Associations between maternal prenatal cortisol concentrations and child outcomes: A systematic review

A frequently proposed mechanism underlying the link between maternal prenatal stress/anxiety and child outcomes is heightened concentrations of maternal cortisol. In this systematic review, empirical findings on associations between maternal prenatal cortisol concentrations and child outcomes (physical/health, cognitive/motor, psychological/behavioral, and cortisol) are summarized. The number of empirical studies that find significant associations between maternal prenatal cortisol and child outcomes is small, but the majority of the studies that do find associations show that maternal cortisol is related to altered child outcomes (e.g. more physical/health problems, lower cognitive/motor development, more psychological/behavioral problems, and higher child cortisol concentrations). Inspection of the studies reveals possible critical gestational periods for maternal cortisol to affect different child outcomes.The heterogeneity in study designs and cortisol assessment methods makes drawing strong conclusions premature. However, the fact that most studies did not find significant associations suggests that maternal cortisol may not to be the sole or even main underlying mechanism in the relation between maternal prenatal stress/anxiety and child outcomes. Limitations of the reviewed studies are discussed, and directions for future research and reporting strategies are provided.     

Emotional stress,cortisol response,and cortisol rhythm in autism spectrum disorders: A systematic review

BackgroundThis systematic review evaluated whether there is evidence for (i) increased emotional stress levels, and (ii) a different biological stress response or rhythm [i.e., cortisol stress response, diurnal rhythm, or cortisol awakening response (CAR)] in individuals with autism spectrum disorder (ASD) relative to controls. Thirdly, the evidence for an association between emotional and biological stress in ASD was reviewed.MethodMEDLINE, Cochrane Library, and SAGE journals were searched until December 2020. In this review, there were no limitations regarding age, sex, or intelligence quotient. Studies were only reviewed if results were compared with controls without a developmental disorder. Only salivary cortisol was considered as biological stress measure.ResultsThirty-one studies were reviewed. Significantly higher self- and parent-reported emotional stress levels were found in individuals with ASD compared to controls. Regarding biological stress, the few studies in adults reported comparable cortisol stress responses and rhythms between both groups. In children/adolescents with ASD relative to controls, an increased, blunted, or similar cortisol stress response was reported, whereas the CAR did not differ in most studies, and diurnal rhythm was described as blunted or similar. Most studies found no significant association between parent-reported emotional stress and biological stress in ASD.ConclusionsCurrent findings suggest that heightened emotional stress is a clinically significant factor in ASD. To unravel the cortisol response and rhythm, research in specific subgroups within the ASD spectrum is warranted, aiming at a higher frequency of cortisol measurements, preferably combined with momentary emotional stress measurements.     

Diurnal rhythm of cortisol during late pregnancy: associations with maternal psychological well-being and fetal growth

Maternal psychological functioning during pregnancy affects both maternal and fetal well-being. The hypothalamic-pituitary-adrenal (HPA) axis provides one mechanism through which maternal psychosocial factors may be transduced to the fetus. However, few studies have examined maternal psychological factors or birth outcomes in relation to the diurnal pattern of cortisol across the day. The current study examined maternal psychological well-being, parity status, and birth weight in relation to the maternal cortisol diurnal rhythm in a group of 98 low-risk pregnant women (51 primiparae). At 36 weeks gestation, participants completed both pregnancy-specific and general self-report measures of psychological functioning and provided saliva samples at 8:00, 12:00, and 16:00h on 2 consecutive working days for the assay of cortisol. The expected diurnal decline in salivary cortisol was observed. Higher trait anxiety was associated with a flatter afternoon decline for all mothers. For primiparae, steeper morning cortisol declines were associated with lower infant birth weight. The findings suggest that regulation of the HPA axis may differ by parity status with downstream implications for fetal growth and development.     

