Maternal Hypothalamic-pituitary-adrenal Axis Research Articles

Pregestational Prediabetes Induces Maternal Hypothalamic-Pituitary-Adrenal (HPA) Axis Dysregulation and Results in Adverse Foetal Outcomes.

Maternal type 2 diabetes mellitus (T2DM) has been shown to result in foetal programming of the hypothalamic-pituitary-adrenal (HPA) axis, leading to adverse foetal outcomes. T2DM is preceded by prediabetes and shares similar pathophysiological complications. However, no studies have investigated the effects of maternal prediabetes on foetal HPA axis function and postnatal offspring development. Hence, this study investigated the effects of pregestational prediabetes on maternal HPA axis function and postnatal offspring development. Pre-diabetic (PD) and non-pre-diabetic (NPD) female Sprague Dawley rats were mated with non-prediabetic males. After gestation, male pups born from the PD and NPD groups were collected. Markers of HPA axis function, adrenocorticotropin hormone (ACTH) and corticosterone, were measured in all dams and pups. Glucose tolerance, insulin and gene expressions of mineralocorticoid (MR) and glucocorticoid (GR) receptors were further measured in all pups at birth and their developmental milestones. The results demonstrated increased basal concentrations of ACTH and corticosterone in the dams from the PD group by comparison to NPD. Furthermore, the results show an increase basal ACTH and corticosterone concentrations, disturbed MR and GR gene expression, glucose intolerance and insulin resistance assessed via the Homeostasis Model Assessment (HOMA) indices in the pups born from the PD group compared to NPD group at all developmental milestones. These observations reveal that pregestational prediabetes is associated with maternal dysregulation of the HPA axis, impacting offspring HPA axis development along with impaired glucose handling.

Placental corticotrophin-releasing hormone trajectories in pregnancy: Associations with postpartum depressive symptoms

ObjectiveDepressive symptoms following birth are common and can have adverse effects for mothers, children, and families. Changes in hypothalamic-pituitary-adrenal (HPA) axis regulation during pregnancy may be implicated in the development of postpartum depressive symptoms, particularly changes in placental corticotropinreleasing hormone (pCRH). However, few studies have tested how dynamic pCRH changes over pregnancy relate to postpartum depressive symptoms. This preregistered investigation tests associations of both pCRH levels and changes from early to late pregnancy with postpartum depressive symptoms. Methods: The sample consists of 173 women studied in early, mid, and late pregnancy who later reported on depressive symptoms with the Edinburgh Postpartum Depression Scale during interviews at 1, 6 and 12 months postpartum. Blood samples were collected at each prenatal timepoint and assayed for pCRH using radioimmunoassay. Latent growth curve analysis was employed to identify distinct trajectories of pCRH during pregnancy.Results: We identified three prenatal pCRH trajectories labeled as typical, flat, and accelerated. Each trajectory showed exponential increases in pCRH levels over the course of gestation but differed in overall levels and rates of change. pCRH levels were not associated with postpartum depressive symptoms. However, women with accelerated pCRH trajectories reported marginally higher depressive symptoms one month postpartum. Primary analysis models adjusted for marital status, income, prepregnancy BMI, parity, prenatal depressive symptoms, and gestational age.Conclusions: These findings add to our understanding of dynamic changes to maternal HPA axis regulation during pregnancy and contribute to growing evidence on how pCRH changes relate to the development of postpartum depressive symptoms

The Mood, Mother and Child Study: Protocol for a Prospective Longitudinal Study and Randomized Controlled Trial.

