8/11/2019 Cronobiologie
1/24
Cortisol circadian rhythmand its role in humanphysiology
Diana Loreta Paun, C. Dumitrache
C.I.Parhon National Institutue of Endocrinology, Bucharest,RomaniaCarol Davila University of Medicine and Pharmacy
8/11/2019 Cronobiologie
2/24
Cortisol
Cortisol is an essentialstress hormone and
deficiency leads to death.
Cortisol is an steroidhormone secreted by theadrenal gland and likemany other physiologicalprocesses in the body has
a circadian rhythm.
8/11/2019 Cronobiologie
3/24
Pacemaker
This rhythm isdistinct and isregulated by the
main circadianoscillator(pacemaker) in thesuprachiasmatic
nucleus (SCN) whichis located in thehypothalamus.
8/11/2019 Cronobiologie
4/24
Synchronization of circadianrhythms
Humans exhibit daily physiologicaland behavioural rhythms withnearly all body functions showing
significant daily variations; theseinclude sleep
body temperature
plasma concentrations of cortisol andgrowth hormone
urinary excretion of potassium
[Moore-Ede et al. 1983]
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3475279/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3475279/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3475279/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3475279/8/11/2019 Cronobiologie
5/24
Synchronization of circadianrhythms
These circadian rhythms areproduced by endogenousprocesses referred to ascircadian oscillators which
coordinate and orchestratemolecular and physiologicalrhythms with changes in theenvironment [Dunlap, 1999].
The autonomic nervoussystem and endocrine signalsare the principal mediators ofthis internal rhythmicity
[Buijs and Kalsbeek, 2001].
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3475279/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3475279/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3475279/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3475279/8/11/2019 Cronobiologie
6/24
The regulation of
glucocorticoid release The HPA axis receives input from the
central pacemaker which controls thecircadian release of corticotrophin-releasing hormone (CRH), this also
stimulated by physical and emotionalstressors. CRH in turn stimulates release of
adrenocorticotrophic hormones (ACTH)from the corticotroph cells in theanterior pituitary, and thence theglucocorticoid cortisol from the adrenalcortex.
In turn, cortisol exerts inhibitory effectsat pituitary and hypothalamic levels, ina classical negative feedback loop.
[Oster et al. 2006].
8/11/2019 Cronobiologie
7/24
Cortisol circadian rhythm
cortisol levels reachlowest levels ataround midnight
levels start to rise ataround 02:00 to03:00
reach a peak ataround 08:30
cortisol levels thenslowly decreaseback to the nadir tocomplete the cycle
over 24 h [Debono et al. 2009; Krieger et al.1971; Weitzman et al. 1971].
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3475279/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3475279/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3475279/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3475279/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3475279/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3475279/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3475279/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3475279/8/11/2019 Cronobiologie
8/24
Timing
Infants are born without a circadianrhythm in cortisol and they acquire itduring their first year of life.
Studies do not agree on the age ofappearance of the circadian rhythm(varying between 2 weeks till the age
of 9 months) nor on whether it isrelated to the appearance of the sleepwake circadian rhythm.
8/11/2019 Cronobiologie
9/24
Cortisol production rate
A number of cortisol secretory episodes occurduring the 24 h of the day making it possible todescribe four different unequal temporal phases.
8/11/2019 Cronobiologie
10/24
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 and2 h after sleep onset,
a preliminary nocturnal secretory episode at the thirdthrough fifth hours of sleep,
a main secretory phase of a series of three to five episodesoccurring during the sixth to eighth hours of sleep and
continuing through the first hour of wakefulness
an intermittent waking secretory activity of four to ninesecretory episodes found in the 212-h waking period.
8/11/2019 Cronobiologie
11/24
Ultradian Pulse
ACTH and cortisolare releasedepisodically in pulsesevery 20-30 minthroughout the day,but the amplitude of
these pulses aregreater in themorning.