Heritability of daytime cortisol levels and cortisol reactivity in children

Individuals differ widely in cortisol output over the day and cortisol reactivity to challenge, both of which are relevant to disease risk. There is limited evidence concerning the heritability of these differences, so we evaluated the heritability of cortisol levels in the afternoon and cortisol reactivity using a twin design. The study involved 80 monozygotic (MZ) and 70 dizygotic (DZ) same-sex twin pairs aged 11.2 years on average. Salivary cortisol was measured in the afternoon at home before and after playing a computer game. Ratings of excitement and upset were also obtained, and objective task performance was assessed. Salivary cortisol levels averaged 4.08 (S.D. 2.3) nmol/l at pretask baseline, and declined on average over the session to 3.45 (1.9) nmol/l immediately after the tasks and 2.87 (1.6) nmol/l 10min later. There were, however, marked individual differences, with cortisol reactivity (difference between pretask baseline and post-task 1) ranging from +4.53 to -6.23nmol/l. Intra-class correlations for all the cortisol parameters were substantially greater for MZ (range 0.41-0.57) than for DZ (0.11-0.29) twin pairs. Quantitative genetic modelling confirmed significant heritability for pretask baseline cortisol (58%), the two post-task values (60 and 56%), and cortisol reactivity (44%). The study lacked power for assessing sex differences. Subjective reports of excitement were also somewhat heritable, but there was little covariation of cortisol and subjective responses, so genetic influences on covariation could not be tested. These findings indicate that individual differences in children's cortisol levels recorded before tasks and cortisol reactivity to behavioural challenges are influenced by genetic factors.     

Psychological coping styles and cortisol over the day in healthy older adults

Patterns of psychological coping are associated with a variety of health outcomes but the underlying pathways are not yet established. The purpose of this study was to assess the relationship between salivary cortisol output over the course of a day and coping style. Data were available from 350 men and 192 women with an average age of 60.9 years. Participants were drawn from the Whitehall II cohort, and had no history of cardiovascular disease. Individuals who were taking medication that might affect cortisol levels were also excluded. Saliva samples were provided on waking, then 0.5, 2.5, 8 and 12 h after waking, and just before the participant went to sleep. Coping style was measured with a standard instrument, the COPE, and data were factor analysed to generate three factors: seeking social support, problem engagement and problem avoidance. The relationships between these factors and the cortisol awakening response (CAR), the slope of cortisol change over the day and total cortisol output over the day (excluding the waking period) were assessed using multiple linear regression. Cortisol output over the day was inversely associated with coping with stress by seeking social support (p=0.034) and by problem engagement (p=0.003), independently of age, gender, body mass index, smoking, depression, self-rated health, time of waking and income. Individuals who coped by problem engagement and seeking support had lower cortisol levels. Additionally, gender, BMI, smoking, self-rated health and time of waking were independently related to cortisol output over the day. There were no significant associations between coping and the CAR or cortisol slope over the day. The results indicate that adaptive coping styles are related to low levels of cortisol over the day, suggesting that neuroendocrine pathways may partly mediate relationships between psychological coping and health.     

Nocturnal melatonin and cortisol secretion in newly admitted psychiatric inpatients

Summary Melatonin secretion has been suggested as a marker of both circadian and noradrenergic dysfunction in affective disorders. Seventy-two newly admitted psychiatric inpatients [49 with major depressive disorder (MDD), 12 with schizophrenia, and 11 with intermittent depressive disorder (IDD)] underwent neuroendocrine screening at 0200, 0800, 1600 and 2300 hours prior to and the day following dexamethasone administration. All groups showed a drop in cortisol following dexamethasone. Dexamethasone nonsuppression was found in 20 of 49 patients with MDD, in none of the schizophrenics and in none of those with intermittent depressive disorder. Mean melatonin levels decreased significantly after the administration of dexamethasone across all four groups. Overall, the schizophrenic group had a significantly greater mean melatonin level than each of other three groups, whereas the three depressive groups did not differ significantly from one another. Only at 2300 hours did both the schizophrenic group and the MDD patients with normal dexamethasone suppression show significantly greater melatonin levels than the MDD patients with dexamethasone nonsuppression or the IDD group. The observed trend for a low circadian melatonin profile in IDD patients with superimposed personality disorders is puzzling.     

Diurnal pattern of cortisol output in postnatal depression

This study investigated the diurnal output of saliva cortisol in women with symptoms of depression postnatally. Twenty-one depressed and 30 non-depressed women at 7.5 weeks postpartum, and 21 non-perinatal controls, collected saliva at waking, 30 min, and 3 and 12 h postwaking. Women who were not depressed postnatally showed a pattern of cortisol secretion over the day similar to non-perinatal controls. There was a significant difference in diurnal pattern between postnatally depressed and postnatally non-depressed women, due to a difference in the first two time points (waking and +30 min): compared to the other two groups who each had a significant increase in cortisol levels from waking to +30 min, the depressed women had significantly higher cortisol levels at waking and no increase at +30 min. The lack of a morning rise in the depressed women is similar to that reported for posttraumatic stress disorder and chronic fatigue syndrome and may reflect a response, in vulnerable women, to the marked cortisol withdrawal that occurs after delivery.     

