Systematic changes in gene expression in postmortem human brains... possible explanation is the
ratio of cortisol to DHEA
Copyright 2004, James Michael Howard, Fayetteville, Arkansas, U.S.A.
The following is the information from "Human Molecular Genetics" regarding the findings of Li, et
al., that the brain activates two different gene states relative to the type of death of
individuals. Just below is the abstract of their article. Just below that is my explanation that
this may represent the response of the brain during "prolonged agona states"to differences in the
ratio of cortisol to DHEA.
Human Molecular Genetics Advance Access published online ahead of print January 20, 2004 Human
Molecular Genetics, 10.1093/hmg/ddh065: "Systematic changes in gene expression in postmortem human
brains associated with tissue pH and terminal medical conditions," J.Z. Li, et al., ABSTRACT:
"Studies of gene expression abnormalities in psychiatric or neurological disorders often involve the
use of postmortem brain tissue. Compared to single-cell organisms or clonal cell lines, the
biological environment and medical history of human subjects cannot be controlled, and are often
difficult to document fully. The chance of finding significant and replicable changes depends on the
nature and magnitude of the observed variations among the studied subjects. During an analysis of
gene expression changes in mood disorders, we observed a remarkable degree of natural variation
among 120 samples, which represented three brain regions in 40 subjects. Most of such diversity can
be accounted for by two distinct expression patterns, which in turn are strongly correlated with
tissue pH. Individuals who suffered prolonged agonal states, such as with respiratory arrest, multi-
organ failure, or coma, tended to have lower pH in the brain; whereas those who experienced brief
deaths, associated with accidents, cardiac events or asphyxia, generally had normal pH. The lower pH
samples exhibited a systematic decrease in expression of genes involved in energy metabolism and
proteolytic activities, and a consistent increase of genes encoding stress-response proteins and
transcription factors. This functional specificity of changed genes suggests that the difference is
not merely due to random RNA degradation in low pH samples; rather it reflects a broad and actively
coordinated biological response in living cells. These findings shed light on critical molecular
mechanisms that are engaged during different forms of terminal stress, and may suggest clinical
targets of protection or restoration."
The findings of Li, et al., may have an explanation. It is my hypothesis that dehydroepiandrosterone
(DHEA) was selected by evolution because of positive effects on all tissues, especially the brain.
It followed that cortisol evolved to counteract the effects of DHEA; I think this is the basis of
the "fight or flight mechanism" and our basic personalities These are the two major steroid hormones
of the adrenal glands. Prolonged exposure to increased levels of cortisol produces very negative
effects on the brain. I suggest this may be the basis of Li, et al.
I suggest the "prolonged agonal states" result in severe stress or a prolonged "fight or flight"
response. In this case, the ratio of cortisol to DHEA would predominate. DHEA is known to increase
metabolism and DHEA is deficient in schizophrenia which exhibits hypometabolism in the brain. Now, I
could not find sufficient support in the literature for this hypothesis regarding Li, et al., but I
did find support in another area which may be applicable.
It is also my hypothesis that "intrauterine growth retardation," (IUGR) results from insufficient
DHEA for proper growth. Therefore, I would expect to see the negative effects of cortisol in IUGR.
This is, in fact, the case and the following abstract demonstrates a similarity to the findings of
Li, et al. I suggest Li, et al., may have demonstrated a relatively prolonged effect of a high
cortisol to DHEA ratio in the brains of "individuals who suffered prolonged agonal states" as
opposed to the brains in individuals who died rapidly. (The supporting abstract is just below.)
Pediatr Res. 2002 Jan;51(1):94-9. Growth, IGF system, and cortisol in children with intrauterine
growth retardation: is catch-up growth affected by reprogramming of the hypothalamic-pituitary-
adrenal axis?
Cianfarani S, Geremia C, Scott CD, Germani D.
Intrauterine growth retardation (IUGR) is one of the major causes of short stature in childhood.
Although postnatal catch-up growth occurs in the majority of IUGR children, approximately 20% of
them remain permanently short. The mechanisms that allow catch-up growth or, on the contrary,
prevent IUGR children from achieving a normal height are still unknown. Our aim was to investigate
whether intrauterine reprogramming of hypothalamic-pituitary-adrenal axis may be involved in
postnatal growth retardation of IUGR children through a modulation of the function of the IGF
system. Anthropometry, IGF system assessment, cortisol measurement, and lipid profile evaluation
were performed in 49 IUGR children. Children were subdivided into two groups according to their
actual height corrected for midparental height: CG (catch-up growth) group, 19 children with
corrected height >or=0 z-score; and NCG (noncatch-up growth) group, 30 subjects with corrected
height <0 z-score. CG children showed significantly higher birth weight (p < 0.005) and body mass
index (p < 0.05). No significant differences in IGF-I, IGF-II, IGF binding protein (IGFBP)-1, IGFBP-
3, soluble IGF-II receptor levels (IGF2R), IGF-II/IGF2R ratio, and relative amounts of IGFBP-3
circulating forms were found between CG and NCG children. None of the IGF system-related variables
correlated with anthropometric indices. NCG children showed significantly higher concentrations of
cortisol (p < 0.005) and cortisol levels resulted inversely to birth weigh (r = -0.34, p < 0.05),
birth length (r = -0.36, p < 0.05), and corrected height (r = -0.44, p < 0.01). Whereas total and
HDL cholesterol concentrations were not significantly different in the two groups, LDL cholesterol
levels were significantly higher in NCG children (p < 0.05), and five of 49 showed LDL cholesterol
concentrations
Quoted message said:3.4 mM (130 mg/dL). LDL cholesterol was inversely related to birth weight (r =
-0.31, p < 0.05), corrected stature (r = -0.32, p < 0.05), and actual height (r
= -0.31, p < 0.05) and directly related to the levels of IGF2R (r = 0.44, p <
.01). Reanalysis of 15 of 30 IUGR newborns in whom we previously reported an inverse relationship
between cord blood cortisol levels and first trimester length gain (r = -0.54, p < 0.005) showed
that the relative amount of the IGFBP-3 18-kD fragment was related inversely to cortisol (r = -0.67,
p < 0.01) and directly to early postnatal growth (r = 0.65, p < 0.05). Our results suggest that catch-
up growth in IUGR children might be affected by intrauterine reprogramming of hypothalamic-pituitary-
adrenal axis, which may result in a permanent modification of the neuroendocrine response to stress:
children with increased cortisol secretion may be at higher risk of growth failure. During the
neonatal period cortisol might act by limiting IGFBP-3 proteolysis and, therefore, reducing IGF
bioavailability.