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Differentiation between genomic and non-genomic feedback controls yields an HPA axis model featuring hypercortisolism as an irreversible bistable switch.
[cushing syndrome]
The
hypothalamic
-
pituitary
-
adrenal
axis
(
HPA
axis
)
is
a
major
part
of
the
neuroendocrine
system
responsible
for
the
regulation
of
the
response
to
physical
or
mental
stress
and
for
the
control
of
the
synthesis
of
the
stress
hormone
cortisol
.
Dysfunctions
of
the
HPA
axis
characterized
by
either
low
(
hypocortisolism
)
or
increased
(
hypercortisolism
)
cortisol
levels
are
implicated
in
various
pathological
conditions
.
Their
understanding
and
therapeutic
correction
may
be
supported
by
mathematical
modeling
and
simulation
of
the
HPA
axis
.
Mass
action
and
Michaelis
Menten
enzyme
kinetics
were
used
to
provide
a
mechanistic
description
of
the
feedback
mechanisms
within
the
pituitary
gland
cells
by
which
cortisol
inhibits
its
own
production
.
A
separation
of
the
nucleus
from
the
cytoplasm
by
compartments
enabled
a
differentiation
between
slow
genomic
and
fast
non-genomic
processes
.
The
model
in
parts
was
trained
against
time
resolved
ACTH
stress
response
data
from
an
in
vitro
cell
culture
of
murine
AtT-
20
pituitary
tumor
cells
and
analyzed
by
bifurcation
discovery
tools
.
A
recently
found
pituitary
gland
cell
membrane
receptor
that
mediates
rapid
non-genomic
actions
of
glucocorticoids
has
been
incorporated
into
our
model
of
the
HPA
axis
.
As
a
consequence
of
the
distinction
between
genomic
and
non-genomic
feedback
processes
our
model
possesses
an
extended
dynamic
repertoire
in
comparison
to
existing
HPA
models
.
In
particular
,
our
model
exhibits
limit
cycle
oscillations
and
bistable
behavior
associated
to
hypocortisolism
but
also
features
a
(
second
)
bistable
switch
which
captures
irreversible
transitions
in
hypercortisolism
to
elevated
cortisol
levels
.
Model
predictive
control
and
inverse
bifurcation
analysis
have
been
previously
applied
in
the
simulation-based
design
of
therapeutic
strategies
for
the
correction
of
hypocortisolism
.
Given
the
HPA
model
extension
presented
in
this
paper
,
these
techniques
may
also
be
used
in
the
study
of
hypercortisolism
.
As
an
example
,
we
show
how
sparsity
enforcing
penalization
may
suggest
network
interventions
that
allow
the
return
from
elevated
cortisol
levels
back
to
nominal
ones
.
Diseases
Validation
Diseases presenting
"hypothalamic-pituitary-adrenal axis"
symptom
adrenal incidentaloma
allergic bronchopulmonary aspergillosis
cushing syndrome
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