Perinatal depression affects >400,000 mother-child dyads in the United States every year and is associated with numerous adverse maternal and child developmental outcomes. Previous research implicates the dysregulation of oxytocin and the hypothalamic-pituitary-adrenal (HPA) axis functioning in mothers and children as potential mechanisms mediating or moderating the transmission of risk associated with maternal depression. The Mood, Mother and Child study will examine the psychobiological sources of risk and resilience within mother-child dyads affected by maternal depression. This manuscript describes (1) the study rationale and aims, (2) the research design and procedures and how they were altered in response to the COVID-19 pandemic, and (3) the data analysis plan to test the study hypotheses. This is a prospective longitudinal study with an embedded randomized controlled trial that examines (1) correlations among postpartum depression and anxiety symptoms, maternal and child oxytocin and HPA axis functioning, and child developmental outcomes and (2) the causal relationship between exogenous oxytocin and HPA reactivity. This study is funded by the National Institute of Child Health and Human Development with institutional review board approval. Recruitment and data collection have commenced, and the expected results will be available in 2024. Analyses are presented for testing the proposed hypotheses. The unique combination of a prospective longitudinal research design with an embedded randomized controlled trial will allow the Mood, Mother and Child study to apply a developmental lens to the study of maternal depression and anxiety symptoms from birth to middle childhood and the psychobiological mechanisms promoting risk and resiliency for both mother and child outcomes. This will be the first study that simultaneously evaluates (1) the role of oxytocin using multiple methodologies, (2) the causal relationships between exogenous oxytocin and HPA axis functioning among mothers with differing levels of depression and anxiety symptoms, and (3) the multiple mediating and moderating roles of parenting behaviors and maternal and child psychobiological characteristics. The goals of these aims are to provide insights into the psychobiological effects of oxytocin in women and inform future clinical trials to treat perinatal mood disorders. ClinicalTrials.gov NCT03593473; https://classic.clinicaltrials.gov/ct2/show/NCT03593473. DERR1-10.2196/51132.

Relations Among Mothers’ Childhood Neglect, Maternal Cortisol Hypoactivity, and Child Maltreatment in the Next Generation

There is substantial evidence that childhood maltreatment can be intergenerational, yet mechanisms responsible for this transmission are just beginning to be understood. Related evidence suggests that childhood maltreatment may lead to long-term dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, and that maternal HPA activity is associated with caregiving quality and child abuse potential. This study sought to extend prior research by testing the relations among mothers’ severity of abuse and neglect in their own childhoods, maternal HPA axis functioning assessed by mothers’ hair cortisol concentration (HCC), and mothers’ involvement with child protective services for any offspring. Fifty-one women completed a measure of childhood maltreatment and provided a hair sample for cortisol extraction during pregnancy. During pregnancy and at four months postpartum, participants provided data on their involvement with State Protective Services (SPS) at any time as a parent due to concerns about the welfare of any of their children. Two mediation models were evaluated to test whether maternal HCC mediated the association of severity of mothers’ childhood abuse (model 1) and mothers’ childhood neglect (model 2) with their family SPS involvement as a parent. Results indicated that lower maternal HCC mediated the association between mothers’ childhood neglect and SPS involvement as a parent. The indirect effect of childhood abuse severity did not reach significance. Findings extend prior work by highlighting mothers’ HPA hypoactivity as a mechanism in the intergenerational transmission of maltreatment.

Maternal glucocorticoids do not directly mediate the effects of maternal social stress on the fetus.

Stress during pregnancy negatively affects the fetus and increases the risk for affective disorders in adulthood. Excess maternal glucocorticoids are thought to mediate fetal programming; however, whether they exert their effects directly or indirectly remains unclear. During pregnancy, protective mechanisms including maternal hypothalamic-pituitary-adrenal (HPA) axis hyporesponsiveness and placental 11β-hydroxysteroid dehydrogenase (11βHSD) type 2, which inactivates glucocorticoids, limit mother-to-fetus glucocorticoid transfer. However, whether repeated stress negatively impacts these mechanisms is not known. Pregnant rats were exposed to repeated social stress on gestational days (GD) 16-20 and several aspects of HPA axis and glucocorticoid regulation, including concentrations of glucocorticoids, gene expression for their receptors (Nr3c1, Nr3c2), receptor chaperones (Fkbp51, Fkbp52) and enzymes that control local glucocorticoid availability (Hsd11b1, Hsd11b2), were investigated in the maternal, placental and fetal compartments on GD20. The maternal HPA axis was activated following stress, though the primary driver was vasopressin, rather than corticotropin-releasing hormone. Despite the stress-induced increase in circulating corticosterone in the dams, only a modest increase was detected in the circulation of female fetuses, with no change in the fetal brain of either sex. Moreover, there was no change in the expression of genes that mediate glucocorticoid actions or modulate local concentrations in the fetal brain. In the placenta labyrinth zone, stress increased Hsd11b2 expression only in males and Fkbp51 expression only in females. Our results indicate that any role glucocorticoids play in fetal programming is likely indirect, perhaps through sex-dependent alterations in placental gene expression, rather than exerting effects via direct crossover into the fetal brain.

