Altered Pituitary-Adrenal Axis Responses to Provocative Challenge Tests in Adult Survivors of Childhood Abuse

Heim, Christine; Newport, D. Jeffrey; Bonsall, Robert W.; Miller, Andrew H.; Nemeroff, Charles B.

doi:10.1176/foc.1.3.282

Cited by 124 publications

(163 citation statements)

References 38 publications

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“…Studies coupled with tests of feedback activity should not be expected to provide monolithic answers that uniformly apply to all stress-related disorders. For example, it is increasingly clear that survivors of trauma frequently exhibit a dissociation of central CRF hyperactivity and adrenal dysfunction that is not witnessed in nontraumatized individuals with depression (Heim et al, 2000(Heim et al, , 2001. Such pathophysiological subtleties will be increasingly important as secondary mechanisms such as negative feedback are incorporated into the model.…”

Section: Discussionmentioning

confidence: 99%

“…A blunted adrenocorticotropin hormone (ACTH) response in the CRF stimulation test has repeatedly been reported in patients with MDD Holsboer et al, 1987;Amsterdam et al, 1988;Kathol et al, 1989;Heim et al, 2001) and PTSD (Smith et al, 1989;Young et al, 1990;Heim et al, 1997Heim et al, , 2001. It has been suggested that this diminished ACTH response to exogenous CRF is a consequence of chronic hyperactivity of CRF-secreting neurons in the hypothalamic paraventricular nucleus that induces a downregulation of CRF receptors at the adenhohypophysis.…”

Section: Introductionmentioning

confidence: 93%

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Cerebrospinal Fluid Corticotropin-Releasing Factor (CRF) and Vasopressin Concentrations Predict Pituitary Response in the CRF Stimulation Test: A Multiple Regression Analysis

Newport

Heim

Owens

et al. 2002

Neuropsychopharmacol

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There is considerable evidence that stress-related psychiatric disorders, including depression and post-traumatic stress disorder (PTSD), are associated with hypersecretion of corticotropin-releasing factor (CRF) within the central nervous system (CNS). One line of evidence that is consistent with central CRF hypersecretion in these disorders is the blunted adrenocorticotropin hormone (ACTH) response to intravenous CRF administration, likely a consequence, at least in part, of downregulation of anterior pituitary CRF receptors. The present study tests the hypothesis that elevated cerebrospinal fluid (CSF) concentrations of CRF and a secondary ACTH secretagogue, arginine vasopressin (AVP), are associated with diminished adenohypophyseal responses in a standard CRF stimulation test. CSF concentrations of CRF and AVP, and plasma ACTH responses to the administration of 1 mg/kg ovine CRF (oCRF) were measured in healthy adult women with and without current major depression and/or a history of significant childhood abuse. The primary outcome measure was ACTH area under the curve (AUC) in the CRF stimulation test. Multiple linear regression was performed to identify the impact of CSF CRF and AVP concentrations upon the pituitary response to CRF stimulation. The regression model explained 56.5% of the variation in the ACTH response to CRF stimulation. The relationship of CSF concentrations of CRF to ACTH responses to CRF were best described by a third-order function that was inversely correlated over most of the range of studied values. The association of ACTH response with CSF concentration of AVP and the dose of oCRF followed second-order kinetics. These findings support the hypothesis that central CRF hypersecretion is associated with a blunted ACTH response to exogenously administered CRF, explaining almost 60% of the variation in the ACTH response to CRF.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

Cerebrospinal Fluid Corticotropin-Releasing Factor (CRF) and Vasopressin Concentrations Predict Pituitary Response in the CRF Stimulation Test: A Multiple Regression Analysis

Newport

Heim

Owens

et al. 2002

Neuropsychopharmacol

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“…Studies of various adult psychiatric patients with a history of early childhood abuse have revealed long-term changes in HPA axis activity (Heim, Newport, Bonsall, Miller, & Nemeroff, 2001), noradrenergic function (see Bremner & Vermetten, 2001), and the serotonergic system (Rinne, Westenberg, den Boer, & Van den Brink, 2000). There is also evidence for long-term changes in HPA axis functioning in children and adolescents with a history of abuse (Cicchetti & Rogosch, 2001;De Bellis et al, 1999;Duval et al, 2004), and a recent study showed an association between childhood maltreatment, neglect, and subtle brain abnormalities in the cingulate cortex and corpus callosum (Teicher, Dumont, Vaituzis, Giedd, & Andersen, 2004).…”

Section: Early Adverse Experiences and Their Effects On Biological Comentioning

confidence: 99%

The evidence for a neurobiological model of childhood antisocial behavior.

