Autism, hormonal metabolism and calcium signalling
Abnormalities in hormonal metabolism are frequently observed
in individuals with autism, with several studies observing abnormal
levels of many hormons and their receptors compared to healthy
controls, as well as abnormal hormonal secretion rhythms [2713159,
For example the analysis of the Hypothalamic-Pituitary-Adrenocortical
(HPA) system responses observed more variable
circadian rhythm as well as significant elevations in cortisol
following exposure to a novel stimulus in children with autism
compared to controls. This exaggerated cortisol response is
indicative of dysfunction of the HPA system in autism .
Over-reaction of the endocrine system to insulin stress in autism
has been recorded in another study, whereas the experimental
stress of insulin-induced hypoglycemia showed slower recovery
of blood glucose, much faster cortisol response and elevation
of growth hormone levels compared to controls [1176974,
Low levels of insulin-like growth factor-I (IGF-I) in cerebrospinal
fluid have also been observed .
Metabolic disorders of serotonin and dopamine
systems have been suggested in autism, with aproximately thirty
percent of individuals with autism exibiting high levels of
serotonin, simultanous with lowered levels of melatonin (see
is converted from serotonin by several enzymes of the pinealocytes
in the pineal gland, including 5-HT N-acetyl transferase and
5-hydroxyindole-O-methyltransferase. Results of the studies
looking at sleep disturbances in autism suggest that both dyssomnias
and parasomnias are very prevalent in the disorders - people
with autism frequently experience sleep disorders and exhibit
atypical sleep architecture [10722958,
Further evidence of dysfunction of pineal endocrine system in
autism was obtained by looking at alterations of the light and
dark circadian rhythm of melatonin, where none of autistic patient
showed a normal melatonin circadian rhythm, together with once
again significantly lower levels of this hormone .
is a hormone linked to melatonin that plays an important role
in amongst other things regulation of appetite and metabolism.
Results from a recent study have demonstrated significant differences
in leptin concentrations between children with autism and controls
Calcium influx through voltage gated calcium channels is directly
involved in both neurotransmitter and hormone secretion.
In newborn mice the relative dominance of LTCC over other types
of calcium channels has been observed .
LTCC are present on different pituitary cells and their activity
is in part modulated by sex steroids 
(see also Gender Differences).
Hormonal secretion evoked by various agents is mediated via
calcium influx through LTCC [9514161,
Calcium signalling plays a central role in regulation of melatonin
biosynthesis, mostly through activities related to
phosphorylation of the transcription factor CREB 
(see Brain for details
on LTCC-CREB). Changes in conductance of LTCC and intracellular
calcium oscillations have dramatic effects on melatonin levels
(see also Neurotransmitters–
Calcium signalling though LTCC plays an important role in the
release of insulin and regulation of the expression
of its gene (via CREB mediated transcription). Significantly
increased amounts of calcium in the cells cause release of previously
synthesised insulin, stored in secretory vesicles (see Gastrointestinal).
Of possible relevance is the observation that both low and elevated
or sustained levels of intracellular calcium impair insulin-stimulated
glucose uptake [2551647,
Thus calcium appears to required for glucose utilization and
plays an essential role in the stimulatory effect of insulin
on leptin secretion. Hoever, excess calcium disrupts leptin
secretion by interfering with metabolic events that are independent
from glucose uptake .
Oxytocin is a neuropeptide hormone that also
acts as a neurotransmitter in the brain and together with vasopressin,
another posterior pituitary hormone, has a role in regulation
of social bonding and behaviors in mammals such as mating, pair-bond
formation, maternal and parenting behavior, and attachment .
Rodents lacking the oxytocin or vasopressin gene or those lacking
the vasopressin V1a receptor show significant deficits in social
behaviour and social recognition .
It has therefore been suggested that deficiencies in oxytocin
pathways in the brain might be a feature of autism. Parallel
to the animal model studies actual alterations in endocrine
oxytocin system have been observed in children with autism .
It may be of relevance in this context tha V1a vasopressin receptor
is a G-protein coupled receptor functionally tighly linked to
LTCC. This coupling is sensitive to pertussis toxin treatment
When stimulated by an agonist (vasopressin) this receptor is
able to induce a complex intracellular calcium signalling cascade
for gene expression in astrocytes, eventually influencing CREB-mediated
events and decreasing expression levels of several cytokines,
notably interleukin-1beta and tumor necrosis factor-alpha. This
V1 agonist-induced decrease of cytokine release from cortical
astrocytes was also shown to be neuroprotective in cortical
In cultured cortical neurons, V1aR activation again influences
the influx of extracellular calcium via regulation of activities
of LTCC .
Oxytocin also seems to be able to regulate calcium currents
via LTCC [7530160,
On the other hand the opposite mechanism has been observed,
whereas entry of calcium through LTCC influences relase rate
of vasopressin and oxytocin hormones .
Even more interesting and of possible relevance to autism is
the observation that although the secretion of these two hormones
seems to be induced by calcium influx at initial stages, the
prolonged activation of LTCC results in decline in their