Associations between Maternal and Offspring Hair Cortisol Concentrations and Child Behavioral Symptoms in Mother-Child Pairs with Perinatal Mental Disorders.

Maternal perinatal mental disorders (PMD) are associated with developmental and behavioral problems in children, probably mediated by the programming of the hypothalamic–pituitary–adrenal (HPA) axis. Increased cortisol concentrations during the antenatal and perinatal periods have been related to long-term effects on children’s behavior and stress response. We aimed to investigate the association of hair cortisol concentrations (HCC) between mothers, with (n = 16) and without PMD (n = 30), and their children, aged between 18 and 48 months. Participants were evaluated with a clinical interview and questionnaires for the Depression Anxiety Stress Scale and the Child Behavior Checklist for ages 1½–5. Maternal and child HCCs were compared between the two groups. Children of the PMD group had increased symptoms of attention deficit hyperactivity disorder. A positive linear association between maternal and child HCC was observed only in the total sample of mother–child dyads and the control group. In the PMD group, children’s HCCs were significantly associated with child anxiety/depression symptoms. Aggressive behavior and oppositional/defiant problems correlated significantly with children’s own HCCs, and their mother’s too. These findings suggest that a chronic dysregulation of maternal and child HPA axis and their associations in the PMD dyads may underlie the linkage among prolonged maternal stress, child behavioral/emotional problems and stress responses.

Prenatal lead exposure and childhood lung function: Influence of maternal cortisol and child sex

IntroductionMaternal hypothalamic-pituitary-adrenal (HPA) axis disruption in pregnancy may contribute to the programming of childhood respiratory disease and may modify the effect of chemical toxins, like lead (Pb), on lung development. Child sex may further modify these effects. We sought to prospectively examine associations between maternal HPA axis disruption, prenatal Pb and childhood lung function and explore potential effect modification by maternal cortisol and child sex on the association between prenatal Pb and lung function outcomes. Materials and methodsAnalyses included 222 mothers and children enrolled in a longitudinal birth cohort study in Mexico City. Maternal diurnal salivary cortisol was assessed in pregnancy; cortisol awakening response (CAR) and diurnal slope were calculated. Blood Pb was measured during the second trimester of pregnancy. Post-bronchodilator lung function was tested at ages 8–11 years. Associations were modeled using generalized linear models with interaction terms, adjusting for covariates. ResultsA higher (flatter) diurnal slope was associated with lower FEV1/FVC ratio (β: 0.433, 95%CI [-0.766, −0.101]). We did not find any main effect associations between prenatal Pb and lung function outcomes. We report an interaction between Pb and cortisol in relation to FEV1/FVC and FEF25–75% (pinteraction<0.05 for all). Higher prenatal Pb was associated with reduced FEV1/FVC only in children whose mothers had a high CAR. Higher prenatal Pb was also associated with reduced FEV1/FVC and FEF25–75% in mothers with a flatter diurnal slope. A 3-way interaction between prenatal Pb, CAR and sex on FEV1/FVC, indicated that boys born to women with high CAR and higher prenatal Pb levels had lower FEV1/FVC ratios (pinteraction = 0.067). ConclusionsAssociations between prenatal Pb and childhood lung function were modified by disrupted maternal cortisol in pregnancy and child sex. These findings underscore the need to consider complex interactions to fully elucidate effects of prenatal Pb exposure on childhood lung function.

Early and current life adversity: Past and present influences on maternal diurnal cortisol rhythms during pregnancy.

Stress during pregnancy affects maternal health and well-being, as well as the health and well-being of the next generation, in part through the hypothalamic-pituitary-adrenal (HPA) axis. Although most studies have focused solely on proximal experiences (i.e., during the pregnancy) as sources of prenatal stress, there has been a recent surge in studies that examine maternal early life adversity as a source of stress system dysregulation during pregnancy. The current study of 178 pregnant women examined the association of economic and life stress experienced during two time periods (i.e., childhood and pregnancy) with maternal HPA axis activity during the third trimester of pregnancy. Findings indicated that a current annual income of less than $15,000 and greater childhood disadvantage were associated with a flatter diurnal cortisol slope. Childhood maltreatment, particularly sexual abuse, was associated with a higher cortisol awakening response (CAR), even when controlling for recent adversity. We found some evidence that past adversity moderates the relationship between current adversity and diurnal cortisol, specifically for economic adversity and waking cortisol. Overall, our findings indicate that early life stressors play an important and underappreciated role in shaping stress biology during pregnancy.

