Fetal programming of the hypothalamic-pituitary-adrenal (HPA) axis: low birth weight and central HPA regulation

Fetal programming of the hypothalamic-pituitary-adrenal (HPA) axis has been proposed as an intermediary in the association between reduced fetal growth and adult cardiovascular and metabolic diseases. Previous studies have shown that small size at birth is associated with increased fasting plasma cortisol and adrenal responsiveness to ACTH stimulation. We have extended these studies by evaluating the salivary cortisol response to awakening and plasma ACTH and cortisol responses to CRH stimulation and a dexamethasone-suppressed CRH (DEX/CRH) test in a group of low birth weight [LBW; <3.18 kg (7 lb), n = 58] and high birth weight [>3.86 kg (8.5 lb), n = 65] men aged 60–69 yr. Despite no difference in basal pituitary-adrenal activity or in their ACTH and cortisol responses to CRH, LBW men had significantly lower pituitary-adrenal responses in the DEX/CRH test. Although these findings do not explain the HPA abnormalities associated with LBW in previous studies, they provide further evidence of dysregulation of the HPA axis in people who were small at birth

Central hypothalamic-pituitary-adrenal activity and the metabolic syndrome: studies using the corticotrophin-releasing hormone test

A number of studies have suggested that the metabolic syndrome (principally, the combination of hypertension, glucose intolerance, and dyslipidemia) is associated with subtle dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis leading to raised circulating cortisol concentrations. The mechanisms underlying these observations are not known. We assessed the salivary cortisol response to awakening and pituitary-adrenal responses during a 100-?g human corticotrophin-releasing hormone (CRH) test and a dexamethasone-suppressed CRH test in a well-characterized group of 65-year-old men (n = 122). In the cohort from which this subgroup was drawn, there were associations between the components of the metabolic syndrome and 9AM cortisol concentration in line with previous studies. However, there were no significant associations between blood pressure, glucose tolerance, and lipid concentrations and the dynamic tests of HPA activity. We therefore found no evidence to suggest that exaggerated pituitary responsiveness or increased central drive to the pituitary, as determined by CRH testing, plays a part in the development of the metabolic syndrome

Size at birth and cardiovascular responses to psychological stressors: evidence for prenatal programming in women

Background: Epidemiological studies have repeatedly shown inverse associations between size at birth and blood pressure in later life. There is some evidence to suggest that exaggerated blood pressure responses to psychological stressors are a forerunner of sustained hypertension.Objective: To determine whether individuals who were smaller at birth have greater blood pressure and heart rate responses to psychological stressors.Design: Prospective cohort study.Methods: A total of 104 men and 79 women (mean age 26.3 years) were recruited from the Adelaide Family Heart Study cohort. Blood pressure was monitored continuously throughout the study using a Portapres and participants undertook a series of three stress tests: Stroop, mirror drawing and public speech. The stress response was defined as the increment from baseline to the mean blood pressure during the three tasks.Results: In women, a 1 kg increase in birthweight was associated with an 8.7 mmHg (95% confidence interval: 3.6-13.8, P = 0.001) reduction in the systolic and a 4.1 mmHg (1.6-6.6, P = 0.002) reduction in the diastolic response to stress. The heart rate response to stress was also inversely related to birthweight. These results remained significant after correction for gestational age and other potential confounding factors. Similar results were found for birth length and head circumference. There were no such relationships in men.Conclusions: This study provides the first human evidence that cardiovascular responses to psychological stressors may be programmed antenatally and suggests a potential mechanism linking reduced fetal growth with raised blood pressure and cardiovascular disease in later life

Size at birth and autonomic function during psychological stress

Small size at birth is associated with exaggerated blood pressure responses to psychological stressors, which increase the risk of developing sustained hypertension in adult life. Explanatory mechanisms for this association are not well characterized. We investigated the hypothesis that an adverse fetal environment, reflected by small size at birth, persistently alters autonomic nervous system and baroreflex control of cardiovascular function, resulting in exaggerated blood pressure and heart rate responses to stressors. Men and women from an Australian prospective cohort study underwent a series of 3 psychological stressors (Stroop, mirror-tracing, and speech) while their blood pressure was recorded continuously using a Portapres. Indices of autonomic function were derived using spectrum analysis (wavelet packet transform), and baroreflex function was estimated using an adaptive autoregressive model. We found that women who were small at birth demonstrated increased levels of low-frequency blood pressure variability at rest (r=-0.28; P<0.05) and during stress (r=-0.42; P<0.001), reduced levels of high-frequency heart period variability (r=0.22; P<0.05), and reduced baroreflex sensitivity (r=0.34; P<0.01). These findings were not present in the men. This study provides evidence that markers of impaired fetal growth are related to autonomic cardiovascular control involving modulation of both sympathetic and parasympathetic function but in a sex-specific manner. We also provide the first human evidence of a relationship between size at birth and baroreflex function