8/11/2019 Cronobiologie
12/24
Factors involved in therhythm of ACTH and Cortisol
Intrinsic rhytmicity of the synthesis andsecretion of CRH and AVP by the
hypothalamus Feeding cycles
Light/dark and activity/rest cycles
Rhytmicity in the adrenal, possiblymediated by adrenal innervation
8/11/2019 Cronobiologie
13/24
Rhytmicity of hypothalamic CRH
Static and dynamicmeasures of CRH and AVP
synthesis show a diurnalrhythm that appears to beinherent in thehypothalamic cell bodies
Hypothalamic rhytmicityappears to be neuronal orintrinsec but not hormonal
Krieger DT Rhythms in CRF, ACTH and corticosteroids, 1979
8/11/2019 Cronobiologie
14/24
Feeding cycles
Concentrations of cortisolare highest beforebreakfast and additionalpeaks appear to be
coincident with lunch Although preprandial peaks
of cortisol are common,there are variable and do
not occur in subjectswhose normal patterns ofactivity do not includethese meals
Follenius, Diurnal cortisol peaks and their relationsships to meal, 1982
8/11/2019 Cronobiologie
15/24
Light/Dark cycles
The simplest correlation with thecircadian rhythms of ACTH andcortisol is light/dark cycles
Once the diurnal rhythm isestablished, it is not change easilyand persist after:
Prolonged bed rest Continuous feeding
2-3 day period of sleep deprivation
Krieger DT Rhythms in CRF, ACTH and corticosteroids, 1979
8/11/2019 Cronobiologie
16/24
Light/Dark cycles
This rhythm remainsunchanged in people whowork night shifts but maintainconventional hours onweekends
When individuals shiftsleep/waking, light/dark andfeeding schedules congruently
such as moving to a distanttime zonethe circadianrhythm of cortisol and ACTHchanges over the course of 3to 5 days.
Krieger DTRhythms in CRF, ACTH and corticosteroids, 1979
8/11/2019 Cronobiologie
17/24
Adrenal Rhyhmicity and OtherFactors
Adrenal activity appears toexhibit some diurnal
rhyhmicity that isindependent of CRH, AVP,and ACTH
this may reflect inherent
rhythmicity may be regulated via
adrenal innervation
Brandenberger G, 1984
8/11/2019 Cronobiologie
18/24
Control of cortisol
secretion A wide variety of physical and psychological
factors can alter the complex control of thediurnal variations of ACTH and cortisolsecretion.
These factors are mediated largely by thecentral nervous system.
Age does not appear to alter diurnal rhythmof cortisol but maximal concentrations ofcortisol occur earlier in the day in agedsubjects.
Sherman B, 1985
8/11/2019 Cronobiologie
19/24
Changes in the Diurnal Rhythmof cortisol
Cortisol secretion can beincreased by:
Mild fear or psychological
stress (anticipation ofvenipuncture)
Severe stress (preparationfor cardiac surgery)
Anticipation of a stress(athletic competition,university examination)
Sutton JR, 1975
8/11/2019 Cronobiologie
20/24
Changes in the Diurnal Rhythmof cortisol
Psyhological stress and also major physicalstress 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.
8/11/2019 Cronobiologie
21/24
Changes in the Diurnal Rhythmof cortisol
Chronic illnesses as congestive heartfailure 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 ofcortisol and ACTH similar to that seenin Cushings disease.
8/11/2019 Cronobiologie
22/24
Changes in the Diurnal Rhythmof cortisol
Circulating cortisol is increased anddiurnal variations are decreased in
anorexia nervosa Cyproheptadine can inhibit rises inACTH and cortisol induced by
hypoglycemia.
8/11/2019 Cronobiologie
23/24
Conclusion
Cortisol has one of the mostdistinct and fascinating circadianrhythms in human physiology.
Cortisol acts as a secondarymessenger between central andperipheral clocks, hence its
importance in the synchronizationof body circadian rhythms.
8/11/2019 Cronobiologie
24/24
THANK YOU