Glucocorticoid receptor sensitivity in early pregnancy in an African American cohort.

Disruption in homeostatic feedback loops between inflammatory mediators and the hypothalamic-pituitary-adrenal (HPA) axis is a key mechanism linking chronic stress to inflammation and adverse health outcomes, including those occurring during pregnancy. In particular, alterations in glucocorticoid sensitivity may occur as a result of chronic stress, including that due to racial discrimination, and may be implicated in the persistent adverse maternal and infant health outcomes experienced by African Americans. While there are a few large-scale studies in human pregnancy that measure both cytokines and HPA axis hormones, to our knowledge, none directly measure glucocorticoid sensitivity at the cellular level, especially in an African American population. We measured the full range of the dexamethasone (DEX) dose-response suppression of TNF-α in first-trimester blood samples from 408 African American women and estimated leukocyte cell type contribution to the production of TNF-α. The mean (SD) DEX level needed to inhibit TNF-α production by 50% (ie, DEX IC50 ) was 9.8 (5.8) nmol/L. Monocytes appeared to be the main driver of Uninhibited TNF-α production, but monocyte counts explained only 14% of the variation. Monocyte counts were only weakly correlated with the DEX IC50 (r=-.11, P<.05). Moreover, there was no statistically significant correlation between the DEX IC50 and circulating pro-inflammatory (CRP, IL-6, IFN-γ) or anti-inflammatory (IL-10) mediators (P>.05). These findings challenge some prior assumptions and position this comprehensive study of glucocorticoid sensitivity as an important anchor point in the growing recognition of interindividual variation in maternal HPA axis regulation and inflammatory responses.

Effects of predation risk on egg steroid profiles across multiple populations of threespine stickleback

Predation often has consistent effects on prey behavior and morphology, but whether the physiological mechanisms underlying these effects show similarly consistent patterns across different populations remains an open question. In vertebrates, predation risk activates the hypothalamic-pituitary-adrenal (HPA) axis, and there is growing evidence that activation of the maternal HPA axis can have intergenerational consequences via, for example, maternally-derived steroids in eggs. Here, we investigated how predation risk affects a suite of maternally-derived steroids in threespine stickleback eggs across nine Alaskan lakes that vary in whether predatory trout are absent, native, or have been stocked within the last 25 years. Using liquid chromatography coupled with mass spectroscopy (LC-MS/MS), we detected 20 steroids within unfertilized eggs. Factor analysis suggests that steroids covary within and across steroid classes (i.e. glucocorticoids, progestogens, sex steroids), emphasizing the modularity and interconnectedness of the endocrine response. Surprisingly, egg steroid profiles were not significantly associated with predator regime, although they were more variable when predators were absent compared to when predators were present, with either native or stocked trout. Despite being the most abundant steroid, cortisol was not consistently associated with predation regime. Thus, while predators can affect steroids in adults, including mothers, the link between maternal stress and embryonic development is more complex than a simple one-to-one relationship between the population-level predation risk experienced by mothers and the steroids mothers transfer to their eggs.

SUN-021 Chronic Psychosocial Stress during Pregnancy Affects Maternal Behavior and Neuroendocrine Function and Modulates Hypothalamic CRH Signaling Pathway and Nuclear Steroid Hormone Receptor Expression

