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


CONCLUSIONS
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.
Yehuda
Rachel
R
Traumatic Stress Studies Division, Mount Sinai School of Medicine and James J. Peters Bronx Veteran Affairs Medical Center, 130 West Kingsbridge Road, Bronx, NY 10468, USA. rachel.yehuda@va.gov
Bierer
Linda M
LM
Andrew
Ruth
R
Schmeidler
James
J
Seckl
Jonathan R
JR
D042842:11-beta-Hydroxysteroid Dehydrogenases / Q000097:blood / Q000378:metabolism; D000305:Adrenal Cortex Hormones / Q000097:blood; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000097:blood / Q000378:metabolism*; D016022:Case-Control Studies; D042944:Cholestenone 5 alpha-Reductase / Q000097:blood / Q000378:metabolism; D002849:Chromatography, Gas; D005260:Female; D005938:Glucocorticoids / Q000097:blood*; D017767:Holocaust / Q000523:psychology*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood*; D007585:Jews; D008016:Life Change Events; D008297:Male; D044342:Malnutrition / Q000097:blood / Q000150:complications* / Q000378:metabolism; D013058:Mass Spectrometry; D008875:Middle Aged; D011863:Radioimmunoassay; D013313:Stress Disorders, Post-Traumatic / Q000209:etiology / Q000378:metabolism / Q000523:psychology; D013315:Stress, Psychological / Q000097:blood / Q000150:complications* / Q000378:metabolism / Q000523:psychology; D017741:Survivors / Q000523:psychology; D013760:Tetrahydrocortisol / Q000031:analogs & derivatives / Q000097:blood
D000305:Adrenal Cortex Hormones; D005938:Glucocorticoids; C006461:allotetrahydrocortisol; D013760:Tetrahydrocortisol; D042842:11-beta-Hydroxysteroid Dehydrogenases; D042944:Cholestenone 5 alpha-Reductase; D006854:Hydrocortisone