Goozen¹,

Fairchild²,

Snoek³

et al. 2007

Psychological Bulletin

414

393

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Children with persistent antisocial and aggressive behavior are diagnosed as having disruptive behavior disorder. The authors review evidence that antisocial children, and especially those who persist with this behavior as they grow older, have a range of neurobiological characteristics. It is argued that serotonergic functioning and stress-regulating mechanisms are important in explaining individual differences in antisocial behavior. Moreover, low fear of punishment and physiological underactivity may predispose antisocial individuals to seek out stimulation or take risks and may help to explain poor conditioning and socialization. The authors propose a theoretical model highlighting the interplay between neurobiological deficits and cognitive and emotional functioning as mediators of the link between early adversity and antisocial behavior problems in childhood. Implications for intervention programs are discussed.

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“…CSF reflects mainly extrahypothalamic sources (Kalin et al, 1987;Vythilingam et al, 2000). Increased hypothalamic CRF in PTSD is thought to explain, in part, the blunted ACTH response to CRF in PTSD found in some (Heim et al, 2001;Smith et al, 1989) but not all studies (Kellner et al, 2002;Rasmusson et al, 2001). Increased hypothalamic CRF has also been inferred from a number of studies that have found elevated cortisol levels in PTSD (De Bellis et al, 1999;Lemieux and Coe, 1995;Liberzon et al, 1999;Maes et al, 1998;Pitman and Orr, 1990).…”

Section: Introductionmentioning

confidence: 98%

Delta Sleep Response to Metyrapone in Post-Traumatic Stress Disorder

Neylan

Lenoci

Maglione

et al. 2003

Neuropsychopharmacol

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Metyrapone blocks cortisol synthesis, which results in the stimulation of hypothalamic cortiocotropin-releasing factor (CRF) and a reduction in delta sleep. We examined the effect of metyrapone administration on endocrine and sleep measures in male subjects with and without chronic PTSD. We hypothesized that metyrapone would result in a decrease in delta sleep and that the magnitude of this decrease would be correlated with the endocrine response. Finally, we utilized the delta sleep response to metyrapone as an indirect measure of hypothalamic CRF activity and hypothesized that PTSD subjects would have decreased delta sleep at baseline and a greater decrease in delta sleep induced by metyrapone. Three nights of polysomnography were obtained in 24 male subjects with combatrelated PTSD and 18 male combat-exposed normal controls. On day 3, metyrapone was administered during normal waking hours until habitual sleep onset preceding night 3. Endocrine responses to metyrapone were measured in plasma obtained the morning following sleep recordings, the day before and after administration. Repeated measures ANOVAs were conducted to compare the endocrine and sleep response to metyrapone in PTSD and controls. PTSD subjects had significantly less delta sleep as indexed by stages 3 and 4, and total delta integrated amplitude prior to metyrapone administration. There were no differences in premetyrapone cortisol or ACTH levels in PTSD vs controls. PTSD subjects had a significantly decreased ACTH response to metyrapone compared to controls. Metyrapone caused an increase in awakenings and a marked decrease in quantitative measures of delta sleep that was significantly greater in controls compared to PTSD. The decline in delta sleep was significantly associated with the magnitude of increase in both 11-deoxycortisol and ACTH. The results suggest that the delta sleep response to metyrapone is a measure of the brain response to increases in hypothalamic CRF. These data also suggest that the ACTH and sleep EEG response to hypothalamic CRF is decreased in PTSD.

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Altered Pituitary-Adrenal Axis Responses to Provocative Challenge Tests in Adult Survivors of Childhood Abuse

Cited by 124 publications

References 38 publications

Cerebrospinal Fluid Corticotropin-Releasing Factor (CRF) and Vasopressin Concentrations Predict Pituitary Response in the CRF Stimulation Test: A Multiple Regression Analysis

Cerebrospinal Fluid Corticotropin-Releasing Factor (CRF) and Vasopressin Concentrations Predict Pituitary Response in the CRF Stimulation Test: A Multiple Regression Analysis

The evidence for a neurobiological model of childhood antisocial behavior.

Delta Sleep Response to Metyrapone in Post-Traumatic Stress Disorder

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