Postpartum depression (PPD) affects up to 20% of women and exerts adverse consequences on mother and child. Gestational stress and abnormalities in neuroendocrine function have been implicated in the development of PPD. Here, we measured effects of chronic psychosocial stress during pregnancy on maternal behavior as well as hypothalamic-pituitary-adrenal (HPA) axis function and regulation in the early postpartum period. From gestational day 6.5 to 17.5, pregnant C57Bl/6 female mice were exposed to a novel chronic stress paradigm consisting of variable psychosocial stressors such as foreign object exposure, rat odor exposure, bedding removal and were assessed from postpartum day 2 to 7 for behavioral alterations in maternal care, depression, and anxiety as well as circadian and brief restraint-stress associated corticosterone response. mRNA changes in molecular regulators of the HPA axis were measured in 1mm micropunches of the hypothalamic paraventricular nucleus (PVN) via qPCR. Mice exhibited deficits in maternal care after undergoing chronic psychosocial stress during pregnancy displayed as increased latency to retrieve pups during pup retrieval task (p<0.01, n=17). Furthermore, they displayed a depressive-like phenotype as measured by increased time spent immobile in forced swim test (p<0.01, n=17) and increased anxiety as measured by increased time spent in dark zone in light/dark transition test (p<0.05, n=7-11). Abnormalities in the activity of the maternal HPA axis were also displayed as seen by a flattening of the circadian rhythm of CORT secretion (p<0.05, n=10-12), increased CORT release following 20 minutes of restraint stress (p<0.05, n=5-8), and increased adrenal gland weights (p<0.05, n=15-20). These changes were associated with increased PVN CRH mRNA (gestational day 17.5 (G17.5): 0.880+0.18 vs. 0.485+0.03, postpartum day 2 (PP2): 1.012+0.05 vs. 0.794+0.05, PP7: 0.775+0.04 vs. 0.487+0.05, p<0.05, n=6-7) and downregulation of CRH receptor 1 (G17.5: 0.821+0.07 vs. 1.03+0.05, PP2: 1.007+0.05 vs. 1.184+0.06, p<0.05, n=6-7) compared to non-stressed control dams, while vasopressin and oxytocin levels remained undisturbed. Furthermore, PVN glucocorticoid receptor (G17.5: 0.844+0.01 vs. 0.938+0.02, p<0.01, n=6-7) and progesterone receptor mRNA were downregulated (PP2: 1.008+0.03 vs. 1.196+0.047, p<0.01, n=6-7), and FK506 binding protein 5 mRNA, a co-chaperone known to negatively orchestrate GR/PR transcriptional activity, was upregulated (G17.5: 2.322+0.37 vs. 1.315+0.05, p<0.05, n=6-7). These results suggest hypothalamic changes in GR/PR signaling pathway as putative regulators of postpartum changes in CRH after stress exposure and postpartum maternal affective dysregulation. The mechanistic role GR/PR play in mediating these changes is further being investigated by selective spatiotemporal GR/PR modulation using Cre-loxP technology.

Maternal cortisol output in pregnancy and newborn telomere length: Evidence for sex-specific effects

Newborn telomere length is a potential biomarker of the effects of maternal-fetal processes on offspring long-term health. A number of maternal psychosocial and environmental factors in pregnancy (e.g., stress, health, socioeconomic status) have been associated with shortened telomere length at birth. The physiological mechanisms responsible for potential effects of maternal factors on newborn telomere length have yet to be identified. Indirect evidence suggests that disruptions in maternal hypothalamic-pituitary-adrenal (HPA) axis functioning in pregnancy may be involved. Studies are needed that test whether maternal HPA axis functioning in pregnancy is associated with newborn telomere length. This study examined whether maternal HPA axis functioning across pregnancy, reflected in hair cortisol collected within one week after delivery, predicted newborn telomere length assessed from leukocyte cord blood collected at birth among 93 sociodemographically diverse mother-infant dyads. We further tested whether associations between maternal hair cortisol and newborn telomere length differed by infant sex, given documented sex differences in prenatal environmental exposure effects on offspring health, patterns of cortisol exposure during gestation, and telomere biology across the lifespan. In a multi-group structural equation modeling analysis that accounted for cortisol exposures across trimesters, maternal cortisol levels in pregnancy were not associated with newborn telomere length in the sample as a whole. However, significant sex differences emerged, with a significant positive association among females and a lack of a significant association among males. In addition, analyses revealed that cortisol levels were higher across trimesters among mothers of male infants than mothers of female infants. The results suggest that functioning of the maternal HPA axis in pregnancy may differ by fetal sex and have sex-specific effects on newborn telomere biology. These findings have implications for understanding the mechanisms by which maternal psychosocial and environmental exposures influence newborn telomere length and for elucidating mechanisms contributing to sex disparities in health.

Social buffering of the maternal and infant HPA axes: Mediation and moderation in the intergenerational transmission of adverse childhood experiences.

