations between physical activity (PA) and hypothalamic-pituitary-adrenocortical axis (HPAA) activity in adolescents. This knowledge could offer insight into the links between PA and well-being in youth. We studied whether objectively-measured PA is associated with diurnal salivary cortisol responses and morning salivary cortisol responses after a low-dose overnight dexamethasone suppression test (DST) in adolescent girls and boys. We conducted a cross-sectional birth cohort study in Helsinki, Finland. At a mean age of 12.4 (SD=0.5) years, 150 girls and 133 boys wore wrist-worn accelerometers over at least 4 days to measure PA. Their salivary cortisol was measured across 1 day and upon awakening after a low-dose overnight DST (3 μg/kg of weight). Girls with higher overall PA and vigorous PA (VPA), and less sedentary time had lower salivary cortisol upon awakening and/or after (decreases between |0.17| and |0.25| SDs per SD increase in overall PA, VPA and decrease in sedentary time; P-values<0.039). Boys with higher overall PA, and less sedentary time had greater suppression of salivary cortisol following overnight DST (suppression between |0.24| and |0.27| SDs per SD increase in overall PA and decrease in sedentary time; P-values<0.012). Overall PA, VPA and sedentary time did not associate with DST suppression in girls or with diurnal salivary cortisol in boys. These results show that PA is associated with altered HPAA function in early adolescents, and that the associations are sex specific., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

An unhealthy lifestyle is thought to contribute to the metabolic syndrome in subjects with psychoses. In the present study we aimed to study whether life stress or cortisol measures may influence dietary patterns in subjects with early stages of psychoses. We studied 81 subjects with early psychoses (65 subjects with a psychotic disorder [PD] and <5 years of illness; 16 subjects at risk for psychosis [high-risk, HR]) and a control group of 25 healthy subjects (HS). Dietary habits were examined by a dietician, who registered food intake (24h recall). Physical activity was assessed by validated questionnaire. Life stress was assessed with Holmes-Rahe Social Readjustment Scale. Fasting morning salivary and plasma cortisol levels were determined. We found that PD and HR reported an unhealthier lifestyle with more smoking, reduced physical activity and poorer dietary habits. HR reported increased intake of calories and saturated fatty acids and reduced protein consumption, when compared to HS. Life stress was a predictor of these adverse behaviours, although we found opposite associations in HR and PD. Life stress was associated with increased intake of refined sugar in PD and decreased intake in HR and HS. Salivary cortisol was related to increased intake of saturated fat only in HR subjects, but cortisol levels in plasma or saliva were not associated with other dietary habits or obesity measures (BMI, waist circumference). Our study suggests that unhealthy diet in early psychoses is influenced by stress, but our data do not support this effect being mediated by hypercortisolism. Future preventive interventions in psychosis may target dietary habits, particularly for those who are at risk for psychosis., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The developing foetus makes adaptations to an adverse in utero environment which may lead to permanent changes in structure and physiology, thus 'programming' the foetus to risk of ill health in later life. Epidemiological studies have shown associations between low birth weight, a surrogate marker of an adverse intrauterine environment, and a range of diseases in adult life including cardiometabolic and psychiatric disease. These associations do not apply exclusively to low birth weight babies but also to newborns within the normal birth weight range. Early life stress, including stressors in the prenatal and early postnatal period, is a key factor that can have long-term effects on offspring health. Animal studies show this is mediated through changes in the maternal and foetal hypothalamic-pituitary-adrenal axes resulting in foetal exposure to excess glucocorticoids. Data in humans are more limited but support that the biological effects of stress in utero may be transmitted through changes in glucocorticoid action or metabolism. Common contemporary physical and social stressors of maternal obesity and socio-economic deprivation impact on the maternal response to pregnancy and the prevailing hormonal milieu that the developing foetus will be exposed to. Prenatal stress may also be compounded by early postnatal stresses such as childhood maltreatment with resultant adverse effects for the offspring. Understanding of the mechanisms whereby these stressors are transmitted from mother to foetus will not only improve our knowledge of normal foetal development but will also help identify novel pathways for early intervention either in the periconceptional, pregnancy or the early postpartum period., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Dysfunctional regulation of the hypothalamic-pituitary-adrenal (HPA) axis has been proposed as an important biological mechanism underlying stress-related diseases; however, a better understanding of the interlinked neuroendocrine events driving the release of cortisol by this stress axis is essential for progress in preventing or halting irreversible development of adverse HPA-function. We aimed to investigate basal HPA-activity in a normal population in late adolescence, the time of life believed to overlap with HPA-axis maturation and establishment of a lasting set point level of HPA function. A total of 1258 participants (mean age 16.6 years) recruited from the Western Australian Pregnancy (Raine) Cohort provided fasting morning blood and saliva samples for basal HPA activity assessment. Irrespective of gender, linear regression modelling identified a positive correlation between the main components of the HPA-cascade of events, ACTH, total cortisol and free cortisol in saliva. Corticosteroid binding globulin (CBG) was inversely associated with free cortisol in saliva, an effect most clearly observed in boys. ACTH levels were lower, but cortisol levels were higher in girls than in boys. Girls may also be exposed to more bioactive cortisol, based on higher average free cortisol measured in saliva at awakening. These relatively higher female free cortisol levels were significantly reduced