Enduring effects of severe developmental adversity, including nutritional deprivation, on cortisol metabolism in aging Holocaust survivors

Abstract

Objective In animal models, early life exposure to major environmental challenges such as malnutrition and stress results in persisting cardiometabolic, neuroendocrine and affective effects. While such effects have been associated with pathogenesis, the widespread occurrence of ‘developmental programming’ suggests it has adaptive function. Glucocorticoids may mediate ‘programming’ and their metabolism is known to be affected by early life events in rodents. To examine these relationships in humans, cortisol metabolism and cardiometabolic disease manifestations were examined in Holocaust survivors in relation to age at exposure and affective dysfunction, notably lifetime posttraumatic stress disorder (PTSD). Methods 51 Holocaust survivors and 22 controls without Axis I disorder collected 24-hr urine samples and were evaluated for psychiatric disorders and cardiometabolic diagnoses. Corticosteroids and their metabolites were assayed by gas chromatography mass spectroscopy (GCMS); cortisol was also measured by radioimmunoassay (RIA). Results Holocaust survivors showed reduced cortisol by RIA, and decreased levels of 5α-tetrahydrocortisol (5α-THF) and total glucocorticoid production by GCMS. The latter was associated with lower cortisol metabolism by 5α-reductase and 11β-hydroxysteroid dehydrogenase (11β-HSD) type-2. The greatest decrements were associated with earliest age of Holocaust exposure and less severe PTSD symptomatology. Cardiometabolic manifestations were associated with decreased 11β-HSD-2 activity. In contrast to the relationship in Holocaust survivors, in controls, 5α-reductase was positively associated with trauma-related symptoms. Conclusion Extreme malnutrition and related stress during development is associated with long-lived alterations in specific pathways of glucocorticoid metabolism. These effects may be adaptive and link with lower risks of cardiometabolic and stress-related disorders in later life.

Sex-specific effects of prenatal stress on glucose homoeostasis and peripheral metabolism in rats

“…Elderly survivors of the World War II Holocaust display threefold lower 5a-reduction of cortisol, indicative of reduced hepatic 5a-reductase type 1 activity (Yehuda et al 2009a). The greatest reductions in 5a-reductase activity were observed in those individuals who were the youngest at exposure to the Holocaust, indicating a potential 'programming' window in early life.…”

“…Programming of altered peripheral glucocorticoid metabolism has been reported in models of prenatal glucocorticoid overexposure with documented changes in hepatic and renal 11bHSD1 expression (Nyirenda et al 2009, Tang et al 2011. Additionally, reduced 5a-reductase activity has been proposed as an important contributor to the 'programmed' phenotype seen in individuals exposed to the severe physical, nutritional and psychological challenges of the World War II Holocaust early in life who subsequently developed post-traumatic stress disorder (PTSD; Yehuda et al 2009a).…”

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

“…The HSD11B2 gene promoter is subject to methylation (17). Children exposed to the horrors of the Nazi Holocaust have reduced renal 11␤-HSD2 activity in old age with the greatest effect seen in those youngest at traumatization (797). These data suggest 11␤-HSD2 is a programming target in humans, possibly to maximize renal sodium retention in what may be anticipated to be a starvation-associated sodium-poor environment.…”

Potenciais biomarcadores da terapia cognitivo-comportamental para o transtorno de estresse pós-traumático: uma revisão sistemática

“…Exceptions were cortisol and some of its metabolites. Yehuda et al 29 found significantly lower 5a-reductase activity in Holocaust survivors and suggested that its reduction may be associated with a vulnerability to development of PTSD. The highest amygdala activation in non-responders and highest anterior cingulate cortex volume in responders before treatment are compatible with the current model of PTSD 30,31 , which is based in neuroimaging data that show exaggerated amygdala activation and decreased activation in frontal areas.…”