Supportive social relationships can reduce both psychological and physiological responses to stressful experiences. Recently, studies have also assessed the potential for social relationships to buffer the intergenerational transmission of stress. The majority of these studies, however, have focussed on social learning as a mechanism responsible for the intergenerational transmission of stress. Evidence of biological mechanisms is lacking. The objective of the current study was, therefore, to determine whether the association between maternal adverse childhood experiences (ACEs) and infant hypothalamic-pituitary-adrenal (HPA) axis function is mediated by maternal HPA axis function during pregnancy and moderated by social support. Data were from 243 mother-infant dyads enrolled in a prospective longitudinal cohort (the Alberta Pregnancy Outcomes and Nutrition Study). Maternal history of ACEs was retrospectively assessed while maternal perceived social support and salivary cortisol were assessed prospectively at 6-22 weeks gestation (Time 1) and 27-37 weeks gestation (Time 2), and infant cortisol reactivity to a laboratory stressor and maternal perceived social support were assessed at 5-10 months postnatal (Time 3). Results revealed that maternal HPA axis function during pregnancy mediated the effects of maternal ACEs on infant HPA axis reactivity, suggesting that the maternal HPA axis is a mechanism by which maternal early life stress is transmitted to offspring. Furthermore, social support in the prenatal and postnatal periods moderated the cascade from maternal ACEs to infant HPA axis reactivity. Specifically, prenatal social support moderated the association between ACEs and maternal HPA axis function during pregnancy, and postnatal social support moderated the association between maternal HPA axis function and infant cortisol reactivity. These findings highlight the social sensitivity of the HPA axis and suggest the utility of social relationships as an intervention target to reduce the effects of maternal early life stress on infant outcomes.

Impact of prenatal stress on mother-infant dyadic behavior during the still-face paradigm

BackgroundMother-infant interaction provides important training for the infant’s ability to cope with stress and the development of resilience. Prenatal stress (PS) and its impact on the offspring’s development have long been a focus of stress research, with studies highlighting both harmful and beneficial effects. The aim of the current study was to examine the possible influence of both psychological stress and hypothalamic-pituitary-adrenal (HPA) axis activity during pregnancy with mother-child dyadic behavior following stress exposure.MethodsThe behavior of 164 mother-infant dyads during the still-face situation was filmed at six months postpartum and coded into three dyadic patterns: 1) both positive, 2) infant protesting-mother positive, and 3) infant protesting-mother negative. PS exposure was assessed prenatally according to psychological measures (i.e., psychopathological, perceived and psychosocial PS; n = 164) and HPA axis activity measures (maternal salivary cortisol, i.e., cortisol decline and area under the curve with respect to ground (AUCg); n = 134).ResultsMother-infant dyads in both the high- and low-stress groups showed decreasing positive and increasing negative dyadic behavior in the reunion episode, which is associated with the well-known “still-face” and “carry-over” effect. Furthermore, mother-infant dyads with higher psychosocial PS exhibited significantly more positive dyadic behavior than the low psychosocial PS group in the first play episode, but not in the reunion episode. Similarly, mother-infant dyads with high HPA axis activity (i.e. high AUCg) but steeper diurnal cortisol decline (i.e. cortisol decline) displayed significantly less negative behavior in the reunion episode than dyads with low HPA axis activity. No significant results were found for psychopathological stress and perceived stress.ConclusionsThe results suggest a beneficial effect of higher psychosocial PS and higher prenatal maternal HPA axis activity in late gestation, which is in line with “stress inoculation” theories.

Maternal hypothalamic-pituitary-adrenal axis response to foraging uncertainty: A model of individual vs. social allostasis and the "Superorganism Hypothesis".

IntroductionFood insecurity is a major global contributor to developmental origins of adult disease. The allostatic load of maternal food uncertainty from variable foraging demand (VFD) activates corticotropin-releasing factor (CRF) without eliciting hypothalamic-pituitary-adrenal (HPA) activation measured on a group level. Individual homeostatic adaptations of the HPA axis may subserve second-order homeostasis, a process we provisionally term “social allostasis.” We postulate that maternal food insecurity induces a “superorganism” state through coordination of individual HPA axis response.MethodsTwenty-four socially-housed bonnet macaque maternal-infant dyads were exposed to 16 weeks of alternating two-week epochs of low or high foraging demand shown to compromise normative maternal-infant rearing. Cerebrospinal fluid (CSF) CRF concentrations and plasma cortisol were measured pre- and post-VFD. Dyadic distance was measured, and blinded observers performed pre-VFD social ranking assessments.ResultsDespite marked individual cortisol responses (mean change = 20%) there was an absence of maternal HPA axis group mean response to VFD (0%). Whereas individual CSF CRF concentrations change = 56%, group mean did increase 25% (p = 0.002). Our "dyadic vulnerability" index (low infant weight, low maternal weight, subordinate maternal social status and reduced dyadic distance) predicted maternal cortisol decreases (p < 0.0001) whereas relatively “advantaged” dyads exhibited maternal cortisol increases in response to VFD exposure.CommentIn response to a chronic stressor, relative dyadic vulnerability plays a significant role in determining the directionality and magnitude of individual maternal HPA axis responses in the service of maintaining a “superorganism” version of HPA axis homeostasis, provisionally termed “social allostasis.”

