Cortisol circadian rhythm

and its role in human

physiology

Diana Loreta Paun, C. Dumitrache

C.I.Parhon National Institutue of Endocrinology, Bucharest,
Romania
Carol Davila University of Medicine and Pharmacy
Cortisol
Cortisol is an essential
stress hormone and
deficiency leads to death.

Cortisol is an steroid
hormone secreted by the
adrenal gland and like
many other physiological
processes in the body has
a circadian rhythm.
Pacemaker
This rhythm is
distinct and is
regulated by the
main circadian
oscillator
(pacemaker) in the
suprachiasmatic
nucleus (SCN) which
is located in the
hypothalamus.

Synchronization of circadian
rhythms

Humans exhibit daily physiological
and behavioural rhythms with
nearly all body functions showing
significant daily variations; these
include
sleep
body temperature
plasma concentrations of cortisol and
growth hormone
urinary excretion of potassium
[Moore-Ede et al. 1983]
Synchronization of circadian
rhythms

These circadian rhythms are
produced by endogenous
processes referred to as
circadian oscillators which
coordinate and orchestrate
molecular and physiological
rhythms with changes in the
environment [Dunlap, 1999].
The autonomic nervous
system and endocrine signals
are the principal mediators of
this internal rhythmicity
[Buijs and Kalsbeek, 2001].

The regulation of
glucocorticoid release
The HPA axis receives input from the
central pacemaker which controls the
circadian release of corticotrophin-
releasing hormone (CRH), this also
stimulated by physical and emotional
stressors.
CRH in turn stimulates release of
adrenocorticotrophic hormones (ACTH)
from the corticotroph cells in the
anterior pituitary, and thence the
glucocorticoid cortisol from the adrenal
cortex.
In turn, cortisol exerts inhibitory effects
at pituitary and hypothalamic levels, in
a classical negative feedback loop.
[Oster et al. 2006].

Cortisol circadian rhythm
cortisol levels reach
lowest levels at
around midnight
levels start to rise at
around 02:00 to
03:00
reach a peak at
around 08:30
cortisol levels then
slowly decrease
back to the nadir to
complete the cycle
over 24 h [Debono et al. 2009; Krieger et al.
1971; Weitzman et al. 1971].
Timing
Infants are born without a circadian
rhythm in cortisol and they acquire it
during their first year of life.
Studies do not agree on the age of
appearance of the circadian rhythm
(varying between 2 weeks till the age
of 9 months) nor on whether it is
related to the appearance of the sleep
wake circadian rhythm.
Cortisol production rate

A number of cortisol secretory episodes occur
during the 24 h of the day making it possible to
describe four different unequal temporal phases.

Cortisol production rate

These phases are represented by:
a period of minimal secretory activity, during which
cortisol secretion is negligible, and occurs 4 h prior to and
2 h after sleep onset,
a preliminary nocturnal secretory episode at the third
through fifth hours of sleep,
a main secretory phase of a series of three to five episodes
occurring during the sixth to eighth hours of sleep and
continuing through the first hour of wakefulness
an intermittent waking secretory activity of four to nine
secretory episodes found in the 212-h waking period.
Ultradian Pulse
ACTH and cortisol
are released
episodically in pulses
every 20-30 min
throughout the day,
but the amplitude of
these pulses are
greater in the
morning.
Factors involved in the
rhythm of ACTH and Cortisol
Intrinsic rhytmicity of the synthesis and
secretion of CRH and AVP by the
hypothalamus
Feeding cycles
Light/dark and activity/rest cycles
Rhytmicity in the adrenal, possibly
mediated by adrenal innervation
Rhytmicity of hypothalamic CRH
Static and dynamic
measures of CRH and AVP
synthesis show a diurnal
rhythm that appears to be
inherent in the
hypothalamic cell bodies
Hypothalamic rhytmicity
appears to be neuronal or
intrinsec but not hormonal
Krieger DT Rhythms in CRF, ACTH and corticosteroids, 1979
Feeding cycles
Concentrations of cortisol
are highest before
breakfast and additional
peaks appear to be
coincident with lunch
Although preprandial peaks
of cortisol are common,
there are variable and do
not occur in subjects
whose normal patterns of
activity do not include
these meals
Follenius, Diurnal cortisol peaks and their relationsships to meal, 1982
Light/Dark cycles
The simplest correlation with the
circadian rhythms of ACTH and
cortisol is light/dark cycles
Once the diurnal rhythm is
established, it is not change easily
and persist after:
Prolonged bed rest
Continuous feeding
2-3 day period of sleep deprivation
Krieger DT Rhythms in CRF, ACTH and corticosteroids, 1979

Light/Dark cycles
This rhythm remains
unchanged in people who
work night shifts but maintain
conventional hours on
weekends
When individuals shift
sleep/waking, light/dark and
feeding schedules congruently
such as moving to a distant
time zone the circadian
rhythm of cortisol and ACTH
changes over the course of 3
to 5 days.
Krieger DT Rhythms in CRF, ACTH and corticosteroids, 1979


Adrenal Rhyhmicity and Other
Factors
Adrenal activity appears to
exhibit some diurnal
rhyhmicity that is
independent of CRH, AVP,
and ACTH
this may reflect inherent
rhythmicity
may be regulated via
adrenal innervation
Brandenberger G, 1984
Control of cortisol
secretion
A wide variety of physical and psychological
factors can alter the complex control of the
diurnal variations of ACTH and cortisol
secretion.
These factors are mediated largely by the
central nervous system.
Age does not appear to alter diurnal rhythm
of cortisol but maximal concentrations of
cortisol occur earlier in the day in aged
subjects.
Sherman B, 1985
Changes in the Diurnal Rhythm
of cortisol
Cortisol secretion can be
increased by:
Mild fear or psychological
stress (anticipation of
venipuncture)
Severe stress (preparation
for cardiac surgery)
Anticipation of a stress
(athletic competition,
university examination)
Sutton JR, 1975
Changes in the Diurnal Rhythm
of cortisol
Psyhological stress and also major physical
stress such as:
severe trauma
major surgery
severe illness
fever
hypoglycemia
burns or exposure to cold
dehydration, hypotension
irradiations
intensive exercise
can increase the secretion of cortisol.
Changes in the Diurnal Rhythm
of cortisol
Chronic illnesses as congestive heart
failure or liver disease also alter the
diurnal rhythm of ACTH and cortisol.
Patients with major depression have
increased basal cortisol as a result of a
blunting of the diurnal rhythm of
cortisol and ACTH similar to that seen
in Cushings disease.

Changes in the Diurnal Rhythm
of cortisol
Circulating cortisol is increased and
diurnal variations are decreased in
anorexia nervosa
Cyproheptadine can inhibit rises in
ACTH and cortisol induced by
hypoglycemia.
Conclusion
Cortisol has one of the most
distinct and fascinating circadian
rhythms in human physiology.
Cortisol acts as a secondary
messenger between central and
peripheral clocks, hence its
importance in the synchronization
of body circadian rhythms.
THANK YOU