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Summary Glucocorticoids: mis-named, physiologically insignificant or only as use as immuno-suppressive drugs?
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An overall summary of glucocorticoids and their role in the body.
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Glucocorticoids: mis-named, physiologically insignificant or only as use asimmuno-suppressive drugs. Discuss.
Glucocorticoids (GC) are a family of steroid hormones which bind to the glucocorticoid receptor
(GR); a member of a large family of nuclear receptors which act as a ligand. Glucocorticoids are
the final product of the hormonal cascade known as the hypothalamo-pituatry adrenal (HPA).
axis At the beginning of the axis corticotrophin releasing hormone (CRH) is released from ventral
hypothalamic neurons into the hypophyseal portal system; transporting CRH (which binds to
CRH1 receptors) on the corticotroph cells of the anterior pituitary gland (APG). Activation of
these cells triggers the enzymatic cleavage of the large prohormone pro-opiomelancortin (POMC)
to adrenocorticotrophin releasing hormone (ACTH) and -lipotrophin.
ACTH is then released into circulation. Arginine vasopressin acts synergistically with CRH to
increase ACTH release. ACTH then travels to the zona fasiculata in the adrenal glands and binds
to ACTH receptors with high affinity, leading to adenylyl cyclase activation, which activates
protein kinase. Protein Kinase A phosphorylates (and therefore activates) cholesterol ester
hydrolase , which converts cholesterol esters to cholesterol. The StAR protein (steroidogenic
acute regulatory protein) helps transport cholesterol from the outer mitochondrial membrane to
the inner mitochondrial matrix, which hydroxylates and cleaves the side chains of cholesterol
forming pregnolone. Pregnolone is then transferred to the smooth endoplasmic reticulum (SER)
whereby it is modified by dehydrogenases and hydrogensases in the SER and mitochondria
where the glucocorticoids cortisol and corticosterone are formed.
Cortisol is then secreted into systemic circulation whereby 75% binds to corticosteroid binding
globulin and 15% binds to albumin. Protein bound cortisol is biologically inactive and the reverse
is true for free cortisol.
Glucocorticoids exert a negative feedback inhibitory effect on the HPA axis suppressing its
release by two separate mechanisms; fast and slow feedback. The former involves inhibition of
ACTH secretion via GC binding to the APG proportional to cortisol levels. The latter is sensitive to
the absolute cortisol level, so repeated administration of GC’s will lead to a decrease of ACTH and
eventual suppression of CRH/ACTH release. Both mechanisms are suggested to be receptor
mediated (1)
The term glucocorticoid by coined by Seyle and Jansen in 1946 (2) is an amalgamation of parts of
the three words pertaining to different features of glucocorticoids. The view that glucocorticoids
may be mis-named depends on whether glucocorticoids actually perform their function. The first
third (gluco) refers to its primary function; to initiate gluconeogenesis, the middle third (cort)
refers to its adrenal cortical synthesis and the final third (oid) refers its steroidal nature. The
common belief is that glucocorticoids, increase gene transcription and production of glucose-6-
phosphatase and tyrosine transaminase/aminotransferase (hepatocyte enzymes) therefore
stimulating hepatic gluconeogenesis. Despite the fact that “adrenalectomy reduces and
dexamethasone (a synthetic glucocorticoid) restores gluconeogenesis” (4-5).Correlation does not
indicate cause and since there is no evidence to suggest that glucocorticoids increase
transcription of gluconeogenic enzymes, this coupled with the fact that are not recognised as
having a role in gluconeogenesis in basic biochemistry textbooks (4) and no empirical evidence
supporting the notion that glucocorticoids directly induce gluconeogenesis is reflective of the fact
that glucocorticoids may not cause but be a co-factor in gluconeogenesis, hence supporting the
notion that GC’s may actually be mis-named as their name is an assumption not an accurate
reflection their function.
Karl Popper’s theory of falsificationism (5) states that if a hypothesis cannot be disproven or
falsified by empirical evidence, then it is accepted as the justified truth we scientists can believe
in; since there is no evidence to dispel the belief that glucocorticoids help generate gluconeogenic
enzymes (thus stimulating gluconeogenesis) one can consider the notion that glucocorticoids are
mis-named can be considered misleading and invalid. I personally agree with Fredrich
Nietzsche’s view that “the irrationality of a thing is no argument against its existence, but a
, consequence of it” (6) so the glucocorticoids may not actually be mis-named, but the mechanism
by which it activates gluconeogenesis may be irrational and a consequence of its complexity.
