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: Fifty-one Holocaust survivors and 22 controls without Axis I disorder collected 24-h urine samples and were evaluated for psychiatric disorders and cardiometabolic diagnoses. Corticosteroids and their metabolites were assayed by gas chromatography-mass spectroscopy (GC-MS); cortisol was also measured by radioimmunoassay (RIA).

Results: Holocaust survivors showed reduced cortisol by RIA, and decreased levels of 5alpha-tetrahydrocortisol (5alpha-THF) and total glucocorticoid production by GC-MS. The latter was associated with lower cortisol metabolism by 5alpha-reductase and 11beta-hydroxysteroid dehydrogenase (11beta-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 11beta-HSD-2 activity. In controls, 5alpha-reductase was positively associated with trauma-related symptoms (i.e., to traumatic exposures unrelated to the Holocaust).

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.

Figure 1. Summary of Metabolic Pathway

11β-HSD is 11β-hydroxysteroid dehydrogenase. 11ß-HSD type 1 (mainly located in liver, adipose tissue and brain) catalyses the reduction of inert cortisone to active cortisol; 11ß-HSD type 2 oxidizes active cortisol to inert cortisone in the kidney. 5α- and 5β -reductase are the rate limiting enzymes in the conversions of cortisol to 5α-tetrahydrocortisol (THF) and 5β-THF, respectively, largely occurring in liver, but also the brain. 5β-reductase is also rate limiting in the conversion of cortisone to tetrahydrocortisone (THE).

Figure 2. Cardiometabolic manifestation scores in Holocaust survivors with and without PTSD and in non-exposed subjects

The three groups differ significantly (F=5.40, df=2,68, p=.007), controlling for age (p=.005) and gender (ns), with post-hoc tests (LSD) demonstrating scores for survivors without PTSD to be significantly lower than those for survivors with PTSD (p=.002) and comparison subjects (p=.053).