Prenatal bisphenol a exposure and dysregulation of infant hypothalamic-pituitary-adrenal axis function: findings from the APrON cohort study

BackgroundAnimal models show that prenatal bisphenol A (BPA) exposure leads to sexually dimorphic disruption of the neuroendocrine system in offspring, including the hypothalamic-pituitary-adrenal (HPA) neuroendocrine system, but human data are lacking. In humans, prenatal BPA exposure is associated with sex-specific behavioural problems in children, and HPA axis dysregulation may be a biological mechanism. The objective of the current study was to examine sex differences in associations between prenatal maternal urinary BPA concentration and HPA axis function in 3 month old infants.MethodsMother-infant pairs (n = 132) were part of the Alberta Pregnancy Outcomes and Nutrition study, a longitudinal birth cohort recruited (2010–2012) during pregnancy. Maternal spot urine samples collected during the 2nd trimester were analyzed for total BPA and creatinine. Infant saliva samples collected prior to and after a blood draw were analyzed for cortisol. Linear growth curve models were used to characterize changes in infant cortisol as a function of prenatal BPA exposure.ResultsHigher maternal BPA was associated with increases in baseline cortisol among females (β = 0.13 log μg/dL; 95% CI: 0.01, 0.26), but decreases among males (β = −0.22 log μg/dL; 95% CI: -0.39, −0.05). In contrast, higher BPA was associated with increased reactivity in males (β = .30 log μg/dL; 95% CI: 0.04, 0.56) but decreased reactivity in females (β = −0.15 log μg/dL; 95% CI: -0.35, 0.05). Models adjusting for creatinine yielded similar results.ConclusionsPrenatal BPA exposure is associated with sex-specific changes in infant HPA axis function. The biological plausibility of these findings is supported by their consistency with evidence in rodent models. Furthermore, these data support the hypotheses that sexually dimorphic changes in children’s behaviour following prenatal BPA exposure are mediated by sexually dimorphic changes in HPA axis function.

Hormonal and Neuromuscular Responses to Breastfeeding: A Pilot Study.

Difficult breastfeeding in the first weeks after birth may result in muscle tension in infants and activation of the maternal hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS). Our primary objective was to examine the feasibility of collecting neuroendocrine markers of maternal HPA axis and SNS activation (salivary cortisol and α-amylase [sAA]) and electromyographic (EMG) markers of infant distress during feeding in the first 2 weeks after birth. We also examined the relationships of these indices to each other and to mother-infant interactive behaviors during feeding. We recruited mothers in the postpartum unit of a teaching hospital and observed a feeding in the dyad's home. Cortisol and sAA were sampled before feeding, 10 min into feeding, at feeding end, and 20 min after feeding. Infant muscle activity was recorded continuously with an EMG data logger. We used the Nursing Child Assessment Feeding Scale to measure mother-infant interaction. The 20 mothers reported no disruption to breastfeeding and no change in infant behavior due to collection measures. Mean cortisol levels decreased significantly; there was no significant change in sAA levels. Relationships were found between interactive behavior and trends in neuroendocrine biomarkers. Longer bursts of infant muscle activity were associated with higher levels of maternal cortisol during feeding but not mother-infant interactive behaviors. Maternal salivary biomarkers and their association with feeding behaviors can be a useful tool for clinical longitudinal research beginning soon after birth. Infant EMG data may be useful for assessing maternal arousal.

