Glucocorticoids

Glucocorticoid synthesis is regulated by the HPA axis via ACTH (Figure   1.3 ).
ACTH is synthesized by the posterior pituitary mainly in response to two syner-
gistic factors  –      CRH   and   antidiuertic  hormone   ( ADH  or vasopressin), both of
which produced in the paraventricular nucleus of the hypothalamus. These pep-
tides travel through the neurohypophyseal stalk to the median eminence from
where they enter the portal circulation and stimulate release of ACTH via binding
to the CRF type 1 receptor or V1b receptor, respectively. ACTH stimulates the
synthesis of cortisol in the adrenal. Cortisol itself exerts negative feedback on the
HPA axis by inhibiting both the release and actions of CRH. ACTH also exerts a
short - loop negative feedback by inhibiting its own secretion.   
Of the two peptides, CRH is the more important. Mice in which this is deleted
have impaired HPA axis, ablated stress response and a loss of the normal circadian
rhythm for glucocorticoid production   [22]  . CRH acts principally at the type 1 recep-
tor with CRF - R1 null mice having a marked impairment of the HPA axis  [23] .
Unstressed ACTH levels in these animals are, however, normal and they are still
able to mount a stress response. This is mediated in part through a second recep-
tor for CRH, as shown by a double knockout strategy   [24] .  Nevertheless,  injection
of antisera to ADH was shown to reduce ACTH levels by 60%, indicating a key
role for ADH  [23]  in the compensatory response. ADH acts synergistically to CRF
but is not an absolute requirement for ACTH release: Brattleboro rats, which are
congenitally devoid of ADH, have a normal HPA axis  [25] , and mice lacking the

V1b receptor  [26]  have normal ACTH and corticosterone levels. Such studies do,
however, demonstrate a key role for ADH in sustaining the ACTH response to
stress.
That the HPA axis is not abolished by combined administration of antisera to
CRF and AVP    –    or indeed by double knockout of the receptors     –     indicates  other
regulatory factors about which less is known. A number of neuroactive com-
pounds, such as Ang II  [27] , catecholamines and glutamate  [28] , have been
implicated.
ACTH circulates unbound to plasma with a half  - life of approximately 15   minutes
and exerts its effects via G - protein - coupled  receptors  belonging  to  the  melanocor-
tin receptor subfamily known as ACTH - R. ACTH - R is mainly expressed in the
adrenal cell plasma membrane, with low expression levels being reported in skin
and adipose tissue  [29] . Although ACTH - R is specifi  c for its ligand, ACTH itself
is also recognized by the other four melanocortin receptors. The receptors are
coupled to adenylyl cyclase: the cAMP – protein kinase A cascade causes the hydro-
lysis of cholesterol esters stored in the zona fasciculata and the synthesis of corti-
sol. The human inheritable condition of   familial glucocorticoid defi  ciency   [ FGD ;
OMIM (202200)] has been attributed to mutations within the ACTH - R gene and
several different FGD mutations within the gene have been so far identifi  ed   [30] .
FGD is characterized by glucocorticoid defi ciency with high plasma ACTH levels
and a normal RAS.
Administration of intravenous ACTH in humans is followed by a rapid (within
minutes) increase in cortisol plasma levels  [31]  , primarily due to   de novo    synthesis.
Although the concentration of steroids is 2 -  to 3 - fold higher in the adrenal gland
than in the plasma, this does not act as a reservoir. A sustained increase in ACTH
levels results in hypertrophy of the adrenal gland due to an increase in cell size,
not number, thereby permitting increased storage of cholesterol. Conversely,
adrenal atrophy occurs if ACTH levels remain chronically low.
Plasma cortisol levels fl  uctuate throughout the day as release occurs in an epi-
sodic, rather than constitutive, manner. Nevertheless, the episodes of release are
more frequent in the late evening and early morning, and there is a true circadian
rhythm (although light does have some effect on the cycle): most secretion occurs
from the third hour of sleep to the early hours of wakefulness and plasma cortisol
can be undetectable during the rest of the day. The rhythm synchronizes, to an
extent, with plasma ACTH concentration and there is a peak in hypothalamic CRF
preceding that of cortisol by 4 – 5   h. However, the circadian rhythm of glucocorti-
coid production persists even when CRF/ACTH levels are clamped  [32]   suggesting
that the periodicity of release is entrained by other factors. Several agents have
been suggested, although neither catecholamines nor serotonin appear to be
involved. The rhythm is disrupted, however, by adrenal denervation, spinal chord
transection or lesions in the ventromedial nucleus of the hypothalamus   [33] .  The
circadian fl  uctuations are of major importance to the normal regulation of the
HPA axis. Furthermore, glucocorticoids demonstrably infl uence the phase of
peripheral oscillators in the kidney, heart and liver, although not in the central
“ clock ”  of the supra chiasmatic nuclei   [34] . Studies in genetically modifi ed mice
suggest that disturbances in HPA signaling are connected with vulnerability to
behavioral abnormalities   [35] . Moreover, there is a well - established  circadian  varia-
tion in cardiovascular risk events, with an increase in events in the morning
compared to other times of day  [36] , coinciding with elevated glucocorticoid and
aldosterone levels. Indeed, there is growing literature showing cortisol secretion/
metabolism to be directly associated with cardiovascular risk. In contrast, an asso-
ciation study found no link between a  glucocorticoid receptor    ( GR )  polymorphism
(with a trend toward elevated cortisol) and adverse cardiovascular events  [37] .