Astronomers cannot travel to space and scrutinize how the galaxies and the whole solar system
respond to experiment (i.e manipulation of planet position) , so at the moment we may not have
the resources,experimental design or correct line of thought to elucidate how glucocorticoid
induced-gluconeogenesis occurs, so the term glucocorticoid may be misleading rather than
misnamed.
Physiological significance can be defined as the importance of a factor to the function of a normal,
homeostatic state. I disagree with the notion that glucocorticoids are physiologically insignificant
as they are vital for the correct functioning of a broad spectrum of physiological processes in
development, metabolism and cognitive function. The physiological significance is reflected in
the fact that glucocorticoids modify foetal growth and thus have a critical role in programming
and maintaining normal development. (7-8) In addition to this glucocorticoids maintain essential
metabolic processes and memory.
Hans Seyle defines stress as the non-specific response to any demand placed on the body (9).
Cortisol levels must be maintained at a normal level as extreme increases in normal levels
(hypercortisolaemia) caused either by stress or Cushing’s syndrome (caused by a ACTH-releasing
tumour), administration of synthetic glucocorticoids have devastating consequences.
Cortisol is important for the maturation of synthesis of steroid and protein receptors, metabolic
and digestive enzymes, voltage and ligand gated ion channels and water and glucose
transporters. Glucocorticoids induce production of surfactant, a phospholipid which reduces
alveolar surface tension, required to prevent alveolar collapse and facilitate lung expansion,
hence the therapeutic use of glucocorticoids to promote lung maturation in premature babies.
Exogenous or endogenous overexposure to glucocorticoids to the mother or foetus causes
retardation of foetal and the foetus in humans and many other species. The fact that
glucocorticoids are critical factors involved in the development of elements vital for a normal
physiological and homeostatic state and life itself dispels the notion that glucocorticoids are
physiologically insignificant. If glucocorticoids were physiologically insignificant then an excess
would not have such a devastating effect.
The major functions of glucocorticoids are to stimulate (10)and accelerate gluconeogenesis (11-
12)
,which requires amino acids and fats (to synthesise glucose and increase energy levels
respectively). Cortisol increases proteolysis in muscle, reduces uptake of protein in all cells
(other than the liver), sharply increasing the level of amino acids in the blood and transport
hepatocytes. Glucocorticoids increase the liver’s ability to concentrate amino acids (13).
Glucocorticoids stimulate gluconeogenesis by up-regulating enzymes which convert amino acids
to glucose and reduce the use of glucose from other cells by inhibiting glucose uptake.
Glucocorticoids stimulate lipolysis in adipose tissue, liberating fatty acids and glycerol, which
provide energy for gluconeogenesis in the liver. Glucocorticoids are the reason why during times
of intense stress or fasting we have energy to think and our bodies to function, if glucocorticoids
are physiologically insignificant then a lack or excess would surely have no effect on
carbohydrate, protein or fat metabolism however the reverse is true. Cortisol deficiency
increases vulnerability to and reduces convalescence from hypoglycemia, conversely cortisol
excess causes muscle atrophy, skin thinning and reduction of matrix, mass and formation; as well
as reduced lipogenesis and fat deposition in central or truncal areas.
Glucocorticoids are not only important for the normal,physiological negative feedback control of
the HPA axis, they are also important for the maintenance of cognitive function. The
hippocampus is the centre of memory and emotion in the brain; type 2 hippocampal GR’s are
responsive to exogenous glucocorticoids and high levels of endogenous glucocorticoids
associated with stress. In times of stress, GR’s are down regulated, impairing negative feedback
and causing over activation of the HPA axis (14). This is detrimental as the hippocampus plays an
important role in the storage of declarative memories. HPA axis over activation affects storage of
long term declarative memories possibly by causing dendritic atrophy of hippocampal neurons
(15). Hippocampal damage induced by corticosteroid treatment can explain declarative memory
impairment associated with hypercortisolaemia (16), declarative memory impairment was seen in
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