by oral contraceptive use, eliminating the gender specific difference in salivary cortisol. Free plasma cortisol, calculated from total circulating cortisol and CBG concentrations, was also significantly reduced in girls using oral contraceptives, possibly via an enhancing effect of oral contraceptives on blood CBG content. This study highlights a clear gender difference in HPA activity under non-stressful natural conditions. This finding may be relevant for research into sex-specific stress-related diseases with a typical onset in late adolescence., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Low birthweight, a marker of an adverse in utero environment, is associated with cardiometabolic disease and brain disorders in adulthood. The adaptive changes made by the fetus in response to the intra-uterine environment result in permanent changes in physiology, structure and metabolism, a phenomenon termed early life programming. One of the key hypotheses to explain programming, namely over exposure of the developing fetus to glucocorticoids, was proposed nearly two decades ago, following the observation that the fetus was protected from high glucocorticoid levels in the mother by the actions of the placental barrier enzyme, 11β-hydroxysteroid dehydrogenase, which converts active glucocorticoids into inactive products. Numerous mechanistic studies in animal models have been carried out to test this hypothesis using manipulations to increase maternal glucocorticoids. Overall, these have resulted in offspring of lower birthweight, with an activated hypothalamic-pituitary-adrenal (HPA) axis and an adverse metabolic profile and behavioural phenotype in adulthood. Altered glucocorticoid activity or action is a good candidate mechanism in humans to link low birthweight with cardiometabolic and brain disorders. We have carried out detailed studies in men and women showing that high levels of endogenous glucocorticoids, or treatment with exogenous glucocorticoids, is associated with an adverse metabolic profile, increased cardiovascular disease and altered mood and cognitive decline. Our laboratory carried out the first translational studies in humans to test the glucocorticoid hypothesis, firstly demonstrating in studies of adult men and women, that low birthweight was associated with high fasting cortisol levels. We went on to dissect the mechanisms underlying the high fasting cortisol, demonstrating activation of the HPA axis, with increased cortisol responses to stimulation with exogenous adrenocorticotrophin hormone, lack of habituation to the stress of venepuncture, and increased cortisol responses to psychosocial stress. We have developed new dynamic tests to dissect the mechanisms regulating HPA axis central negative feedback sensitivity in humans, and demonstrated that this may be altered in obesity, one component of the metabolic syndrome. There are now studies in humans demonstrating that high circulating levels of maternal cortisol during pregnancy correlate negatively with birthweight, suggesting that excess glucocorticoids can by-pass the placental barrier. Deficiencies in the barrier enzyme, potentially increasing fetal glucocorticoid exposure, can also arise in association with maternal stress, malnutrition and disease, and can be inhibited by consumption of liquorice, which contains glycyrrhizin, an HSD inhibitor. Importantly, studies in humans have now demonstrated that high maternal cortisol in pregnancy and/or inhibition of HSD2 are associated with programmed outcomes in childhood including higher blood pressure, behavioural disorders as well as altered brain structure. We are investigating this further, using novel magnetic resonance imaging techniques to study the developing fetal brain in utero. The translational studies in support of the glucocorticoid hypothesis, and demonstrating that glucocorticoids are both mediators and targets of programming, are exciting and raise the question of whether this information can be used to identify those individuals most at risk of later life disease. In a recent study we showed that alterations in DNA methylation at genes important in regulating cortisol levels, tissue glucocorticoid action, blood pressure and fetal growth, are present in adulthood in association with both early life parameters and cardiometabolic risk factors. These preliminary data add to the limited literature in humans indicating a persisting epigenetic link between early life events and subsequent disease risk. Such findings open novel avenues for further exploration of the contribution of glucocorticoids to later life disease., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Introduction: Some postpartum women experience intrusive thoughts of harming the infant. The hypothalamic-pituitary-adrenal (HPA) axis, which has been linked to postpartum depression, may play a role in the aetiology of postpartum thoughts of harming the infant. We aimed to study whether HPA axis hormones measured early postpartum are related to postpartum intrusive thoughts., Method: 132 women who delivered a child at a university hospital participated in a follow-up study with visits at 2-3 days postpartum and 8th week postpartum. Participants were assessed for trait anxiety, social support, peripartum or postpartum anxiety or depression, stressful life events and obstetric variables including perinatal complications and lactation. Postpartum thoughts of harming the infant were assessed with a semi-structured interview. Serum cortisol, and plasma CRH and ACTH levels were measured within 48 h postpartum at 8-9 AM. A logistic regression was performed to explore the relationship between clinical variables, hormonal measures and postpartum intrusive thoughts., Results: Patients with postpartum thoughts of harming the infant had, when compared to those women without intrusive thoughts, higher ACTH levels (7.59 pmol/L vs 5.09 pmol/L, p<0.05) without significant differences in CRH or cortisol levels. In the logistic regression analysis, adjusted for breast-feeding and psychopathological status, only ln ACTH was associated with the presence of postpartum thoughts of harming the infant (OR=5.2, CI 95% 1.2-22.6, p=0.029). No other clinical variables were associated with postpartum intrusive thoughts., Conclusions: Our study suggests that a dysregulation of the hypothalamic-pituitary-adrenal axis may play a role in the aetiology of postpartum thoughts of harming the infant., (Copyright © 2010 Elsevier Ltd. All rights reserved.)