Absence of cortisol awakening response in children and salivary cortisone as related,
promising stress marker.
(reply on HRE_201112011_0_s_1)
Nathalie Michels
Department of Public Health, Ghent University, Belgium
I thank Dr. Atabek for his interesting comments [1] on our article ‘Children’s morning and
evening salivary cortisol: pattern, instruction compliance and sampling confounders’ [2],
raising the important point on frequent cortisol awakening response (CAR) absence, the
scientific uncertainty about its general existence and possible underlying factors.
I absolutely agree (as was stated in our discussion section) that the hypothalamic-pituitaryadrenal (HPA) axis can be influenced by sleep related factors. Napping during the day would
not be an important influencing factor in our age group: a current habit of napping was only
reported by two parents. Other sleep related factors are quantity and quality of sleep [3]
(including transitional awakening) and ambient factors like amount of light [4]. If enabled by
research budget and logistics, all of these influencing factors could be recorded by sleep
actigraphy (since recent devices also include a light sensor) [5]. As Dr Atabek aptly said,
extra-pituitary input from the hippocampus and suprachiasmatic nucleus exist in both the
pre-awakening and immediate post-awakening period [6] and this involvement of the
suprachiasmatic nucleus (our internal light sensor) could indicate e.g. the influence of light
during awakening. Specifically for paediatric research, with parentally reported sampling
time as a proxy of self report, actigraphy could offer a major advantage by detecting the
critical lag between the real awakening time and the parental reported (=determined)
awakening time [7]. In our opinion, this parent-induced and also the unintended time lag
caused by transient awakening are the most plausible factors for CAR absence in our child
population, although the possibility of CAR absence as general characteristic cannot be
excluded.
In the letter, more medical influencing factors like pain and aspirin use were suggested.
However, saliva sampling only occurred when completely healthy.
As mentioned by Dr. Atabek, salivary cortisone (the inert cortisol form oxidized by 11βhydroxysteroid dehydrogenase) represents another promising stress marker as it even
better reflects the active free serum cortisol and as higher salivary cortisone concentrations
with a similar diurnal rhythm were reported [8, 9]. Unfortunately, salivary cortisone has not
been measured in our study, but both cortisol and cortisone have recently simultaneously
been measured on hair as stress marker in girls [10]. Since the cortisol-to-cortisone
converting enzyme activity has been related to HPA activity and stress [11-13], also the
cortisol-to-cortisone ratio could be an interesting stress marker to be studied in further
research [14, 15].
References
1
Atabek M: The paradox of cortisol awakening response in children: A critical
perspective. Horm Res Paediatr [Epub ahead of print] 2012
2
Michels N, Sioen I, De Vriendt T, Huybrechts I, Vanaelst B, De Henauw S: Children's
morning and evening salivary cortisol: Pattern, instruction compliance and sampling
confounders. Horm Res Paediatr [Epub ahead of print] 2011
3
Raikkonen K, Matthews KA, Pesonen AK, Pyhala R, Paavonen EJ, Feldt K, Jones A,
Phillips DI, Seckl JR, Heinonen K, Lahti J, Komsi N, Jarvenpaa AL, Eriksson JG, Strandberg TE,
Kajantie E: Poor sleep and altered hypothalamic-pituitary-adrenocortical and sympathoadrenal-medullary system activity in children. J Clin Endocrinol Metab 2010;95:2254-2261.
4
Scheer FA, Buijs RM: Light affects morning salivary cortisol in humans. J Clin
Endocrinol Metab 1999;84:3395-3398.
5
Martin JL, Hakim AD: Wrist actigraphy. Chest 2011;139:1514-1527.
6
Clow A, Hucklebridge F, Stalder T, Evans P, Thorn L: The cortisol awakening response:
More than a measure of hpa axis function. Neurosci Biobehav Rev 2010;35:97-103.
7
Dockray S, Bhattacharyya MR, Molloy GJ, Steptoe A: The cortisol awakening response
in relation to objective and subjective measures of waking in the morning.
Psychoneuroendocrinology 2008;33:77-82.
8
Perogamvros I, Keevil BG, Ray DW, Trainer PJ: Salivary cortisone is a potential
biomarker for serum free cortisol. J Clin Endocrinol Metab 2010;95:4951-4958.
9
Morineau G, Boudi A, Barka A, Gourmelen M, Degeilh F, Hardy N, al-Halnak A,
Soliman H, Gosling JP, Julien R, Brerault JL, Boudou P, Aubert P, Villette JM, Pruna A, Galons
H, Fiet J: Radioimmunoassay of cortisone in serum, urine, and saliva to assess the status of
the cortisol-cortisone shuttle. Clin Chem 1997;43:1397-1407.
10
Vanaelst B, De Vriendt T, Huybrechts I, Michels N, Vyncke K, Sioen I, Bamman K, Rivet
N, Raul J, Molnar D, De Henauw S: Cortisol and cortisone in hair of elementary-school
children and its relationship with childhood stress. Submitted
11
Cooper MS, Stewart PM: 11beta-hydroxysteroid dehydrogenase type 1 and its role in
the hypothalamus-pituitary-adrenal axis, metabolic syndrome, and inflammation. J Clin
Endocrinol Metab 2009;94:4645-4654.
12
Yehuda R, Seckl J: Minireview: Stress-related psychiatric disorders with low cortisol
levels: A metabolic hypothesis. Endocrinology 2011;152:4496-4503.
13
Welberg LA, Thrivikraman KV, Plotsky PM: Chronic maternal stress inhibits the
capacity to up-regulate placental 11beta-hydroxysteroid dehydrogenase type 2 activity. J
Endocrinol 2005;186:R7-R12.
14
Plenis A, Konieczna L, Oledzka I, Kowalski P, Baczek T: Simultaneous determination of
urinary cortisol, cortisone and corticosterone in parachutists, depressed patients and healthy
controls in view of biomedical and pharmacokinetic studies. Mol Biosyst 2011;7:1487-1500.
15
Romer B, Lewicka S, Kopf D, Lederbogen F, Hamann B, Gilles M, Schilling C, Onken V,
Frankhauser P, Deuschle M: Cortisol metabolism in depressed patients and healthy controls.
Neuroendocrinology 2009;90:301-306.