Child MTHFR C677T genotype and HPA stress regulation at 6 years of age

Major depression is often characterized by elevated daily cortisol concentrations reflecting altered hypothalamic pituitary adrenal (HPA) regulation. A dysregulated maternal HPA axis may exert early programming effects on fetal HPA activity. The methylenetetrahydrofolate reductase (MTHFR) gene, an enzyme required for folate metabolism, has a variant (C677T) associated with depression. It remains unknown whether the C677T variant moderates the effect of antenatal maternal depression in shaping HPA function during early childhood. To study if an association between antenatal maternal mood and offspring HPA regulation may be moderated by C677T genotype, salivary cortisol concentrations were obtained from children (n=59) over four days [early morning awakening (mean 7:42 ± 0.91 h), 15 min later (8:02 ± .96 h), and evening (18:40 ± 2.35 h)]. Using a linear regression model, prenatal SRI antidepressant exposure, and maternal mood (Hamilton Depression Rating Scale) at 33 weeks and 6 years, did not predict cortisol concentrations. However, children with 677TT genotype (n=9) had higher evening cortisol concentrations (β=−0.384, P=0.004), and a smaller change from early morning to evening (β=0.292, P=0.037), compared to children with 677CC and CT. These data suggest that children with a MTHFR 677TT genotype have both elevated and altered diurnal cortisol patterns, possibly indicating HPA axis dysregulation.Supported by Canadian Institutes of Health Research, and the Human Early Learning Partnership.

Nick Hales Award Lecture 2011: glucocorticoids and early life programming of cardiometabolic disease.

Epidemiological studies have demonstrated an association between low birthweight and a range of diseases in adult life including cardiometabolic and psychiatric diseases. One of the key mechanisms proposed to underlie early life 'programming' of disease is overexposure of the developing foetus to glucocorticoids. This review will explore the data from human studies that glucocorticoids are not only mediators of programming, but also targets of programming. Cohort studies of men and women of known birthweight have demonstrated that low birthweight is associated with high fasting cortisol levels. In healthy individuals and in people with type 2 diabetes who are at high cardiovascular risk, there is a similar association between high fasting cortisol and the metabolic syndrome. The high cortisol levels appear to be due to activation of the hypothalamic-pituitary-adrenal (HPA) axis though detailed studies to further explore central negative feedback sensitivity are required. The evidence in humans that glucocorticoids mediate programming is more scanty, though changes in maternal body composition, stress and anxiety levels and activity of the placental barrier enzyme 11 β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) may all influence maternal HPA axis activity. Emerging studies are supportive that high maternal cortisol levels in humans and/or deficiencies placental 11β-HSD2 humans are associated with lower birthweight and adverse metabolic and neurocognitive outcomes in the offspring.

Changes in the Maternal Hypothalamic‐Pituitary‐Adrenal Axis During the Early Puerperium may be Related to the Postpartum ‘Blues’

Most women experience time-limited and specific mood changes in the days after birth known as the maternity blues (Blues). The maternal hypothalamic-pituitary-adrenal (HPA) axis undergoes gradual changes during pregnancy because of an increasing production of placental corticotrophin-releasing hormone (CRH). The abrupt withdrawal of placental CRH at birth results in a re-equilibration of the maternal HPA axis in the days post-delivery. These changes may be involved in the aetiology of the Blues given the central role of the HPA axis in the aetiology of mood disorders in general, and in perinatal depression in particular. We aimed to test the novel hypothesis that the experience of the Blues may be related to increased secretion of hypothalamic adrenocorticotrophic hormone (ACTH) secretagogue peptides, after the reduction in negative-feedback inhibition on the maternal hypothalamus caused by withdrawal of placental CRH. We therefore examined hormonal changes in the HPA axis in the days after delivery in relation to daily mood changes: our specific prediction was that mood changes would parallel ACTH levels, reflecting increased hypothalamic peptide secretion. Blood concentrations of CRH, ACTH, cortisol, progesterone and oestriol were measured in 70 healthy women during the third trimester of pregnancy, and on days 1-6 post-delivery. Blues scores were evaluated during the postpartum days. Oestriol, progesterone and CRH levels fell rapidly from pregnancy up to day 6, whereas cortisol levels fell modestly. ACTH concentrations declined from pregnancy to day 3 post-delivery and thereafter increased up to day 6. Blues scores increased, peaking on day 5, and were positively correlated with ACTH; and negatively correlated with oestriol levels during the postpartum days, and with the reduction in CRH concentrations from pregnancy. These findings give indirect support to the hypothesis that the 'reactivation' of hypothalamic ACTH secretagogue peptides may be involved in the aetiology of the Blues.