Salivary cortisol in women with and without perimenstrual mood changes

An increase in the activity of the hypothalamic–pituitary–adrenal axis (HPA axis) is frequently associated with major depression. During the premenstrual phase of their reproductive cycle some women experience depressive mood changes that are proposed to be of similar intensity to that experienced during periods of major depression. This study examined the secretion of cortisol, the end-product in the HPA axis, at different stages of the menstrual cycle in women with and without premenstrual depression. Women who experienced only mild physical and emotional changes in the premenstrual phase of their cycle had a significantly higher cortisol secretion on a premenstrual day (measured hourly) compared to a postmenstrual day. Those who were significantly more depressed premenstrually showed the opposite pattern of cortisol secretion with significantly lower levels on the premenstrual day compared with the postmenstrual day. Across the menstrual cycle, women who were significantly more depressed premenstrually also had lower evening cortisol levels in their premenstrual phase. The results of this study indicate that, unlike major depression where the underlying neurological changes are manifest as overactivity of the HPA axis, premenstrual depressive changes are associated with reduced HPA axis activity. Premenstrual depression may, therefore, be similar neurologically to seasonal affective disorder, which is associated with underactivity of the HPA axis.     

The relationship between alexithymia and salivary cortisol levels in somatoform disorders

The purpose of this study was to investigate cortisol levels as a function of the hypothalamic–pituitary–adrenal axis (HPA) in relation to alexithymia in patients with somatoform disorders (SFD). Diurnal salivary cortisol was sampled in 32 patients with SFD who also underwent a psychiatric examination and filled in questionnaires (Toronto Alexithymia Scale, TAS scale; Screening for Somatoform Symptoms, SOMS scale; Hamilton Depression Scale, HAMD). The mean TAS total score in the sample was 55.6±9.6, 32% of patients being classified as alexithymic on the basis of their TAS scores. Depression scores were moderate (HAMD=13.2, Beck Depression Inventory, BDI=16.5). The patients’ alexithymia scores (TAS scale “Difficulty identifying feelings”) correlated significantly positively with their somatization scale scores (Symptom Checklist-90 Revised, SCL-90-R); r=0.3438 (P<0.05) and their scores on the Global Severity Index (GSI) on the SCL-90-R; r=0.781 (P<0.01). Regression analysis was performed with cortisol variables as the dependent variables. Cortisol levels [measured by the area under the curve–ground (AUC-G), area under the curve–increase (AUC-I) and morning cortisol (MCS)] were best predicted in a multiple linear regression model by lower depressive scores (HAMD) and more psychopathological symptoms (SCL-90-R). No significant correlations were found between the patients’ alexithymia scores (TAS) and cortisol levels. The healthy control group (n=25) demonstrated significantly higher cortisol levels than did the patients with SFD; in both tests P<0.001 for AUC-G and AUC-I. However, the two groups did not differ in terms of their mean morning cortisol levels (P>0.05). The results suggest that pre-existing hypocortisolism might possibly be associated with SFD.     

Effects of stimulants and atomoxetine on cortisol levels in children with ADHD

Children with attention deficit hyperactivity disorder (ADHD) have lower diurnal cortisol levels than non-ADHD comparison subjects. Aiming at elucidating the effects of medications used to treat ADHD, we investigated saliva cortisol in children with ADHD: 20 without medication, 147 on methylphenidate, and 21 on atomoxetine. The only significant finding was that children on atomoxetine had higher cortisol levels at bedtime than unmedicated children.     

Diurnal cortisol responses to dextroamphetamine in normal subjects

(1) Dextroamphetamine, in doses of 0.1 and 0.15 mg/kg, was administered intravenously morning and evening to normal young men and postmenopausal women, and plasma cortisol responses were assessed. (2) There were no differences in cortisol responses between the young men and older women at either dose. (3) The higher dose elicited a significant and reliable acute cortisol release, while the lower dose did not. (4) In the evening, 0.15 mg/kg amphetamine elicited a larger cortisol increase from baseline than the same dose in the morning. (5) Within morning or evening periods, baseline cortisol values were not significantly correlated with magnitude of cortisol responses, although trends for inverse correlations were observed. (6) It is suggested that these normal diurnal differences in the acute cortisol response to amphetamine may be related to a corresponding rhythm in the responsitivity to amphetamine of neuroendocrine neurotransmitters. (7) The previously reported abnormal cortisol response to amphetamine in a group of endogenous depressives probably is not primarily related to variables of age, sex or baseline cortisol level.     

Hair as a retrospective calendar of cortisol production-Increased cortisol incorporation into hair in the third trimester of pregnancy

Hair has long been used in toxicology, forensic science, doping control and other fields as a biological specimen for the detection of environmental agents, drugs, or toxins. Most recent evidence suggests that also hormones are incorporated and trapped inside the growing hair. This has led to the hypothesis that cortisol measurement of distinct hair segments could provide a retrospective calendar of cortisol production for the individual. In this first proof-of-concept study in humans, we analyzed cortisol in hair donated by mothers with a neonate child (n-Mothers; N=103), mothers with toddlers 3-9 months of age (t-Mothers; N=19), and control women (N=20). We cut hair strands from each women into at least three 3-cm segments, which, based on an average hair growth rate of 1cm per month, would represent hair grown over the past three, six, and nine months, respectively. Since in the third trimester of pregnancy there is a well-documented increased production of cortisol, we expected to see elevated levels of cortisol in the most proximal hair segment of women who had just given birth to a child (n-Mothers) compared with the control women. Likewise, we expected to see elevated levels in the second, third, or fourth segment of mothers of 3-month olds, 6-months olds, and 9-months olds, respectively. These hair segments, cut at 4-12 cm from the scalp, would represent hair grown throughout the third trimester of pregnancy. Results showed that there was a strong monotonic decline in cortisol concentration from the segment closest to the scalp to the most distal hair segment (p<0.0001). Cortisol levels decreased by 30-40% from one segment to the next for the most recent four hair segments. Segments from hair older than one year had similarly, low levels of cortisol. Comparisons of cortisol levels in hair between n-Mothers and control women yielded the expected results: cortisol levels in the first 3-cm hair segment (i.e., closest to the scalp) of n-Mothers were two-fold higher than in controls (p<0.0001), probably reflecting increased cortisol levels throughout the third trimester of pregnancy. No differences in cortisol content were apparent for the second or third 3-cm segments in n-Mothers (p>0.2). When hair from mothers with 6-9 months old toddlers was analyzed, the hair segment representing the third trimester period contained the same amount of cortisol as the hair grown more recently in mothers with 3-4 months old toddlers only. Age of the women, hair curvature, hair color, and frequency of hair washes per week were unrelated to cortisol levels. We conclude that cortisol measured in human hair can be a valid reflection of increased cortisol production for a period of up to six months. Due to a rapid decline of cortisol levels in human adult hair, a retrospective calendar of cortisol exposure may be limited to the past six months.     

Psychological stress and cortisol secretion in anhedonic alcoholic men

We investigated plasma cortisol in a psychological stress paradigm in seven weaned anhedonic alcoholics in comparison with seven age-matched healthy controls. Alcoholics had significantly higher mean plasma cortisol at baseline and no increase following a psychological stress paradigm. Anhedonic alcoholics judged the experimental situation less agreeable than controls. Anhedonic alcoholics may have blunted cortisol response to psychological stress.     

皮质醇水平与抑郁症关系的研究进展

皮质醇由肾上腺皮质束状带以及内层的网状带所分泌,是下丘脑-垂体-肾上腺轴的终末产物.皮质醇对机体的物质代谢、免疫功能和多种器官的生理功能的发挥具有十分重要的作用.近来研究表明：皮质醇水平与抑郁症发生的病理生理及发病机制有重要的关联,而且其水平的恢复可能与抗抑郁药物治疗有关.现就皮质醇与抑郁症的相关性研究进行综述.     

Melatonin and cortisol in individuals with spinal cord injury

Study objectivesThe aim of this study was to investigate circadian rhythm and sleep complaints in individuals with spinal cord injury (SCI) as determined by diurnal saliva melatonin and cortisol as well as activity measurements and subjective sleep quality.MethodsFourteen patients with cervical SCI (cSCI), six patients with thoracic SCI (tSCI) and eight able-bodied controls all underwent two consecutive weeks wearing a wrist actigraph in addition to filling out a sleep diary. During one 24-h period, cortisol and melatonin were measured at 4-h intervals. Furthermore, participants’ sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) and their overall daytime sleepiness was assessed using the Epworth Sleepiness Scale (ESS).ResultsThe cSCI group demonstrated lower melatonin levels compared with the tSCI group and the controls at the 24:00 and 04:00 time points. Moreover, at one time point the tSCI group had a higher cortisol level than the cSCI group and the controls. In addition, baseline systolic blood pressure and oxygen saturation were significantly lower in the cSCI group. No differences were found in activity measurements or self-reported sleep quality.ConclusionsIndividuals with cSCI demonstrate reduced melatonin secretion compared with tSCI individuals, but not in other circadian measures. This supports an involvement of melatonergic cervical fibers associated with the cervical lesion.